Publications by authors named "Teresa Ribeiro-Rodrigues"

24 Publications

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Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Authors:
Daniel J Klionsky Amal Kamal Abdel-Aziz Sara Abdelfatah Mahmoud Abdellatif Asghar Abdoli Steffen Abel Hagai Abeliovich Marie H Abildgaard Yakubu Princely Abudu Abraham Acevedo-Arozena Iannis E Adamopoulos Khosrow Adeli Timon E Adolph Annagrazia Adornetto Elma Aflaki Galila Agam Anupam Agarwal Bharat B Aggarwal Maria Agnello Patrizia Agostinis Javed N Agrewala Alexander Agrotis Patricia V Aguilar S Tariq Ahmad Zubair M Ahmed Ulises Ahumada-Castro Sonja Aits Shu Aizawa Yunus Akkoc Tonia Akoumianaki Hafize Aysin Akpinar Ahmed M Al-Abd Lina Al-Akra Abeer Al-Gharaibeh Moulay A Alaoui-Jamali Simon Alberti Elísabet Alcocer-Gómez Cristiano Alessandri Muhammad Ali M Abdul Alim Al-Bari Saeb Aliwaini Javad Alizadeh Eugènia Almacellas Alexandru Almasan Alicia Alonso Guillermo D Alonso Nihal Altan-Bonnet Dario C Altieri Élida M C Álvarez Sara Alves Cristine Alves da Costa Mazen M Alzaharna Marialaura Amadio Consuelo Amantini Cristina Amaral Susanna Ambrosio Amal O Amer Veena Ammanathan Zhenyi An Stig U Andersen Shaida A Andrabi Magaiver Andrade-Silva Allen M Andres Sabrina Angelini David Ann Uche C Anozie Mohammad Y Ansari Pedro Antas Adam Antebi Zuriñe Antón Tahira Anwar Lionel Apetoh Nadezda Apostolova Toshiyuki Araki Yasuhiro Araki Kohei Arasaki Wagner L Araújo Jun Araya Catherine Arden Maria-Angeles Arévalo Sandro Arguelles Esperanza Arias Jyothi Arikkath Hirokazu Arimoto Aileen R Ariosa Darius Armstrong-James Laetitia Arnauné-Pelloquin Angeles Aroca Daniela S Arroyo Ivica Arsov Rubén Artero Dalia Maria Lucia Asaro Michael Aschner Milad Ashrafizadeh Osnat Ashur-Fabian Atanas G Atanasov Alicia K Au Patrick Auberger Holger W Auner Laure Aurelian Riccardo Autelli Laura Avagliano Yenniffer Ávalos Sanja Aveic Célia Alexandra Aveleira Tamar Avin-Wittenberg Yucel Aydin Scott Ayton Srinivas Ayyadevara Maria Azzopardi Misuzu Baba Jonathan M Backer Steven K Backues Dong-Hun Bae Ok-Nam Bae Soo Han Bae Eric H Baehrecke Ahruem Baek Seung-Hoon Baek Sung Hee Baek Giacinto Bagetta Agnieszka Bagniewska-Zadworna Hua Bai Jie Bai Xiyuan Bai Yidong Bai Nandadulal Bairagi Shounak Baksi Teresa Balbi Cosima T Baldari Walter Balduini Andrea Ballabio Maria Ballester Salma Balazadeh Rena Balzan Rina Bandopadhyay Sreeparna Banerjee Sulagna Banerjee Ágnes Bánréti Yan Bao Mauricio S Baptista Alessandra Baracca Cristiana Barbati Ariadna Bargiela Daniela Barilà Peter G Barlow Sami J Barmada Esther Barreiro George E Barreto Jiri Bartek Bonnie Bartel Alberto Bartolome Gaurav R Barve Suresh H Basagoudanavar Diane C Bassham Robert C Bast Alakananda Basu Henri Batoko Isabella Batten Etienne E Baulieu Bradley L Baumgarner Jagadeesh Bayry Rupert Beale Isabelle Beau Florian Beaumatin Luiz R G Bechara George R Beck Michael F Beers Jakob Begun Christian Behrends Georg M N Behrens Roberto Bei Eloy Bejarano Shai Bel Christian Behl Amine Belaid Naïma Belgareh-Touzé Cristina Bellarosa Francesca Belleudi Melissa Belló Pérez Raquel Bello-Morales Jackeline Soares de Oliveira Beltran Sebastián Beltran Doris Mangiaracina Benbrook Mykolas Bendorius Bruno A Benitez Irene Benito-Cuesta Julien Bensalem Martin W Berchtold Sabina Berezowska Daniele Bergamaschi Matteo Bergami Andreas Bergmann Laura Berliocchi Clarisse Berlioz-Torrent Amélie Bernard Lionel Berthoux Cagri G Besirli Sebastien Besteiro Virginie M Betin Rudi Beyaert Jelena S Bezbradica Kiran Bhaskar Ingrid Bhatia-Kissova Resham Bhattacharya Sujoy Bhattacharya Shalmoli Bhattacharyya Md Shenuarin Bhuiyan Sujit Kumar Bhutia Lanrong Bi Xiaolin Bi Trevor J Biden Krikor Bijian Viktor A Billes Nadine Binart Claudia Bincoletto Asa B Birgisdottir Geir Bjorkoy Gonzalo Blanco Ana Blas-Garcia Janusz Blasiak Robert Blomgran Klas Blomgren Janice S Blum Emilio Boada-Romero Mirta Boban Kathleen Boesze-Battaglia Philippe Boeuf Barry Boland Pascale Bomont Paolo Bonaldo Srinivasa Reddy Bonam Laura Bonfili Juan S Bonifacino Brian A Boone Martin D Bootman Matteo Bordi Christoph Borner Beat C Bornhauser Gautam Borthakur Jürgen Bosch Santanu Bose Luis M Botana Juan Botas Chantal M Boulanger Michael E Boulton Mathieu Bourdenx Benjamin Bourgeois Nollaig M Bourke Guilhem Bousquet Patricia Boya Peter V Bozhkov Luiz H M Bozi Tolga O Bozkurt Doug E Brackney Christian H Brandts Ralf J Braun Gerhard H Braus Roberto Bravo-Sagua José M Bravo-San Pedro Patrick Brest Marie-Agnès Bringer Alfredo Briones-Herrera V Courtney Broaddus Peter Brodersen Jeffrey L Brodsky Steven L Brody Paola G Bronson Jeff M Bronstein Carolyn N Brown Rhoderick E Brown Patricia C Brum John H Brumell Nicola Brunetti-Pierri Daniele Bruno Robert J Bryson-Richardson Cecilia Bucci Carmen Buchrieser Marta Bueno Laura Elisa Buitrago-Molina Simone Buraschi Shilpa Buch J Ross Buchan Erin M Buckingham Hikmet Budak Mauricio Budini Geert Bultynck Florin Burada Joseph R Burgoyne M Isabel Burón Victor Bustos Sabrina Büttner Elena Butturini Aaron Byrd Isabel Cabas Sandra Cabrera-Benitez Ken Cadwell Jingjing Cai Lu Cai Qian Cai Montserrat Cairó Jose A Calbet Guy A Caldwell Kim A Caldwell Jarrod A Call Riccardo Calvani Ana C Calvo Miguel Calvo-Rubio Barrera Niels Os Camara Jacques H Camonis Nadine Camougrand Michelangelo Campanella Edward M Campbell François-Xavier Campbell-Valois Silvia Campello Ilaria Campesi Juliane C Campos Olivier Camuzard Jorge Cancino Danilo Candido de Almeida Laura Canesi Isabella Caniggia Barbara Canonico Carles Cantí Bin Cao Michele Caraglia Beatriz Caramés Evie H Carchman Elena Cardenal-Muñoz Cesar Cardenas Luis Cardenas Sandra M Cardoso Jennifer S Carew Georges F Carle Gillian Carleton Silvia Carloni Didac Carmona-Gutierrez Leticia A Carneiro Oliana Carnevali Julian M Carosi Serena Carra Alice Carrier Lucie Carrier Bernadette Carroll A Brent Carter Andreia Neves Carvalho Magali Casanova Caty Casas Josefina Casas Chiara Cassioli Eliseo F Castillo Karen Castillo Sonia Castillo-Lluva Francesca Castoldi Marco Castori Ariel F Castro Margarida Castro-Caldas Javier Castro-Hernandez Susana Castro-Obregon Sergio D Catz Claudia Cavadas Federica Cavaliere Gabriella Cavallini Maria Cavinato Maria L Cayuela Paula Cebollada Rica Valentina Cecarini Francesco Cecconi Marzanna Cechowska-Pasko Simone Cenci Victòria Ceperuelo-Mallafré João J Cerqueira Janete M Cerutti Davide Cervia Vildan Bozok Cetintas Silvia Cetrullo Han-Jung Chae Andrei S Chagin Chee-Yin Chai Gopal Chakrabarti Oishee Chakrabarti Tapas Chakraborty Trinad Chakraborty Mounia Chami Georgios Chamilos David W Chan Edmond Y W Chan Edward D Chan H Y Edwin Chan Helen H Chan Hung Chan Matthew T V Chan Yau Sang Chan Partha K Chandra Chih-Peng Chang Chunmei Chang Hao-Chun Chang Kai Chang Jie Chao Tracey Chapman Nicolas Charlet-Berguerand Samrat Chatterjee Shail K Chaube Anu Chaudhary Santosh Chauhan Edward Chaum Frédéric Checler Michael E Cheetham Chang-Shi Chen Guang-Chao Chen Jian-Fu Chen Liam L Chen Leilei Chen Lin Chen Mingliang Chen Mu-Kuan Chen Ning Chen Quan Chen Ruey-Hwa Chen Shi Chen Wei Chen Weiqiang Chen Xin-Ming Chen Xiong-Wen Chen Xu Chen Yan Chen Ye-Guang Chen Yingyu Chen Yongqiang Chen Yu-Jen Chen Yue-Qin Chen Zhefan Stephen Chen Zhi Chen Zhi-Hua Chen Zhijian J Chen Zhixiang Chen Hanhua Cheng Jun Cheng Shi-Yuan Cheng Wei Cheng Xiaodong Cheng Xiu-Tang Cheng Yiyun Cheng Zhiyong Cheng Zhong Chen Heesun Cheong Jit Kong Cheong Boris V Chernyak Sara Cherry Chi Fai Randy Cheung Chun Hei Antonio Cheung King-Ho Cheung Eric Chevet Richard J Chi Alan Kwok Shing Chiang Ferdinando Chiaradonna Roberto Chiarelli Mario Chiariello Nathalia Chica Susanna Chiocca Mario Chiong Shih-Hwa Chiou Abhilash I Chiramel Valerio Chiurchiù Dong-Hyung Cho Seong-Kyu Choe Augustine M K Choi Mary E Choi Kamalika Roy Choudhury Norman S Chow Charleen T Chu Jason P Chua John Jia En Chua Hyewon Chung Kin Pan Chung Seockhoon Chung So-Hyang Chung Yuen-Li Chung Valentina Cianfanelli Iwona A Ciechomska Mariana Cifuentes Laura Cinque Sebahattin Cirak Mara Cirone Michael J Clague Robert Clarke Emilio Clementi Eliana M Coccia Patrice Codogno Ehud Cohen Mickael M Cohen Tania Colasanti Fiorella Colasuonno Robert A Colbert Anna Colell Miodrag Čolić Nuria S Coll Mark O Collins María I Colombo Daniel A Colón-Ramos Lydie Combaret Sergio Comincini Márcia R Cominetti Antonella Consiglio Andrea Conte Fabrizio Conti Viorica Raluca Contu Mark R Cookson Kevin M Coombs Isabelle Coppens Maria Tiziana Corasaniti Dale P Corkery Nils Cordes Katia Cortese Maria do Carmo Costa Sarah Costantino Paola Costelli Ana Coto-Montes Peter J Crack Jose L Crespo Alfredo Criollo Valeria Crippa Riccardo Cristofani Tamas Csizmadia Antonio Cuadrado Bing Cui Jun Cui Yixian Cui Yong Cui Emmanuel Culetto Andrea C Cumino Andrey V Cybulsky Mark J Czaja Stanislaw J Czuczwar Stefania D'Adamo Marcello D'Amelio Daniela D'Arcangelo Andrew C D'Lugos Gabriella D'Orazi James A da Silva Hormos Salimi Dafsari Ruben K Dagda Yasin Dagdas Maria Daglia Xiaoxia Dai Yun Dai Yuyuan Dai Jessica Dal Col Paul Dalhaimer Luisa Dalla Valle