Publications by authors named "Roger Williams"

336 Publications

Soluble TIM3 and Its Ligands Galectin-9 and CEACAM1 Are in Disequilibrium During Alcohol-Related Liver Disease and Promote Impairment of Anti-bacterial Immunity.

Front Physiol 2021 10;12:632502. Epub 2021 Mar 10.

Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.

Background And Aims: Immunoregulatory checkpoint receptors (CR) contribute to the profound immunoparesis observed in alcohol-related liver disease (ALD) and neutralization of inhibitory-CRs TIM3/PD1 on anti-bacterial T-cells can rescue innate and adaptive anti-bacterial immunity. Recently described soluble-CR forms can modulate immunity in inflammatory conditions, but the contributions of soluble-TIM3 and soluble-PD1 and other soluble-CRs to immune derangements in ALD remain unclear.

Methods: In Alcoholic Hepatitis (AH; = 19), alcohol-related cirrhosis (ARC; = 53) and healthy control (HC; = 27) subjects, we measured by Luminex technology (i) plasma levels of 16 soluble-CRs, 12 pro/anti-inflammatory cytokines and markers of gut bacterial translocation; (ii) pre-hepatic, post-hepatic and non-hepatic soluble-CR plasma levels in ARC patients undergoing TIPS; (iii) soluble-CRs production from ethanol-treated immunocompetent precision cut human liver slices (PCLS); (iv) whole-blood soluble-CR expression upon bacterial challenge. By FACS, we assessed the relationship between soluble-TIM3 and membrane-TIM3 and rescue of immunity in bacterial-challenged PBMCs.

Results: Soluble-TIM3 was the dominant plasma soluble-CR in ALD vs. HC ( = 0.00002) and multivariate analysis identified it as the main driver of differences between groups. Soluble-CRs were strongly correlated with pro-inflammatory cytokines, gut bacterial translocation markers and clinical indices of disease severity. Ethanol exposure or bacterial challenge did not induce soluble-TIM3 production from PCLS nor from whole-blood. Bacterial challenge prompted membrane-TIM3 hyperexpression on PBMCs from ALD patient's vs. HC ( < 0.002) and was inversely correlated with plasma soluble-TIM3 levels in matched patients. TIM3 ligands soluble-Galectin-9 and soluble-CEACAM1 were elevated in ALD plasma (AH > ARC; < 0.002). neutralization of Galectin-9 and soluble-CEACAM1 improved the defective anti-bacterial and anti-inflammatory cytokine production from -challenged PBMCs in ALD patients.

Conclusions: Alcohol-related liver disease patients exhibit supra-physiological plasma levels of soluble-TIM3, particularly those with greater disease severity. This is also associated with increased levels of soluble TIM3-ligands and membrane-TIM3 expression on immune cells. Soluble-TIM3 can block the TIM3-ligand synapse and improve anti-bacterial immunity; however, the increased levels of soluble TIM3-binding ligands in patients with ALD negate any potential immunostimulatory effects. We believe that anti-TIM3 neutralizing antibodies currently in Phase I clinical trials or soluble-TIM3 should be investigated further for their ability to enhance anti-bacterial immunity. These agents could potentially represent an innovative immune-based supportive approach to rescue anti-bacterial defenses in ALD patients.
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http://dx.doi.org/10.3389/fphys.2021.632502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987668PMC
March 2021

New dimensions for hospital services and early detection of disease: a Review from the Lancet Commission into liver disease in the UK.

Lancet 2021 Mar 10. Epub 2021 Mar 10.

Aneurin Bevan University Health Board, Newport, UK.

This Review, in addressing the unacceptably high mortality of patients with liver disease admitted to acute hospitals, reinforces the need for integrated clinical services. The masterplan described is based on regional, geographically sited liver centres, each linked to four to six surrounding district general hospitals-a pattern of care similar to that successfully introduced for stroke services. The plan includes the establishment of a lead and deputy lead clinician in each acute hospital, preferably a hepatologist or gastroenterologist with a special interest in liver disease, who will have prime responsibility for organising the care of admitted patients with liver disease on a 24/7 basis. Essential for the plan is greater access to intensive care units and high-dependency units, in line with the reconfiguration of emergency care due to the COVID-19 pandemic. This Review strongly recommends full implementation of alcohol care teams in hospitals and improved working links with acute medical services. We also endorse recommendations from paediatric liver services to improve overall survival figures by diagnosing biliary atresia earlier based on stool colour charts and better caring for patients with impaired cognitive ability and developmental mental health problems. Pilot studies of earlier diagnosis have shown encouraging progress, with 5-6% of previously undiagnosed cases of severe fibrosis or cirrhosis identified through use of a portable FibroScan in primary care. Similar approaches to the detection of early asymptomatic disease are described in accounts from the devolved nations, and the potential of digital technology in improving the value of clinical consultation and screening programmes in primary care is highlighted. The striking contribution of comorbidities, particularly obesity and diabetes (with excess alcohol consumption known to be a major factor in obesity), to mortality in COVID-19 reinforces the need for fiscal and other long delayed regulatory measures to reduce the prevalence of obesity. These measures include the food sugar levy and the introduction of the minimum unit price policy to reduce alcohol consumption. Improving public health, this Review emphasises, will not only mitigate the severity of further waves of COVID-19, but is crucial to reducing the unacceptable burden from liver disease in the UK.
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http://dx.doi.org/10.1016/S0140-6736(20)32396-5DOI Listing
March 2021

Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes.

Nat Commun 2021 03 10;12(1):1564. Epub 2021 Mar 10.

MRC Laboratory of Molecular Biology, Cambridge, UK.

The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a-GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations.
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http://dx.doi.org/10.1038/s41467-021-21695-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946940PMC
March 2021

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

Unsaturation, curvature and charge: effects of membrane parameters on PIK3C3/VPS34-containing complexes.

Autophagy 2021 Mar 15;17(3):823-825. Epub 2021 Jan 15.