Tobias Dallenga Guillaume Dalmasso Markus Damme Ilaria Dando Nico P Dantuma April L Darling Hiranmoy Das Srinivasan Dasarathy Santosh K Dasari Srikanta Dash Oliver Daumke Adrian N Dauphinee Jeffrey S Davies Valeria A Dávila Roger J Davis Tanja Davis Sharadha Dayalan Naidu Francesca De Amicis Karolien De Bosscher Francesca De Felice Lucia De Franceschi Chiara De Leonibus Mayara G de Mattos Barbosa Guido R Y De Meyer Angelo De Milito Cosimo De Nunzio Clara De Palma Mauro De Santi Claudio De Virgilio Daniela De Zio Jayanta Debnath Brian J DeBosch Jean-Paul Decuypere Mark A Deehan Gianluca Deflorian James DeGregori Benjamin Dehay Gabriel Del Rio Joe R Delaney Lea M D Delbridge Elizabeth Delorme-Axford M Victoria Delpino Francesca Demarchi Vilma Dembitz Nicholas D Demers Hongbin Deng Zhiqiang Deng Joern Dengjel Paul Dent Donna Denton Melvin L DePamphilis Channing J Der Vojo Deretic Albert Descoteaux Laura Devis Sushil Devkota Olivier Devuyst Grant Dewson Mahendiran Dharmasivam Rohan Dhiman Diego di Bernardo Manlio Di Cristina Fabio Di Domenico Pietro Di Fazio Alessio Di Fonzo Giovanni Di Guardo Gianni M Di Guglielmo Luca Di Leo Chiara Di Malta Alessia Di Nardo Martina Di Rienzo Federica Di Sano George Diallinas Jiajie Diao Guillermo Diaz-Araya Inés Díaz-Laviada Jared M Dickinson Marc Diederich Mélanie Dieudé Ivan Dikic Shiping Ding Wen-Xing Ding Luciana Dini Jelena Dinić Miroslav Dinic Albena T Dinkova-Kostova Marc S Dionne Jörg H W Distler Abhinav Diwan Ian M C Dixon Mojgan Djavaheri-Mergny Ina Dobrinski Oxana Dobrovinskaya Radek Dobrowolski Renwick C J Dobson Jelena Đokić Serap Dokmeci Emre Massimo Donadelli Bo Dong Xiaonan Dong Zhiwu Dong Gerald W Dorn Ii Volker Dotsch Huan Dou Juan Dou Moataz Dowaidar Sami Dridi Liat Drucker Ailian Du Caigan Du Guangwei Du Hai-Ning Du Li-Lin Du André du Toit Shao-Bin Duan Xiaoqiong Duan Sónia P Duarte Anna Dubrovska Elaine A Dunlop Nicolas Dupont Raúl V Durán Bilikere S Dwarakanath Sergey A Dyshlovoy Darius Ebrahimi-Fakhari Leopold Eckhart Charles L Edelstein Thomas Efferth Eftekhar Eftekharpour Ludwig Eichinger Nabil Eid Tobias Eisenberg N Tony Eissa Sanaa Eissa Miriam Ejarque Abdeljabar El Andaloussi Nazira El-Hage Shahenda El-Naggar Anna Maria Eleuteri Eman S El-Shafey Mohamed Elgendy Aristides G Eliopoulos María M Elizalde Philip M Elks Hans-Peter Elsasser Eslam S Elsherbiny Brooke M Emerling N C Tolga Emre Christina H Eng Nikolai Engedal Anna-Mart Engelbrecht Agnete S T Engelsen Jorrit M Enserink Ricardo Escalante Audrey Esclatine Mafalda Escobar-Henriques Eeva-Liisa Eskelinen Lucile Espert Makandjou-Ola Eusebio Gemma Fabrias Cinzia Fabrizi Antonio Facchiano Francesco Facchiano Bengt Fadeel Claudio Fader Alex C Faesen W Douglas Fairlie Alberto Falcó Bjorn H Falkenburger Daping Fan Jie Fan Yanbo Fan Evandro F Fang Yanshan Fang Yognqi Fang Manolis Fanto Tamar Farfel-Becker Mathias Faure Gholamreza Fazeli Anthony O Fedele Arthur M Feldman Du Feng Jiachun Feng Lifeng Feng Yibin Feng Yuchen Feng Wei Feng Thais Fenz Araujo Thomas A Ferguson Álvaro F Fernández Jose C Fernandez-Checa Sonia Fernández-Veledo Alisdair R Fernie Anthony W Ferrante Alessandra Ferraresi Merari F Ferrari Julio C B Ferreira Susan Ferro-Novick Antonio Figueras Riccardo Filadi Nicoletta Filigheddu Eduardo Filippi-Chiela Giuseppe Filomeni Gian Maria Fimia Vittorio Fineschi Francesca Finetti Steven Finkbeiner Edward A Fisher Paul B Fisher Flavio Flamigni Steven J Fliesler Trude H Flo Ida Florance Oliver Florey Tullio Florio Erika Fodor Carlo Follo Edward A Fon Antonella Forlino Francesco Fornai Paola Fortini Anna Fracassi Alessandro Fraldi Brunella Franco Rodrigo Franco Flavia Franconi Lisa B Frankel Scott L Friedman Leopold F Fröhlich Gema Frühbeck Jose M Fuentes Yukio Fujiki Naonobu Fujita Yuuki Fujiwara Mitsunori Fukuda Simone Fulda Luc Furic Norihiko Furuya Carmela Fusco Michaela U Gack Lidia Gaffke Sehamuddin Galadari Alessia Galasso Maria F Galindo Sachith Gallolu Kankanamalage Lorenzo Galluzzi Vincent Galy Noor Gammoh Boyi Gan Ian G Ganley Feng Gao Hui Gao Minghui Gao Ping Gao Shou-Jiang Gao Wentao Gao Xiaobo Gao Ana Garcera Maria Noé Garcia Verónica E Garcia Francisco García-Del Portillo Vega Garcia-Escudero Aracely Garcia-Garcia Marina Garcia-Macia Diana García-Moreno Carmen Garcia-Ruiz Patricia García-Sanz Abhishek D Garg Ricardo Gargini Tina Garofalo Robert F Garry Nils C Gassen Damian Gatica Liang Ge Wanzhong Ge Ruth Geiss-Friedlander Cecilia Gelfi Pascal Genschik Ian E Gentle Valeria Gerbino Christoph Gerhardt Kyla Germain Marc Germain David A Gewirtz Elham Ghasemipour Afshar Saeid Ghavami Alessandra Ghigo Manosij Ghosh Georgios Giamas Claudia Giampietri Alexandra Giatromanolaki Gary E Gibson Spencer B Gibson Vanessa Ginet Edward Giniger Carlotta Giorgi Henrique Girao Stephen E Girardin Mridhula Giridharan Sandy Giuliano Cecilia Giulivi Sylvie Giuriato Julien Giustiniani Alexander Gluschko Veit Goder Alexander Goginashvili Jakub Golab David C Goldstone Anna Golebiewska Luciana R Gomes Rodrigo Gomez Rubén Gómez-Sánchez Maria Catalina Gomez-Puerto Raquel Gomez-Sintes Qingqiu Gong Felix M Goni Javier González-Gallego Tomas Gonzalez-Hernandez Rosa A Gonzalez-Polo Jose A Gonzalez-Reyes Patricia González-Rodríguez Ing Swie Goping Marina S Gorbatyuk Nikolai V Gorbunov Kıvanç Görgülü Roxana M Gorojod Sharon M Gorski Sandro Goruppi Cecilia Gotor Roberta A Gottlieb Illana Gozes Devrim Gozuacik Martin Graef Markus H Gräler Veronica Granatiero Daniel Grasso Joshua P Gray Douglas R Green Alexander Greenhough Stephen L Gregory Edward F Griffin Mark W Grinstaff Frederic Gros Charles Grose Angelina S Gross Florian Gruber Paolo Grumati Tilman Grune Xueyan Gu Jun-Lin Guan Carlos M Guardia Kishore Guda Flora Guerra Consuelo Guerri Prasun Guha Carlos Guillén Shashi Gujar Anna Gukovskaya Ilya Gukovsky Jan Gunst Andreas Günther Anyonya R Guntur Chuanyong Guo Chun Guo Hongqing Guo Lian-Wang Guo Ming Guo Pawan Gupta Shashi Kumar Gupta Swapnil Gupta Veer Bala Gupta Vivek Gupta Asa B Gustafsson David D Gutterman Ranjitha H B Annakaisa Haapasalo James E Haber Aleksandra Hać Shinji Hadano Anders J Hafrén Mansour Haidar Belinda S Hall Gunnel Halldén Anne Hamacher-Brady Andrea Hamann Maho Hamasaki Weidong Han Malene Hansen Phyllis I Hanson Zijian Hao Masaru Harada Ljubica Harhaji-Trajkovic Nirmala Hariharan Nigil Haroon James Harris Takafumi Hasegawa Noor Hasima Nagoor Jeffrey A Haspel Volker Haucke Wayne D Hawkins Bruce A Hay Cole M Haynes Soren B Hayrabedyan Thomas S Hays Congcong He Qin He Rong-Rong He You-Wen He Yu-Ying He Yasser Heakal Alexander M Heberle J Fielding Hejtmancik Gudmundur Vignir Helgason Vanessa Henkel Marc Herb Alexander Hergovich Anna Herman-Antosiewicz Agustín Hernández Carlos Hernandez Sergio Hernandez-Diaz Virginia Hernandez-Gea Amaury Herpin Judit Herreros Javier H Hervás Daniel Hesselson Claudio Hetz Volker T Heussler Yujiro Higuchi Sabine Hilfiker Joseph A Hill William S Hlavacek Emmanuel A Ho Idy H T Ho Philip Wing-Lok Ho Shu-Leong Ho Wan Yun Ho G Aaron Hobbs Mark Hochstrasser Peter H M Hoet Daniel Hofius Paul Hofman Annika Höhn Carina I Holmberg Jose R Hombrebueno Chang-Won Hong Yi-Ren Hong Lora V Hooper Thorsten Hoppe Rastislav Horos Yujin Hoshida I-Lun Hsin Hsin-Yun Hsu Bing Hu Dong Hu Li-Fang Hu Ming Chang Hu Ronggui Hu Wei Hu Yu-Chen Hu Zhuo-Wei Hu Fang Hua Jinlian Hua Yingqi Hua Chongmin Huan Canhua Huang Chuanshu Huang Chuanxin Huang Chunling Huang Haishan Huang Kun Huang Michael L H Huang Rui Huang Shan Huang Tianzhi Huang Xing Huang Yuxiang Jack Huang Tobias B Huber Virginie Hubert Christian A Hubner Stephanie M Hughes William E Hughes Magali Humbert Gerhard Hummer James H Hurley Sabah Hussain Salik Hussain Patrick J Hussey Martina Hutabarat Hui-Yun Hwang Seungmin Hwang Antonio Ieni Fumiyo Ikeda Yusuke Imagawa Yuzuru Imai Carol Imbriano Masaya Imoto Denise M Inman Ken Inoki Juan Iovanna Renato V Iozzo Giuseppe Ippolito Javier E Irazoqui Pablo Iribarren Mohd Ishaq Makoto Ishikawa Nestor Ishimwe Ciro Isidoro Nahed Ismail Shohreh Issazadeh-Navikas Eisuke Itakura Daisuke Ito Davor Ivankovic Saška Ivanova Anand Krishnan V Iyer José M Izquierdo Masanori Izumi Marja Jäättelä Majid Sakhi Jabir William T Jackson Nadia Jacobo-Herrera Anne-Claire Jacomin Elise Jacquin Pooja Jadiya Hartmut Jaeschke Chinnaswamy Jagannath Arjen J Jakobi Johan Jakobsson Bassam Janji Pidder Jansen-Dürr Patric J Jansson Jonathan Jantsch Sławomir Januszewski Alagie Jassey Steve Jean Hélène Jeltsch-David Pavla Jendelova Andreas Jenny Thomas E Jensen Niels Jessen Jenna L Jewell Jing Ji Lijun Jia Rui Jia Liwen Jiang Qing Jiang Richeng Jiang Teng Jiang Xuejun Jiang Yu Jiang Maria Jimenez-Sanchez Eun-Jung Jin Fengyan Jin Hongchuan Jin Li Jin Luqi Jin Meiyan Jin Si Jin Eun-Kyeong Jo Carine Joffre Terje Johansen Gail V W Johnson Simon A Johnston Eija Jokitalo Mohit Kumar Jolly Leo A B Joosten Joaquin Jordan Bertrand Joseph Dianwen Ju Jeong-Sun Ju Jingfang Ju Esmeralda Juárez Delphine Judith Gábor Juhász Youngsoo Jun Chang Hwa Jung Sung-Chul Jung Yong Keun Jung Heinz Jungbluth Johannes Jungverdorben Steffen Just Kai Kaarniranta Allen Kaasik Tomohiro Kabuta Daniel Kaganovich Alon Kahana Renate Kain Shinjo Kajimura Maria Kalamvoki Manjula Kalia Danuta S Kalinowski Nina Kaludercic Ioanna Kalvari Joanna Kaminska Vitaliy O Kaminskyy Hiromitsu Kanamori Keizo Kanasaki Chanhee Kang Rui Kang Sang Sun Kang Senthilvelrajan Kaniyappan Tomotake Kanki Thirumala-Devi Kanneganti Anumantha G Kanthasamy Arthi Kanthasamy Marc Kantorow Orsolya Kapuy Michalis V Karamouzis Md Razaul Karim Parimal Karmakar Rajesh G Katare Masaru Kato Stefan H E Kaufmann Anu Kauppinen Gur P Kaushal Susmita Kaushik Kiyoshi Kawasaki Kemal Kazan Po-Yuan Ke Damien J Keating Ursula Keber John H Kehrl Kate E Keller Christian W Keller Jongsook Kim Kemper Candia M Kenific Oliver Kepp Stephanie Kermorgant Andreas Kern Robin Ketteler Tom G Keulers Boris Khalfin Hany Khalil Bilon Khambu Shahid Y Khan Vinoth Kumar Megraj Khandelwal Rekha Khandia Widuri Kho Noopur V Khobrekar Sataree Khuansuwan Mukhran Khundadze Samuel A Killackey Dasol Kim Deok Ryong Kim Do-Hyung Kim Dong-Eun Kim Eun Young Kim Eun-Kyoung Kim Hak-Rim Kim Hee-Sik Kim Hyung-Ryong Kim Jeong Hun Kim Jin Kyung Kim Jin-Hoi Kim Joungmok Kim Ju Hwan Kim Keun Il Kim Peter K Kim Seong-Jun Kim Scot R Kimball Adi Kimchi Alec C Kimmelman Tomonori Kimura Matthew A King Kerri J Kinghorn Conan G Kinsey Vladimir Kirkin Lorrie A Kirshenbaum Sergey L Kiselev Shuji Kishi Katsuhiko Kitamoto Yasushi Kitaoka Kaio Kitazato Richard N Kitsis Josef T Kittler Ole Kjaerulff Peter S Klein Thomas Klopstock Jochen Klucken Helene Knævelsrud Roland L Knorr Ben C B Ko Fred Ko Jiunn-Liang Ko Hotaka Kobayashi Satoru Kobayashi Ina Koch Jan C Koch Ulrich Koenig Donat Kögel Young Ho Koh Masato Koike Sepp D Kohlwein Nur M Kocaturk Masaaki Komatsu Jeannette König Toru Kono Benjamin T Kopp Tamas Korcsmaros Gözde Korkmaz Viktor I Korolchuk Mónica Suárez Korsnes Ali Koskela Janaiah Kota Yaichiro Kotake Monica L Kotler Yanjun Kou Michael I Koukourakis Evangelos Koustas Attila L Kovacs Tibor Kovács Daisuke Koya Tomohiro Kozako Claudine Kraft Dimitri Krainc Helmut Krämer Anna D Krasnodembskaya Carole Kretz-Remy Guido Kroemer Nicholas T Ktistakis Kazuyuki Kuchitsu Sabine Kuenen Lars Kuerschner Thomas Kukar Ajay Kumar Ashok Kumar Deepak Kumar Dhiraj Kumar Sharad Kumar Shinji Kume Caroline Kumsta Chanakya N Kundu Mondira Kundu Ajaikumar B Kunnumakkara Lukasz Kurgan Tatiana G Kutateladze Ozlem Kutlu SeongAe Kwak Ho Jeong Kwon Taeg Kyu Kwon Yong Tae Kwon Irene Kyrmizi Albert La Spada Patrick Labonté Sylvain Ladoire Ilaria Laface Frank Lafont Diane C Lagace Vikramjit Lahiri Zhibing Lai Angela S Laird Aparna Lakkaraju Trond Lamark Sheng-Hui Lan Ane Landajuela Darius J R Lane Jon D Lane Charles H Lang Carsten Lange Ülo Langel Rupert Langer Pierre Lapaquette Jocelyn Laporte Nicholas F LaRusso Isabel Lastres-Becker Wilson Chun Yu Lau Gordon W Laurie Sergio Lavandero Betty Yuen Kwan Law Helen Ka-Wai Law Rob Layfield Weidong Le Herve Le Stunff Alexandre Y Leary Jean-Jacques Lebrun Lionel Y W Leck Jean-Philippe Leduc-Gaudet Changwook Lee Chung-Pei Lee Da-Hye Lee Edward B Lee Erinna F Lee Gyun Min Lee He-Jin Lee Heung Kyu Lee Jae Man Lee Jason S Lee Jin-A Lee Joo-Yong Lee Jun Hee Lee Michael Lee Min Goo Lee Min Jae Lee Myung-Shik Lee Sang Yoon Lee Seung-Jae Lee Stella Y Lee Sung Bae Lee Won Hee Lee Ying-Ray Lee Yong-Ho Lee Youngil Lee Christophe Lefebvre Renaud Legouis Yu L Lei Yuchen Lei Sergey Leikin Gerd Leitinger Leticia Lemus Shuilong Leng Olivia Lenoir Guido Lenz Heinz Josef Lenz Paola Lenzi Yolanda León Andréia M Leopoldino Christoph Leschczyk Stina Leskelä Elisabeth Letellier Chi-Ting Leung Po Sing Leung Jeremy S Leventhal Beth Levine Patrick A Lewis Klaus Ley Bin Li Da-Qiang Li Jianming Li Jing Li Jiong Li Ke Li Liwu Li Mei Li Min Li Min Li Ming Li Mingchuan Li Pin-Lan Li Ming-Qing Li Qing Li Sheng Li Tiangang Li Wei Li Wenming Li Xue Li Yi-Ping Li Yuan Li Zhiqiang Li Zhiyong Li Zhiyuan Li Jiqin Lian Chengyu Liang Qiangrong Liang Weicheng Liang Yongheng Liang YongTian Liang Guanghong Liao Lujian Liao Mingzhi Liao Yung-Feng Liao Mariangela Librizzi Pearl P Y Lie Mary A Lilly Hyunjung J Lim Thania R R Lima Federica Limana Chao Lin Chih-Wen Lin Dar-Shong Lin Fu-Cheng Lin Jiandie D Lin Kurt M Lin Kwang-Huei Lin Liang-Tzung Lin Pei-Hui Lin Qiong Lin Shaofeng Lin Su-Ju Lin Wenyu Lin Xueying Lin Yao-Xin Lin Yee-Shin Lin Rafael Linden Paula Lindner Shuo-Chien Ling Paul Lingor Amelia K Linnemann Yih-Cherng Liou Marta M Lipinski Saška Lipovšek Vitor A Lira Natalia Lisiak Paloma B Liton Chao Liu Ching-Hsuan Liu Chun-Feng Liu Cui Hua Liu Fang Liu Hao Liu Hsiao-Sheng Liu Hua-Feng Liu Huifang Liu Jia Liu Jing Liu Julia Liu Leyuan Liu Longhua Liu Meilian Liu Qin Liu Wei Liu Wende Liu Xiao-Hong Liu Xiaodong Liu Xingguo Liu Xu Liu Xuedong Liu Yanfen Liu Yang Liu Yang Liu Yueyang Liu Yule Liu J Andrew Livingston Gerard Lizard Jose M Lizcano Senka Ljubojevic-Holzer Matilde E LLeonart David Llobet-Navàs Alicia Llorente Chih Hung Lo Damián Lobato-Márquez Qi Long Yun Chau Long Ben Loos Julia A Loos Manuela G López Guillermo López-Doménech José Antonio López-Guerrero Ana T López-Jiménez Óscar López-Pérez Israel López-Valero Magdalena J Lorenowicz Mar Lorente Peter Lorincz Laura Lossi Sophie Lotersztajn Penny E Lovat Jonathan F Lovell Alenka Lovy Péter Lőw Guang Lu Haocheng Lu Jia-Hong Lu Jin-Jian Lu Mengji Lu Shuyan Lu Alessandro Luciani John M Lucocq Paula Ludovico Micah A Luftig Morten Luhr Diego Luis-Ravelo Julian J Lum Liany Luna-Dulcey Anders H Lund Viktor K Lund Jan D Lünemann Patrick Lüningschrör Honglin Luo Rongcan Luo Shouqing Luo Zhi Luo Claudio Luparello Bernhard Lüscher Luan Luu Alex Lyakhovich Konstantin G Lyamzaev Alf Håkon Lystad Lyubomyr Lytvynchuk Alvin C Ma Changle Ma Mengxiao Ma Ning-Fang Ma Quan-Hong Ma Xinliang Ma Yueyun Ma Zhenyi Ma Ormond A MacDougald Fernando Macian Gustavo C MacIntosh Jeffrey P MacKeigan Kay F Macleod Sandra Maday Frank Madeo Muniswamy Madesh Tobias Madl Julio Madrigal-Matute Akiko Maeda Yasuhiro Maejima Marta Magarinos Poornima Mahavadi Emiliano Maiani Kenneth Maiese Panchanan Maiti Maria Chiara Maiuri Barbara Majello Michael B Major Elena Makareeva Fayaz Malik Karthik Mallilankaraman Walter Malorni Alina Maloyan Najiba Mammadova Gene Chi Wai Man Federico Manai Joseph D Mancias Eva-Maria Mandelkow Michael A Mandell Angelo A Manfredi Masoud H Manjili Ravi Manjithaya Patricio Manque Bella B Manshian Raquel Manzano Claudia Manzoni Kai Mao Cinzia Marchese Sandrine Marchetti Anna Maria Marconi Fabrizio Marcucci Stefania Mardente Olga A Mareninova Marta Margeta Muriel Mari Sara Marinelli Oliviero Marinelli Guillermo Mariño Sofia Mariotto Richard S Marshall Mark R Marten Sascha Martens Alexandre P J Martin Katie R Martin Sara Martin Shaun Martin Adrián Martín-Segura Miguel A Martín-Acebes Inmaculada Martin-Burriel Marcos Martin-Rincon Paloma Martin-Sanz José A Martina Wim Martinet Aitor Martinez Ana Martinez Jennifer Martinez Moises Martinez Velazquez Nuria Martinez-Lopez Marta Martinez-Vicente Daniel O Martins Joilson O Martins Waleska K Martins Tania Martins-Marques Emanuele Marzetti Shashank Masaldan Celine Masclaux-Daubresse Douglas G Mashek Valentina Massa Lourdes Massieu Glenn R Masson Laura Masuelli Anatoliy I Masyuk Tetyana V Masyuk Paola Matarrese Ander Matheu Satoaki Matoba Sachiko Matsuzaki Pamela Mattar Alessandro Matte Domenico Mattoscio José L Mauriz Mario Mauthe Caroline Mauvezin Emanual Maverakis Paola Maycotte Johanna Mayer Gianluigi Mazzoccoli Cristina Mazzoni Joseph R Mazzulli Nami McCarty Christine McDonald Mitchell R McGill Sharon L McKenna BethAnn McLaughlin Fionn McLoughlin Mark A McNiven Thomas G McWilliams Fatima Mechta-Grigoriou Tania Catarina Medeiros Diego L Medina Lynn A Megeney Klara Megyeri Maryam Mehrpour Jawahar L Mehta Alfred J Meijer Annemarie H Meijer Jakob Mejlvang Alicia Meléndez Annette Melk Gonen Memisoglu Alexandrina F Mendes Delong Meng Fei Meng Tian Meng Rubem Menna-Barreto Manoj B Menon Carol Mercer Anne E Mercier Jean-Louis Mergny Adalberto Merighi Seth D Merkley Giuseppe Merla Volker Meske Ana Cecilia Mestre Shree Padma Metur Christian Meyer Hemmo Meyer Wenyi Mi Jeanne Mialet-Perez Junying Miao Lucia Micale Yasuo Miki Enrico Milan Małgorzata Milczarek Dana L Miller Samuel I Miller Silke Miller Steven W Millward Ira Milosevic Elena A Minina Hamed Mirzaei Hamid Reza Mirzaei Mehdi Mirzaei Amit Mishra Nandita Mishra Paras Kumar Mishra Maja Misirkic Marjanovic Roberta Misasi Amit Misra Gabriella Misso Claire Mitchell Geraldine Mitou Tetsuji Miura Shigeki Miyamoto Makoto Miyazaki Mitsunori Miyazaki Taiga Miyazaki Keisuke Miyazawa Noboru Mizushima Trine H Mogensen Baharia Mograbi Reza Mohammadinejad Yasir Mohamud Abhishek Mohanty Sipra Mohapatra Torsten Möhlmann Asif Mohmmed Anna Moles Kelle H Moley Maurizio Molinari Vincenzo Mollace Andreas Buch Møller Bertrand Mollereau Faustino Mollinedo Costanza Montagna Mervyn J Monteiro Andrea Montella L Ruth Montes Barbara Montico Vinod K Mony Giacomo Monzio Compagnoni Michael N Moore Mohammad A Moosavi Ana L Mora Marina Mora David Morales-Alamo Rosario Moratalla Paula I Moreira Elena Morelli Sandra Moreno Daniel Moreno-Blas Viviana Moresi Benjamin Morga Alwena H Morgan Fabrice Morin Hideaki Morishita Orson L Moritz Mariko Moriyama Yuji Moriyasu Manuela Morleo Eugenia Morselli Jose F Moruno-Manchon Jorge Moscat Serge Mostowy Elisa Motori Andrea Felinto Moura Naima Moustaid-Moussa Maria Mrakovcic Gabriel Muciño-Hernández Anupam Mukherjee Subhadip Mukhopadhyay Jean M Mulcahy Levy Victoriano Mulero Sylviane Muller Christian Münch Ashok Munjal Pura Munoz-Canoves Teresa Muñoz-Galdeano Christian Münz Tomokazu Murakawa Claudia Muratori Brona M Murphy J Patrick Murphy Aditya Murthy Timo T Myöhänen Indira U Mysorekar Jennifer Mytych Seyed Mohammad Nabavi Massimo Nabissi Péter Nagy Jihoon Nah Aimable Nahimana Ichiro Nakagawa Ken Nakamura Hitoshi Nakatogawa Shyam S Nandi Meera Nanjundan Monica Nanni Gennaro Napolitano Roberta Nardacci Masashi Narita Melissa Nassif Ilana Nathan Manabu Natsumeda Ryno J Naude Christin Naumann Olaia Naveiras Fatemeh Navid Steffan T Nawrocki Taras Y Nazarko Francesca Nazio Florentina Negoita Thomas Neill Amanda L Neisch Luca M Neri Mihai G Netea Patrick Neubert Thomas P Neufeld Dietbert Neumann Albert Neutzner Phillip T Newton Paul A Ney Ioannis P Nezis Charlene C W Ng Tzi Bun Ng Hang T T Nguyen Long T Nguyen Hong-Min Ni Clíona Ní Cheallaigh Zhenhong Ni M Celeste Nicolao Francesco Nicoli Manuel Nieto-Diaz Per Nilsson Shunbin Ning Rituraj Niranjan Hiroshi Nishimune Mireia Niso-Santano Ralph A Nixon Annalisa Nobili Clevio Nobrega Takeshi Noda Uxía Nogueira-Recalde Trevor M Nolan Ivan Nombela Ivana Novak Beatriz Novoa Takashi Nozawa Nobuyuki Nukina Carmen Nussbaum-Krammer Jesper Nylandsted Tracey R O'Donovan Seónadh M O'Leary Eyleen J O'Rourke Mary P O'Sullivan Timothy E O'Sullivan Salvatore Oddo Ina Oehme Michinaga Ogawa Eric Ogier-Denis Margret H Ogmundsdottir Besim Ogretmen Goo Taeg Oh Seon-Hee Oh Young J Oh Takashi Ohama Yohei Ohashi Masaki Ohmuraya Vasileios Oikonomou Rani Ojha Koji Okamoto Hitoshi Okazawa Masahide Oku Sara Oliván Jorge M A Oliveira Michael Ollmann James A Olzmann Shakib Omari M Bishr Omary Gizem Önal Martin Ondrej Sang-Bing Ong Sang-Ging Ong Anna Onnis Juan A Orellana Sara Orellana-Muñoz Maria Del Mar Ortega-Villaizan Xilma R Ortiz-Gonzalez Elena Ortona Heinz D Osiewacz Abdel-Hamid K Osman Rosario Osta Marisa S Otegui Kinya Otsu Christiane Ott Luisa Ottobrini Jing-Hsiung James Ou Tiago F Outeiro Inger Oynebraten Melek Ozturk Gilles Pagès Susanta Pahari Marta Pajares Utpal B Pajvani Rituraj Pal Simona Paladino Nicolas Pallet Michela Palmieri Giuseppe Palmisano Camilla Palumbo Francesco Pampaloni Lifeng Pan Qingjun Pan Wenliang Pan Xin Pan Ganna Panasyuk Rahul Pandey Udai B Pandey Vrajesh Pandya Francesco Paneni Shirley Y Pang Elisa Panzarini Daniela L Papademetrio Elena Papaleo Daniel Papinski Diana Papp Eun Chan Park Hwan Tae Park Ji-Man Park Jong-In Park Joon Tae Park Junsoo Park Sang Chul Park Sang-Youel Park Abraham H Parola Jan B Parys Adrien Pasquier Benoit Pasquier João F Passos Nunzia Pastore Hemal H Patel Daniel Patschan Sophie Pattingre Gustavo Pedraza-Alva Jose Pedraza-Chaverri Zully Pedrozo Gang Pei Jianming Pei Hadas Peled-Zehavi Joaquín M Pellegrini Joffrey Pelletier Miguel A Peñalva Di Peng Ying Peng Fabio Penna Maria Pennuto Francesca Pentimalli Cláudia Mf Pereira Gustavo J S Pereira Lilian C Pereira Luis Pereira de Almeida Nirma D Perera Ángel Pérez-Lara Ana B Perez-Oliva María Esther Pérez-Pérez Palsamy Periyasamy Andras Perl Cristiana Perrotta Ida Perrotta Richard G Pestell Morten Petersen Irina Petrache Goran Petrovski Thorsten Pfirrmann Astrid S Pfister Jennifer A Philips Huifeng Pi Anna Picca Alicia M Pickrell Sandy Picot Giovanna M Pierantoni Marina Pierdominici Philippe Pierre Valérie Pierrefite-Carle Karolina Pierzynowska Federico Pietrocola Miroslawa Pietruczuk Claudio Pignata Felipe X Pimentel-Muiños Mario Pinar Roberta O Pinheiro Ronit Pinkas-Kramarski Paolo Pinton Karolina Pircs Sujan Piya Paola Pizzo Theo S Plantinga Harald W Platta Ainhoa Plaza-Zabala Markus Plomann Egor Y Plotnikov Helene Plun-Favreau Ryszard Pluta Roger Pocock Stefanie Pöggeler Christian Pohl Marc Poirot Angelo Poletti Marisa Ponpuak Hana Popelka Blagovesta Popova Helena Porta Soledad Porte Alcon Eliana Portilla-Fernandez Martin Post Malia B Potts Joanna Poulton Ted Powers Veena Prahlad Tomasz K Prajsnar Domenico Praticò Rosaria Prencipe Muriel Priault Tassula Proikas-Cezanne Vasilis J Promponas Christopher G Proud Rosa Puertollano Luigi Puglielli Thomas Pulinilkunnil Deepika Puri Rajat Puri Julien Puyal Xiaopeng Qi Yongmei Qi Wenbin Qian Lei Qiang Yu Qiu Joe Quadrilatero Jorge Quarleri Nina Raben Hannah Rabinowich Debora Ragona Michael J Ragusa Nader Rahimi Marveh Rahmati Valeria Raia Nuno Raimundo Namakkal-Soorappan Rajasekaran Sriganesh Ramachandra Rao Abdelhaq Rami Ignacio Ramírez-Pardo David B Ramsden Felix Randow Pundi N Rangarajan Danilo Ranieri Hai Rao Lang Rao Rekha Rao Sumit Rathore J Arjuna Ratnayaka Edward A Ratovitski Palaniyandi Ravanan Gloria Ravegnini Swapan K Ray Babak Razani Vito Rebecca Fulvio Reggiori Anne Régnier-Vigouroux Andreas S Reichert David Reigada Jan H Reiling Theo Rein Siegfried Reipert Rokeya Sultana Rekha Hongmei Ren Jun Ren Weichao Ren Tristan Renault Giorgia Renga Karen Reue Kim Rewitz Bruna Ribeiro de Andrade Ramos S Amer Riazuddin Teresa M Ribeiro-Rodrigues Jean-Ehrland Ricci Romeo Ricci Victoria Riccio Des R Richardson Yasuko Rikihisa Makarand V Risbud Ruth M Risueño Konstantinos Ritis Salvatore Rizza Rosario Rizzuto Helen C Roberts Luke D Roberts Katherine J Robinson Maria Carmela Roccheri Stephane Rocchi George G Rodney Tiago Rodrigues Vagner Ramon Rodrigues Silva Amaia Rodriguez Ruth Rodriguez-Barrueco Nieves Rodriguez-Henche Humberto Rodriguez-Rocha Jeroen Roelofs Robert S Rogers Vladimir V Rogov Ana I Rojo Krzysztof Rolka Vanina Romanello Luigina Romani Alessandra Romano Patricia S Romano David Romeo-Guitart Luis C Romero Montserrat Romero Joseph C Roney Christopher Rongo Sante Roperto Mathias T Rosenfeldt Philip Rosenstiel Anne G Rosenwald Kevin A Roth Lynn Roth Steven Roth Kasper M A Rouschop Benoit D Roussel Sophie Roux Patrizia Rovere-Querini Ajit Roy Aurore Rozieres Diego Ruano David C Rubinsztein Maria P Rubtsova Klaus Ruckdeschel Christoph Ruckenstuhl Emil Rudolf Rüdiger Rudolf Alessandra Ruggieri Avnika Ashok Ruparelia Paola Rusmini Ryan R Russell Gian Luigi Russo Maria Russo Rossella Russo Oxana O Ryabaya Kevin M Ryan Kwon-Yul Ryu Maria Sabater-Arcis Ulka Sachdev Michael Sacher Carsten Sachse Abhishek Sadhu Junichi Sadoshima Nathaniel Safren Paul Saftig Antonia P Sagona Gaurav Sahay Amirhossein Sahebkar Mustafa Sahin Ozgur Sahin Sumit Sahni Nayuta Saito Shigeru Saito Tsunenori Saito Ryohei Sakai Yasuyoshi Sakai Jun-Ichi Sakamaki Kalle Saksela Gloria Salazar Anna Salazar-Degracia Ghasem H Salekdeh Ashok K Saluja Belém Sampaio-Marques Maria Cecilia Sanchez Jose A Sanchez-Alcazar Victoria Sanchez-Vera Vanessa Sancho-Shimizu J Thomas Sanderson Marco Sandri Stefano Santaguida Laura Santambrogio Magda M Santana Giorgio Santoni Alberto Sanz Pascual Sanz Shweta Saran Marco Sardiello Timothy J Sargeant Apurva Sarin Chinmoy Sarkar Sovan Sarkar Maria-Rosa Sarrias Surajit Sarkar Dipanka Tanu Sarmah Jaakko Sarparanta Aishwarya Sathyanarayan Ranganayaki Sathyanarayanan K Matthew Scaglione Francesca Scatozza Liliana Schaefer Zachary T Schafer Ulrich E Schaible Anthony H V Schapira Michael Scharl Hermann M Schatzl Catherine H Schein Wiep Scheper David Scheuring Maria Vittoria Schiaffino Monica Schiappacassi Rainer Schindl Uwe Schlattner Oliver Schmidt Roland Schmitt Stephen D Schmidt Ingo Schmitz Eran Schmukler Anja Schneider Bianca E Schneider Romana Schober Alejandra C Schoijet Micah B Schott Michael Schramm Bernd Schröder Kai Schuh Christoph Schüller Ryan J Schulze Lea Schürmanns Jens C Schwamborn Melanie Schwarten Filippo Scialo Sebastiano Sciarretta Melanie J Scott Kathleen W Scotto A Ivana Scovassi Andrea Scrima Aurora Scrivo David Sebastian Salwa Sebti Simon Sedej Laura Segatori Nava Segev Per O Seglen Iban Seiliez Ekihiro Seki Scott B Selleck Frank W Sellke Joshua T Selsby Michael Sendtner Serif Senturk Elena Seranova Consolato Sergi Ruth Serra-Moreno Hiromi Sesaki Carmine Settembre Subba Rao Gangi Setty Gianluca Sgarbi Ou Sha John J Shacka Javeed A Shah Dantong Shang Changshun Shao Feng Shao Soroush Sharbati Lisa M Sharkey Dipali Sharma Gaurav Sharma Kulbhushan Sharma Pawan Sharma Surendra Sharma Han-Ming Shen Hongtao Shen Jiangang Shen Ming Shen Weili Shen Zheni Shen Rui Sheng Zhi Sheng Zu-Hang Sheng Jianjian Shi Xiaobing Shi Ying-Hong Shi Kahori Shiba-Fukushima Jeng-Jer Shieh Yohta Shimada Shigeomi Shimizu Makoto Shimozawa Takahiro Shintani Christopher J Shoemaker Shahla Shojaei Ikuo Shoji Bhupendra V Shravage Viji Shridhar Chih-Wen Shu Hong-Bing Shu Ke Shui Arvind K Shukla Timothy E Shutt Valentina Sica Aleem Siddiqui Amanda Sierra Virginia Sierra-Torre Santiago Signorelli Payel Sil Bruno J de Andrade Silva Johnatas D Silva Eduardo Silva-Pavez Sandrine Silvente-Poirot Rachel E Simmonds Anna Katharina Simon Hans-Uwe Simon Matias Simons Anurag Singh Lalit P Singh Rajat Singh Shivendra V Singh Shrawan K Singh Sudha B Singh Sunaina Singh Surinder Pal Singh Debasish Sinha Rohit Anthony Sinha Sangita Sinha Agnieszka Sirko Kapil Sirohi Efthimios L Sivridis Panagiotis Skendros Aleksandra Skirycz Iva Slaninová Soraya S Smaili Andrei Smertenko Matthew D Smith Stefaan J Soenen Eun Jung Sohn Sophia P M Sok Giancarlo Solaini Thierry Soldati Scott A Soleimanpour Rosa M Soler Alexei Solovchenko Jason A Somarelli Avinash Sonawane Fuyong Song Hyun Kyu Song Ju-Xian Song Kunhua Song Zhiyin Song Leandro R Soria Maurizio Sorice Alexander A Soukas Sandra-Fausia Soukup Diana Sousa Nadia Sousa Paul A Spagnuolo Stephen A Spector M M Srinivas Bharath Daret St Clair Venturina Stagni Leopoldo Staiano Clint A Stalnecker Metodi V Stankov Peter B Stathopulos Katja Stefan Sven Marcel Stefan Leonidas Stefanis Joan S Steffan Alexander Steinkasserer Harald Stenmark Jared Sterneckert Craig Stevens Veronika Stoka Stephan Storch Björn Stork Flavie Strappazzon Anne Marie Strohecker Dwayne G Stupack Huanxing Su Ling-Yan Su Longxiang Su Ana M Suarez-Fontes Carlos S Subauste Selvakumar Subbian Paula V Subirada Ganapasam Sudhandiran Carolyn M Sue Xinbing Sui Corey Summers Guangchao Sun Jun Sun Kang Sun Meng-Xiang Sun Qiming Sun Yi Sun Zhongjie Sun Karen K S Sunahara Eva Sundberg Katalin Susztak Peter Sutovsky Hidekazu Suzuki Gary Sweeney J David Symons Stephen Cho Wing Sze Nathaniel J Szewczyk Anna Tabęcka-Łonczynska Claudio Tabolacci Frank Tacke Heinrich Taegtmeyer Marco Tafani Mitsuo Tagaya Haoran Tai Stephen W G Tait Yoshinori Takahashi Szabolcs Takats Priti Talwar Chit Tam Shing Yau Tam Davide Tampellini Atsushi Tamura Chong Teik Tan Eng-King Tan Ya-Qin Tan Masaki Tanaka Motomasa Tanaka Daolin Tang Jingfeng Tang Tie-Shan Tang Isei Tanida Zhipeng Tao Mohammed Taouis Lars Tatenhorst Nektarios Tavernarakis Allen Taylor Gregory A Taylor Joan M Taylor Elena Tchetina Andrew R Tee Irmgard Tegeder David Teis Natercia Teixeira Fatima Teixeira-Clerc Kumsal A Tekirdag Tewin Tencomnao Sandra Tenreiro Alexei V Tepikin Pilar S Testillano Gianluca Tettamanti Pierre-Louis Tharaux Kathrin Thedieck Arvind A Thekkinghat Stefano Thellung Josephine W Thinwa V P Thirumalaikumar Sufi Mary Thomas Paul G Thomes Andrew Thorburn Lipi Thukral Thomas Thum Michael Thumm Ling Tian Ales Tichy Andreas Till Vincent Timmerman Vladimir I Titorenko Sokol V Todi Krassimira Todorova Janne M Toivonen Luana Tomaipitinca Dhanendra Tomar Cristina Tomas-Zapico Sergej Tomić Benjamin Chun-Kit Tong Chao Tong Xin Tong Sharon A Tooze Maria L Torgersen Satoru Torii Liliana Torres-López Alicia Torriglia Christina G Towers Roberto Towns Shinya Toyokuni Vladimir Trajkovic Donatella Tramontano Quynh-Giao Tran Leonardo H Travassos Charles B Trelford Shirley Tremel Ioannis P Trougakos Betty P Tsao Mario P Tschan Hung-Fat Tse Tak Fu Tse Hitoshi Tsugawa Andrey S Tsvetkov David A Tumbarello Yasin Tumtas María J Tuñón Sandra Turcotte Boris Turk Vito Turk Bradley J Turner Richard I Tuxworth Jessica K Tyler Elena V Tyutereva Yasuo Uchiyama Aslihan Ugun-Klusek Holm H Uhlig Marzena Ułamek-Kozioł Ilya V Ulasov Midori Umekawa Christian Ungermann Rei Unno Sylvie Urbe Elisabet Uribe-Carretero Suayib Üstün Vladimir N Uversky Thomas Vaccari Maria I Vaccaro Björn F Vahsen Helin Vakifahmetoglu-Norberg Rut Valdor Maria J Valente Ayelén Valko Richard B Vallee Angela M Valverde Greet Van den Berghe Stijn van der Veen Luc Van Kaer Jorg van Loosdregt Sjoerd J L van Wijk Wim Vandenberghe Ilse Vanhorebeek Marcos A Vannier-Santos Nicola Vannini M Cristina Vanrell Chiara Vantaggiato Gabriele Varano Isabel Varela-Nieto Máté Varga M Helena Vasconcelos Somya Vats Demetrios G Vavvas Ignacio Vega-Naredo Silvia Vega-Rubin-de-Celis Guillermo Velasco Ariadna P Velázquez Tibor Vellai Edo Vellenga Francesca Velotti Mireille Verdier Panayotis Verginis Isabelle Vergne Paul Verkade Manish Verma Patrik Verstreken Tim Vervliet Jörg Vervoorts Alexandre T Vessoni Victor M Victor Michel Vidal Chiara Vidoni Otilia V Vieira Richard D Vierstra Sonia Viganó Helena Vihinen Vinoy Vijayan Miquel Vila Marçal Vilar José M Villalba Antonio Villalobo Beatriz Villarejo-Zori Francesc Villarroya Joan Villarroya Olivier Vincent Cecile Vindis Christophe Viret Maria Teresa Viscomi Dora Visnjic Ilio Vitale David J Vocadlo Olga V Voitsekhovskaja Cinzia Volonté Mattia Volta Marta Vomero Clarissa Von Haefen Marc A Vooijs Wolfgang Voos Ljubica Vucicevic Richard Wade-Martins Satoshi Waguri Kenrick A Waite Shuji Wakatsuki David W Walker Mark J Walker Simon A Walker Jochen Walter Francisco G Wandosell Bo Wang Chao-Yung Wang Chen Wang Chenran Wang Chenwei Wang Cun-Yu Wang Dong Wang Fangyang Wang Feng Wang Fengming Wang Guansong Wang Han Wang Hao Wang Hexiang Wang Hong-Gang Wang Jianrong Wang Jigang Wang Jiou Wang Jundong Wang Kui Wang Lianrong Wang Liming Wang Maggie Haitian Wang Meiqing Wang Nanbu Wang Pengwei Wang Peipei Wang Ping Wang Ping Wang Qing Jun Wang Qing Wang Qing Kenneth Wang Qiong A Wang Wen-Tao Wang Wuyang Wang Xinnan Wang Xuejun Wang Yan Wang Yanchang Wang Yanzhuang Wang Yen-Yun Wang Yihua Wang Yipeng Wang Yu Wang Yuqi Wang Zhe Wang Zhenyu Wang Zhouguang Wang Gary Warnes Verena Warnsmann Hirotaka Watada Eizo Watanabe Maxinne Watchon Anna Wawrzyńska Timothy E Weaver Grzegorz Wegrzyn Ann M Wehman Huafeng Wei Lei Wei Taotao Wei Yongjie Wei Oliver H Weiergräber Conrad C Weihl Günther Weindl Ralf Weiskirchen Alan Wells Runxia H Wen Xin Wen Antonia Werner Beatrice Weykopf Sally P Wheatley J Lindsay Whitton Alexander J Whitworth Katarzyna Wiktorska Manon E Wildenberg Tom Wileman Simon Wilkinson Dieter Willbold Brett Williams Robin S B Williams Roger L Williams Peter R Williamson Richard A Wilson Beate Winner Nathaniel J Winsor Steven S Witkin Harald Wodrich Ute Woehlbier Thomas Wollert Esther Wong Jack Ho Wong Richard W Wong Vincent Kam Wai Wong W Wei-Lynn Wong An-Guo Wu Chengbiao Wu Jian Wu Junfang Wu Kenneth K Wu Min Wu Shan-Ying Wu Shengzhou Wu Shu-Yan Wu Shufang Wu William K K Wu Xiaohong Wu Xiaoqing Wu Yao-Wen Wu Yihua Wu Ramnik J Xavier Hongguang Xia Lixin Xia Zhengyuan Xia Ge Xiang Jin Xiang Mingliang Xiang Wei Xiang Bin Xiao Guozhi Xiao Hengyi Xiao Hong-Tao Xiao Jian Xiao Lan Xiao Shi Xiao Yin Xiao Baoming Xie Chuan-Ming Xie Min Xie Yuxiang Xie Zhiping Xie Zhonglin Xie Maria Xilouri Congfeng Xu En Xu Haoxing Xu Jing Xu JinRong Xu Liang Xu Wen Wen Xu Xiulong Xu Yu Xue Sokhna M S Yakhine-Diop Masamitsu Yamaguchi Osamu Yamaguchi Ai Yamamoto Shunhei Yamashina Shengmin Yan Shian-Jang Yan Zhen Yan Yasuo Yanagi Chuanbin Yang Dun-Sheng Yang Huan Yang Huang-Tian Yang Hui Yang Jin-Ming Yang Jing Yang Jingyu Yang Ling Yang Liu Yang Ming Yang Pei-Ming Yang Qian Yang Seungwon Yang Shu Yang Shun-Fa Yang Wannian Yang Wei Yuan Yang Xiaoyong Yang Xuesong Yang Yi Yang Ying Yang Honghong Yao Shenggen Yao Xiaoqiang Yao Yong-Gang Yao Yong-Ming Yao Takahiro Yasui Meysam Yazdankhah Paul M Yen Cong Yi Xiao-Ming Yin Yanhai Yin Zhangyuan Yin Ziyi Yin Meidan Ying Zheng Ying Calvin K Yip Stephanie Pei Tung Yiu Young H Yoo Kiyotsugu Yoshida Saori R Yoshii Tamotsu Yoshimori Bahman Yousefi Boxuan Yu Haiyang Yu Jun Yu Jun Yu Li Yu Ming-Lung Yu Seong-Woon Yu Victor C Yu W Haung Yu Zhengping Yu Zhou Yu Junying Yuan Ling-Qing Yuan Shilin Yuan Shyng-Shiou F Yuan Yanggang Yuan Zengqiang Yuan Jianbo Yue Zhenyu Yue Jeanho Yun Raymond L Yung David N Zacks Gabriele Zaffagnini Vanessa O Zambelli Isabella Zanella Qun S Zang Sara Zanivan Silvia Zappavigna Pilar Zaragoza Konstantinos S Zarbalis Amir Zarebkohan Amira Zarrouk Scott O Zeitlin Jialiu Zeng Ju-Deng Zeng Eva Žerovnik Lixuan Zhan Bin Zhang Donna D Zhang Hanlin Zhang Hong Zhang Hong Zhang Honghe Zhang Huafeng Zhang Huaye Zhang Hui Zhang Hui-Ling Zhang Jianbin Zhang Jianhua Zhang Jing-Pu Zhang Kalin Y B Zhang Leshuai W Zhang Lin Zhang Lisheng Zhang Lu Zhang Luoying Zhang Menghuan Zhang Peng Zhang Sheng Zhang Wei Zhang Xiangnan Zhang Xiao-Wei Zhang Xiaolei Zhang Xiaoyan Zhang Xin Zhang Xinxin Zhang Xu Dong Zhang Yang Zhang Yanjin Zhang Yi Zhang Ying-Dong Zhang Yingmei Zhang Yuan-Yuan Zhang Yuchen Zhang Zhe Zhang Zhengguang Zhang Zhibing Zhang Zhihai Zhang Zhiyong Zhang Zili Zhang Haobin Zhao Lei Zhao Shuang Zhao Tongbiao Zhao Xiao-Fan Zhao Ying Zhao Yongchao Zhao Yongliang Zhao Yuting Zhao Guoping Zheng Kai Zheng Ling Zheng Shizhong Zheng Xi-Long Zheng Yi Zheng Zu-Guo Zheng Boris Zhivotovsky Qing Zhong Ao Zhou Ben Zhou Cefan Zhou Gang Zhou Hao Zhou Hong Zhou Hongbo Zhou Jie Zhou Jing Zhou Jing Zhou Jiyong Zhou Kailiang Zhou Rongjia Zhou Xu-Jie Zhou Yanshuang Zhou Yinghong Zhou Yubin Zhou Zheng-Yu Zhou Zhou Zhou Binglin Zhu Changlian Zhu Guo-Qing Zhu Haining Zhu Hongxin Zhu Hua Zhu Wei-Guo Zhu Yanping Zhu Yushan Zhu Haixia Zhuang Xiaohong Zhuang Katarzyna Zientara-Rytter Christine M Zimmermann Elena Ziviani Teresa Zoladek Wei-Xing Zong Dmitry B Zorov Antonio Zorzano Weiping Zou Zhen Zou Zhengzhi Zou Steven Zuryn Werner Zwerschke Beate Brand-Saberi X Charlie Dong Chandra Shekar Kenchappa Zuguo Li Yong Lin Shigeru Oshima Yueguang Rong Judith C Sluimer Christina L Stallings Chun-Kit Tong

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

Hong Kong Baptist University, School of Chinese Medicine, Hong Kong, China.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes.

Life Sci Alliance 2020 12 23;3(12). Epub 2020 Oct 23.

University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, Portugal

Ischemic heart disease has been associated with an impairment on intercellular communication mediated by both gap junctions and extracellular vesicles. We have previously shown that connexin 43 (Cx43), the main ventricular gap junction protein, assembles into channels at the extracellular vesicle surface, mediating the release of vesicle content into target cells. Here, using a comprehensive strategy that included cell-based approaches, animal models and human patients, we demonstrate that myocardial ischemia impairs the secretion of Cx43 into circulating, intracardiac and cardiomyocyte-derived vesicles. In addition, we show that ubiquitin signals Cx43 release in basal conditions but appears to be dispensable during ischemia, suggesting an interplay between ischemia-induced Cx43 degradation and secretion. Overall, this study constitutes a step forward for the characterization of the signals and molecular players underlying vesicle protein sorting, with strong implications on long-range intercellular communication, paving the way towards the development of innovative diagnostic and therapeutic strategies for cardiovascular disorders.
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http://dx.doi.org/10.26508/lsa.202000821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652393PMC
December 2020

Simple and Fast SEC-Based Protocol to Isolate Human Plasma-Derived Extracellular Vesicles for Transcriptional Research.

Mol Ther Methods Clin Dev 2020 Sep 15;18:723-737. Epub 2020 Jul 15.

Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal.

Extracellular vesicles (EVs) are membranous structures that protect RNAs from damage when circulating in complex biological fluids, such as plasma. RNAs are extremely specific to health and disease, being powerful tools for diagnosis, treatment response monitoring, and development of new therapeutic strategies for several diseases. In this context, EVs are potential sources of disease biomarkers and promising delivery vehicles. However, standardized and reproducible EV isolation protocols easy to implement in clinical practice are missing. Here, a size exclusion chromatography-based protocol for EV-isolation from human plasma was optimized. We propose a workflow to isolate EVs for transcriptional research that allows concomitant analysis of particle number and size, total protein, and quantification of a major plasma contaminant. This protocol yields 7.54 × 10 ± 1.22 × 10 particles, quantified by nanoparticle tracking analysis, with a mean size of 115.7 ± 11.12 nm and a mode size of 83.13 ± 4.72 nm, in a ratio of 1.19 × 10 ± 7.38 × 10 particles/μg of protein, determined by Micro Bicinchoninic Acid (BCA) Protein Assay, and 3.09 ± 0.7 ng RNA, assessed by fluorescence-based RNA-quantitation, from only 900 μL of plasma. The protocol is fast and easy to implement and has potential for application in biomarkers research, therapeutic strategies development, and clinical practice.
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http://dx.doi.org/10.1016/j.omtm.2020.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452272PMC
September 2020

Exosomes derived from microglia exposed to elevated pressure amplify the neuroinflammatory response in retinal cells.

Glia 2020 12 9;68(12):2705-2724. Epub 2020 Jul 9.

Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Glaucoma is a degenerative disease that causes irreversible loss of vision and is characterized by retinal ganglion cell (RGC) loss. Others and we have demonstrated that chronic neuroinflammation mediated by reactive microglial cells plays a role in glaucomatous pathology. Exosomes are extracellular vesicles released by most cells, including microglia, that mediate intercellular communication. The role of microglial exosomes in glaucomatous degeneration remains unknown. Taking the prominent role of microglial exosomes in brain neurodegenerative diseases, we studied the contribution of microglial-derived exosomes to the inflammatory response in experimental glaucoma. Microglial cells were exposed to elevated hydrostatic pressure (EHP), to mimic elevated intraocular pressure, the main risk factor for glaucoma. Naïve microglia (BV-2 cells or retinal microglia) were exposed to exosomes derived from BV-2 cells under EHP conditions (BV-Exo-EHP) or cultured in control pressure (BV-Exo-Control). We found that BV-Exo-EHP increased the production of pro-inflammatory cytokines, promoted retinal microglia motility, phagocytic efficiency, and proliferation. Furthermore, the incubation of primary retinal neural cell cultures with BV-Exo-EHP increased cell death and the production of reactive oxygen species. Exosomes derived from retinal microglia (MG-Exo-Control or MG-Exo-EHP) were injected in the vitreous of C57BL/6J mice. MG-Exo-EHP sustained activation of retinal microglia, mediated cell death, and impacted RGC number. Herein, we show that exosomes derived from retinal microglia have an autocrine function and propagate the inflammatory signal in conditions of elevated pressure, contributing to retinal degeneration in glaucomatous conditions.
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http://dx.doi.org/10.1002/glia.23880DOI Listing
December 2020

Caveolin-1 Modulation Increases Efficacy of a Galacto-Conjugated Phthalocyanine in Bladder Cancer Cells Resistant to Photodynamic Therapy.

Mol Pharm 2020 06 12;17(6):2145-2154. Epub 2020 May 12.

Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.

Photodynamic therapy (PDT) has demonstrated encouraging anticancer therapeutic results, but the current clinically approved photosensitizers (PSs) are not ideal in the treatment of bladder cancer. Conventional PSs have low selectivity to the bladder tumor tissue and induce toxicity or bystander effects on nontumor urothelium. Previous studies demonstrated that the use of galactose-photosensitizer (PS) conjugates is a more selective method of delivering PDT-mediated toxicity due to their ability to recognize carbohydrate-binding domains overexpressed in bladder tumors. Using patient-derived bladder tumor specimens cultured and bladder cancer cell lines with different PDT sensitivity, we find that a galactose-phthalocyanine (PcGal) accumulates in bladder tumors expressing galactose-binding proteins and internalizes through an endocytic process. The endocytosis mechanism is cell line-dependent. In HT-1376 bladder cancer lines resistant to PDT, depletion of caveolin-1-the main structural protein of caveolae structures-increased the amount of sugar-binding proteins, i.e. GLUT1, at the cell membrane resulting in an improved PcGal uptake and PDT efficacy. These data show the potential of cultures of bladder cancer, that ideally could mimic the original microenvironment, in screening galacto-PDT agents. Additionally, our studies demonstrate that PDT efficacy in bladder cancer depends on the endocytic mechanisms that regulate PS accumulation and internalization in cancer cells.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00298DOI Listing
June 2020

The Role of Proteostasis in the Regulation of Cardiac Intercellular Communication.

Adv Exp Med Biol 2020 ;1233:279-302

Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), Center for Innovative Biomedicine and Biotechnology (CIBB), Clinical Academic Centre of Coimbra (CACC), University of Coimbra, Coimbra, Portugal.

Given the low mitotic activity of cardiomyocytes, the contractile unit of the heart, these cells strongly rely on efficient and highly regulated mechanisms of protein degradation to eliminate unwanted potentially toxic proteins. This is particularly important in the context of disease, where an impairment of protein quality control mechanisms underlies the onset and development of diverse cardiovascular maladies. One of the biological processes which is tightly regulated by proteolysis mechanisms is intercellular communication. The different types of cells that form the heart, including cardiomyocytes, endothelial cells, fibroblasts, and macrophages, can communicate directly, through gap junctions (GJ) or tunneling nanotubes (TNT), or at long distances, via extracellular vesicles (EV) or soluble factors.The direct communication between cardiomyocytes is vital to ensure the anisotropic propagation of the electrical impulse, which allows the heart to beat in a coordinated and synchronized manner, as a functional syncytium. The rapid and efficient propagation of the depolarization wave is mainly conducted by low resistance channels called GJ, formed by six subunits of a family of proteins named Cxs. Dysfunctional GJ intercellular communication, due to increased degradation and/or redistribution of connexin43 (Cx43), the main Cx present in the heart, has been associated with several cardiac disorders, such as myocardial ischemia, hypertrophy, arrhythmia, and heart failure. Besides electrical coupling, a fine-tuned exchange of information, namely proteins and microRNAs, conveyed by EV is important to ensure organ function and homeostasis. Disease-induced deregulation of EV-mediated communication between cardiac cells has been implicated in diverse processes such as inflammation, angiogenesis, and fibrosis. Therefore, a better understanding of the mechanisms whereby proteolysis modulates the cross talk between cardiac cells is of utmost importance to develop new strategies to tackle diseases caused by defects in intercellular communication.
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http://dx.doi.org/10.1007/978-3-030-38266-7_12DOI Listing
April 2020

A Conserved LIR Motif in Connexins Mediates Ubiquitin-Independent Binding to LC3/GABARAP Proteins.

Cells 2020 04 7;9(4). Epub 2020 Apr 7.

Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.

Gap junctions (GJ) are specialized cell-cell contacts formed by connexins (Cxs), which provide direct communication between adjacent cells. Cx43 ubiquitination has been suggested to induce the internalization of GJs, as well as the recruitment of the autophagy receptor p62 to mediate binding to LC3B and degradation by macroautophagy. In this report, we describe a functional LC3 interacting region (LIR), present in the amino terminal of most Cx protein family members, which can mediate the autophagy degradation of Cx43 without the need of ubiquitin. Mutation of the LIR motif on Cx37, Cx43, Cx46 and Cx50 impairs interaction with LC3B and GABARAP without compromising protein ubiquitination. Through in vitro protein-protein interaction assays, we demonstrate that this LIR motif is required for the binding of Cx43 to LC3B and GABARAP. Overall, our findings describe an alternative mechanism whereby Cxs interact with LC3/GABARAP proteins, envisioning a new model for the autophagy degradation of connexins.
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http://dx.doi.org/10.3390/cells9040902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226732PMC
April 2020

Exosomes and STUB1/CHIP cooperate to maintain intracellular proteostasis.

PLoS One 2019 15;14(10):e0223790. Epub 2019 Oct 15.

CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal.

Deregulation of proteostasis is a main feature of many age-related diseases, often leading to the accumulation of toxic oligomers and insoluble protein aggregates that accumulate intracellularly or in the extracellular space. To understand the mechanisms whereby toxic or otherwise unwanted proteins are secreted to the extracellular space, we inactivated the quality-control and proteostasis regulator ubiquitin ligase STUB1/CHIP. Data indicated that STUB1 deficiency leads both to the intracellular accumulation of protein aggregates and to an increase in the secretion of small extracellular vesicles (sEVs), including exosomes. Secreted sEVs are enriched in ubiquitinated and/or undegraded proteins and protein oligomers. Data also indicates that oxidative stress induces an increase in the release of sEVs in cells depleted from STUB1. Overall, the results presented here suggest that cells use exosomes to dispose of damaged and/or undegraded proteins as a means to reduce intracellular accumulation of proteotoxic material.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794069PMC
March 2020

Biological Functions of Connexin43 Beyond Intercellular Communication.

Trends Cell Biol 2019 10 26;29(10):835-847. Epub 2019 Jul 26.

Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Portugal. Electronic address:

Connexin43 (Cx43) is commonly associated with direct cell-cell communication through gap junctions (GJs). However, recent groundbreaking studies have challenged this dogma, implicating Cx43 in other biological processes, such as transcription, metabolism, autophagy, and ion channel trafficking. How Cx43 participates in these processes remains largely unknown, although its high turnover rate, capacity to bind to myriad proteins, and the discovery of truncated isoforms of Cx43, ascribe to this protein unanticipated roles in chief processes that require fine-tuned regulation. Accordingly, Cx43 can be regarded as a central integrative hub to which diverse cues converge to be processed in a concerted manner. In this review, we examine the noncanonical roles of Cx43 and discuss the implications of these functions in human diseases and future therapeutic strategies.
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http://dx.doi.org/10.1016/j.tcb.2019.07.001DOI Listing
October 2019

Ischaemia alters the effects of cardiomyocyte-derived extracellular vesicles on macrophage activation.

J Cell Mol Med 2019 02 4;23(2):1137-1151. Epub 2018 Dec 4.

Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Myocardial ischaemia is associated with an exacerbated inflammatory response, as well as with a deregulation of intercellular communication systems. Macrophages have been implicated in the maintenance of heart homeostasis and in the progression and resolution of the ischaemic injury. Nevertheless, the mechanisms underlying the crosstalk between cardiomyocytes and macrophages remain largely underexplored. Extracellular vesicles (EVs) have emerged as key players of cell-cell communication in cardiac health and disease. Hence, the main objective of this study was to characterize the impact of cardiomyocyte-derived EVs upon macrophage activation. Results obtained demonstrate that EVs released by H9c2 cells induced a pro-inflammatory profile in macrophages, via p38MAPK activation and increased expression of iNOS, IL-1β and IL-6, being these effects less pronounced with ischaemic EVs. EVs derived from neonatal cardiomyocytes, maintained either in control or ischaemia, induced a similar pattern of p38MAPK activation, expression of iNOS, IL-1β, IL-6, IL-10 and TNFα. Importantly, adhesion of macrophages to fibronectin was enhanced by EVs released by cardiomyocytes under ischaemia, whereas phagocytic capacity and adhesion to cardiomyocytes were higher in macrophages incubated with control EVs. Additionally, serum-circulating EVs isolated from human controls or acute myocardial infarction patients induce macrophage activation. According to our model, in basal conditions, cardiomyocyte-derived EVs maintain a macrophage profile that ensure heart homeostasis, whereas during ischaemia, this crosstalk is affected, likely impacting healing and post-infarction remodelling.
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http://dx.doi.org/10.1111/jcmm.14014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349194PMC
February 2019

Intravascular imaging, histopathological analysis, and catecholamine quantification following catheter-based renal denervation in a swine model: the impact of prebifurcation energy delivery.

Hypertens Res 2018 Sep 13;41(9):708-717. Epub 2018 Jul 13.

Cardiology Department, Coimbra's Hospital and University Centre - General Hospital, Coimbra, Portugal.

The purpose of this study was to evaluate the impact of prebifurcation renal denervation in a swine model and assess its safety through optical coherence tomography (OCT). Prebifurcation renal denervation with a multi-electrode catheter was performed in one renal artery of 12 healthy pigs, with the contralateral artery and kidney being used as controls. Angiograms and OCT pullbacks were obtained peri-procedurally and 1 month post procedure. Renal tissue catecholamines were quantified, and the arterial wall and peri-adventitial tissue were analyzed histologically. Intraluminal changes (endothelial swelling, spasm, and thrombus formation) were observed acutely by OCT in most of the treated arteries and were no longer visible at follow-up. Histology revealed a statistically significant accumulation of collagen (fibrosis) and a near absence of tyrosine hydroxylase labeling in the denervated artery, suggesting a clear reduction in nervous terminals. Renal tissue catecholamine levels were similar between both sides, probably due to the low number of ablation points and the renorenal reflex. The present study demonstrates that renal denervation is associated with acute intimal disruptions, areas of fibrosis, and a reduction in nervous terminals. The lack of difference in renal tissue catecholamine levels is indicative of the need to perform the highest and safest number of ablation points in both renal arteries. These findings are important because they demonstrate the histological consequences of radiofrequency energy application and its medium-term safety.
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http://dx.doi.org/10.1038/s41440-018-0072-yDOI Listing
September 2018

Role of connexin 43 in different forms of intercellular communication - gap junctions, extracellular vesicles and tunnelling nanotubes.

J Cell Sci 2017 Nov 12;130(21):3619-3630. Epub 2017 Oct 12.

Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-548 Coimbra, Portugal

Communication is important to ensure the correct and efficient flow of information, which is required to sustain active social networks. A fine-tuned communication between cells is vital to maintain the homeostasis and function of multicellular or unicellular organisms in a community environment. Although there are different levels of complexity, intercellular communication, in prokaryotes to mammalians, can occur through secreted molecules (either soluble or encapsulated in vesicles), tubular structures connecting close cells or intercellular channels that link the cytoplasm of adjacent cells. In mammals, these different types of communication serve different purposes, may involve distinct factors and are mediated by extracellular vesicles, tunnelling nanotubes or gap junctions. Recent studies have shown that connexin 43 (Cx43, also known as GJA1), a transmembrane protein initially described as a gap junction protein, participates in all these forms of communication; this emphasizes the concept of adopting strategies to maximize the potential of available resources by reutilizing the same factor in different scenarios. In this Review, we provide an overview of the most recent advances regarding the role of Cx43 in intercellular communication mediated by extracellular vesicles, tunnelling nanotubes and gap junctions.
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http://dx.doi.org/10.1242/jcs.200667DOI Listing
November 2017

Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis.

Cardiovasc Res 2017 Sep;113(11):1338-1350

Institute for Biomedical Imaging and Life Sciences (IBILI), University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal.

Aims: Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide and results from an obstruction in the blood supply to a region of the heart. In an attempt to replenish oxygen and nutrients to the deprived area, affected cells release signals to promote the development of new vessels and confer protection against MI. However, the mechanisms underlying the growth of new vessels in an ischaemic scenario remain poorly understood. Here, we show that cardiomyocytes subjected to ischaemia release exosomes that elicit an angiogenic response of endothelial cells (ECs).

Methods And Results: Exosomes secreted by H9c2 myocardial cells and primary cardiomyocytes, cultured either in control or ischaemic conditions were isolated and added to ECs. We show that ischaemic exosomes, in comparison with control exosomes, confer protection against oxidative-induced lesion, promote proliferation, and sprouting of ECs, stimulate the formation of capillary-like structures and strengthen adhesion complexes and barrier properties. Moreover, ischaemic exosomes display higher levels of metalloproteases (MMP) and promote the secretion of MMP by ECs. We demonstrate that miR-222 and miR-143, the relatively most abundant miRs in ischaemic exosomes, partially recapitulate the angiogenic effect of exosomes. Additionally, we show that ischaemic exosomes stimulate the formation of new functional vessels in vivo using in ovo and Matrigel plug assays. Finally, we demonstrate that intramyocardial delivery of ischaemic exosomes improves neovascularization following MI.

Conclusions: This study establishes that exosomes secreted by cardiomyocytes under ischaemic conditions promote heart angiogenesis, which may pave the way towards the development of add-on therapies to enhance myocardial blood supply.
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http://dx.doi.org/10.1093/cvr/cvx118DOI Listing
September 2017

Targeted Approach for Proteomic Analysis of a Hidden Membrane Protein.

Methods Mol Biol 2017 ;1619:151-172

Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, Coimbra, 3000 548, Portugal.

Given the properties of plasma membrane proteins, namely, their hydrophobicity, low solubility, and high resistance to digestion and extraction, their identification by traditional mass spectrometry (MS) has been a challenging task. Hence, proteomic studies involving the transmembrane protein connexin43 (Cx43) are scarce. Additionally, studies demonstrating the presence of proteins embedded in the lipid bilayer of extracellular vesicles (EVs) are difficult to perform and require specific changes and fine adjustments in the experimental and technical procedure to allow their detection by MS. In this review, we provide a detailed description of the protocol we have used to detect Cx43 in EVs of human peripheral blood. This includes some of the modifications that we have introduced in order to improve the detection of Cx43 in EVs, including an optimization of vesicle isolation, Cx43 purification, MS acquisition data, and further analysis.
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http://dx.doi.org/10.1007/978-1-4939-7057-5_12DOI Listing
March 2018

Characterization of phospholipid nitroxidation by LC-MS in biomimetic models and in H9c2 Myoblast using a lipidomic approach.

Free Radic Biol Med 2017 05 17;106:219-227. Epub 2017 Feb 17.

Mass Spectrometry Centre, Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal. Electronic address:

Under nitroxidative stress conditions, lipids are prone to be modified by reaction with reactive nitrogen species (RNS) and different modifications were reported to occur in fatty acids. However, in the case of phospholipids (PL) studied under nitroxidative stress conditions, only nitroalkene derivatives of phosphatidylcholine (PC) and phosphatidylethanolamine (PE), were reported when using both in vitro biomimetic conditions and in vivo model system of type 1 diabetes mellitus. Therefore, in order to further explore other nitroxidative modifications of PL, a biomimetic model of nitroxidation combined with liquid chromatography mass spectrometry (MS) and MS/MS approaches were used to characterize the nitrated and nitroxidized derivatives of PCs and PEs. Single and multiple nitrated derivatives of phospholipids (PLs) such as nitroso and dinitroso, nitro, dinitro, and nitronitroso derivatives, together with nitroxidized derivatives were identified. Further, the specific MS/MS fragmentation pathways of these products were studied. Product ions arising from loss of HNO and HNO, from the combined loss of HNO (or HNO) and polar head groups, [NO-FA+O+H] and [NO-FA+O-H] (n=1-2) product ions corresponding to the modified fatty acyl chains were observed, depending on each modification. The knowledge obtained from the study of the MS/MS fragmentation pattern has allowed us to identify nitrated PCs, including NO-PC, (NO)-PCs, (NO)(NO)-PC, NO-PC; nitrated PEs, NO-PEs; and nitroxidized PCs, (NO)(2O)-PC in H9c2 cells under starvation, but not under ischemia or control conditions. The physiological relevance of this nitrated and nitroxidized PCs and PEs species observed exclusively in cardiomyoblast cells (H9c2) under starvation is still unknown but deserves to be explored.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.02.033DOI Listing
May 2017

Proteostasis and SUMO in the heart.

Int J Biochem Cell Biol 2016 10 20;79:443-450. Epub 2016 Sep 20.

Institute for Biomedical Imaging and Life Sciences (IBILI) Research Consortium, University of Coimbra, Coimbra, Portugal; Center for Neuroscience and Cell Biology (CNC), Institute for Biomedical Imaging and Life Sciences (IBILI) (CNC.IBILI), University of Coimbra, Coimbra, Portugal. Electronic address:

Heart proteostasis relies on a complex and integrated network of molecular processes surveilling organ performance under physiological and pathological conditions. For this purpose, cardiac cells depend on the correct function of their proteolytic systems, such as the ubiquitin-proteasome system (UPS), autophagy and the calpain system. Recently, the role of protein SUMOylation (an ubiquitin-like modification), has emerged as important modulator of cardiac proteostasis, which will be the focus of this review.
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http://dx.doi.org/10.1016/j.biocel.2016.09.015DOI Listing
October 2016

Alteration in Phospholipidome Profile of Myoblast H9c2 Cell Line in a Model of Myocardium Starvation and Ischemia.

J Cell Physiol 2016 10 16;231(10):2266-74. Epub 2016 Mar 16.

Department of Chemistry, Mass Spectrometry Center, QOPNA, University of Aveiro, Aveiro, Portugal.

Myocardium infarction is one of the most deathly cardiovascular diseases. It is characterized by myocardium ischemia as a result of nutrients depletion and hypoxia. The cell can respond to this injury by autophagy or apoptosis, which determines the evolution and possible recovery of the myocardium infarction. Lipids play an important role in cardiovascular disease. However reports stating lipidome variations in cardiovascular disease are scarce and the role that lipids play in this pathological condition is not completely understood. The aim of this work was to identify changes in lipid profile of a myoblast H9c2 cell line under starvation and ischemia, to better understand and recognize new biomarkers for myocardial infarction. Lipidomic profile was evaluated by HILIC-LC-MS and GC-MS. Cardiac cells showed alterations in phosphatidylcholines PC (34:1) and PC (36:2), lysophosphatidylcholines lyso PC(16:0), lysoPC(18:1) and lysoPC(18:0), phosphatidylethanolamine PE (34:1), phosphatidylserine PS (36:1), phosphatidylinositol PI (36:2), PI (38:3) and PI (38:5), sphingomyelin SM (34:1) and cardiolipins CL(68:4), CL(72:5) and CL(74:7) in ischemia and/or starvation, in comparison with control. Specific differences observed only in starvation were decrease of SM (34:1) and FA (20:4), and increase of PS (36:1). Differences observed only in ischemia were decrease of PC (36:2), lyso PC (16:0) and FA (18:1) and simultaneous increase of FA (16:0), and FA (18:0). Interestingly, PC (34:1) increased in ischemia and decreased in starvation. In conclusion, our work suggests that lipids are potential markers for evaluation of cell fate, either cell death or recovery, which will be useful to improve diagnosis and prognostic of cardiovascular diseases. J. Cell. Physiol. 231: 2266-2274, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcp.25344DOI Listing
October 2016

Gap junctional protein Cx43 is involved in the communication between extracellular vesicles and mammalian cells.

Sci Rep 2015 Aug 19;5:13243. Epub 2015 Aug 19.

Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal.

Intercellular communication is vital to ensure tissue and organism homeostasis and can occur directly, between neighbour cells via gap junctions (GJ), or indirectly, at longer distances, through extracellular vesicles, including exosomes. Exosomes, as intercellular carriers of messenger molecules, mediate the transfer of biological information between donor and acceptor cells. Although the biological effects of exosomes in target cells have been intensively studied, the mechanisms that govern exosomal uptake are not fully understood. Here, we show that Connexin 43 (Cx43), the most widely expressed GJ protein, is present in exosomes in the form of hexameric channels and, more importantly, that exosomal Cx43 is able to modulate the interaction and transfer of information between exosomes and acceptor cells. This study envisions a new paradigm where Cx43-containing channels mediate the release of exosomal content into cells, which constitutes a novel and unanticipated mechanism to modulate intercellular communication.
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http://dx.doi.org/10.1038/srep13243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541155PMC
August 2015

The Force at the Tip--Modelling Tension and Proliferation in Sprouting Angiogenesis.

PLoS Comput Biol 2015 Aug 6;11(8):e1004436. Epub 2015 Aug 6.

CFisUC, Department of Physics, University of Coimbra, Coimbra, Portugal.

Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art.
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http://dx.doi.org/10.1371/journal.pcbi.1004436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527825PMC
August 2015

Connexin 43 ubiquitination determines the fate of gap junctions: restrict to survive.

Biochem Soc Trans 2015 Jun;43(3):471-5

*Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Azinhaga de Sta Comba, 3000-354 Coimbra, Portugal.

Connexins (Cxs) are transmembrane proteins that form channels which allow direct intercellular communication (IC) between neighbouring cells via gap junctions. Mechanisms that modulate the amount of channels at the plasma membrane have emerged as important regulators of IC and their de-regulation has been associated with various diseases. Although Cx-mediated IC can be modulated by different mechanisms, ubiquitination has been described as one of the major post-translational modifications involved in Cx regulation and consequently IC. In this review, we focus on the role of ubiquitin and its effect on gap junction intercellular communication.
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http://dx.doi.org/10.1042/BST20150036DOI Listing
June 2015

Heart ischemia results in connexin43 ubiquitination localized at the intercalated discs.

Biochimie 2015 May 3;112:196-201. Epub 2015 Mar 3.

Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

Efficient electric activation and action potential propagation in the heart largely depends on gap junction (GJ) channels, formed by connexins (Cx) localized at the intercalated discs (IDs). Therefore, fine-tuning and maintenance of GJ in cardiomyocytes is essential for normal heart function. Several mechanisms have been implicated in the regulation of the amount of Cx43 at the plasma membrane. Results from our lab demonstrated that Nedd4-mediated ubiquitination of Cx43 signals internalization and degradation of GJ. However, the pathophysiological relevance of this mechanism has never been addressed before. The main objective of this study was to evaluate the involvement of ubiquitination on GJ remodeling, in the ischemic heart. To address this, we used the rat heart Langendorff model and evaluated the ubiquitination profile of Cx43 and its interaction with Nedd4, after 30 min of no-flow ischemia. By confocal microscopy, we show that ischemia induces extensive co-localization of ubiquitin and Nedd4 with Cx43 localized at IDs. Moreover, by subcellular fractionation and co-immunoprecipitation assays, we demonstrate an increased interaction with Nedd4 and ubiquitination of Cx43 localized at IDs. Altogether, these results suggest that ubiquitin is involved in the remodeling of GJ during myocardial ischemia, which requires the recruitment of Nedd4.
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http://dx.doi.org/10.1016/j.biochi.2015.02.020DOI Listing
May 2015

Autophagy and ubiquitination in cardiovascular diseases.

DNA Cell Biol 2015 Apr 20;34(4):243-51. Epub 2015 Jan 20.

1 Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra , Coimbra, Portugal .

A main function of the heart is to pump blood to the tissues and organs of the body. Although formed by different types of cells, the cardiomyocytes are the ones responsible for the coordinated and synchronized heart contraction. Given their low mitotic activity, cardiomyocytes largely depend on protein degradation mechanisms to maintain proteostasis and energetic balance. Autophagy, one of the main pathways whereby cells eliminate damaged, nonfunctional, or obsolete proteins, and organelles, is vital to ensure cell function, including in cardiomyocytes, both in rest and stress conditions. However, the impact of autophagy activation in the heart, being either protective or harmful, is not consensual and likely depends upon the severity of the stimuli and consequently the autophagy players involved. One of the signals that direct proteins for autophagy degradation, namely in the context of heart disorders, is ubiquitin. Indeed, the attachment of ubiquitin moieties to a target substrate and further recognition by autophagy adaptors constitute a main regulatory pathway that directs proteins to the lysosome. Therefore, a better understanding of the mechanisms and signals that regulate the autophagy process in the heart, including substrates targeting, is of utmost importance to design new approaches directed to this degradation pathway. We have previously shown that ubiquitination of the gap junction (GJ) protein Connexin43 (Cx43) triggers its degradation by autophagy through a process that requires the ubiquitin adaptors epidermal growth factor receptor substrate 15 (Eps15) and p62. This is particularly relevant in the heart because GJs, that form intercellular channels, are responsible for the rapid and efficient anisotropic propagation of the electrical impulse through the cardiomyocytes, essential for synchronized contraction of the cardiac muscle. In this review, we present recent studies devoted to the involvement of autophagy in heart homeostasis, with a particular focus on ubiquitin and GJs.
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http://dx.doi.org/10.1089/dna.2014.2765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389907PMC
April 2015

AMSH-mediated deubiquitination of Cx43 regulates internalization and degradation of gap junctions.

FASEB J 2014 Nov 28;28(11):4629-41. Epub 2014 Jul 28.

Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, and

Gap junctions (GJs) are specialized cell-cell contacts formed by connexins (Cxs), which provide direct intercellular communication between eukaryotic cells. Although Cx43 has long been known to be a substrate for ubiquitination, the reversal of this modification by deubiquitylases (DUBs) has never been described. Here we report that the DUB-associated molecule with the SH3 domain of STAM (AMSH) interacts with Cx43 and mediates its deubiquitination. In this study, we demonstrate that Cx43 is modified with lysine 63-linked polyubiquitin chains and that these increase the interaction between Cx43 and AMSH. We also show that AMSH is recruited to GJ plaque sites at the plasma membrane, where it mediates the deubiquitination of Cx43. Using siRNA depletion or overexpression of a catalytically inactive mutant of AMSH, we show that by decreasing Cx43 deubiquitination, both the internalization and degradation rate of Cx43 are increased. Overall, these data strongly suggest that AMSH-mediated deubiquitination of Cx43 protects GJs from degradation.
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http://dx.doi.org/10.1096/fj.13-248963DOI Listing
November 2014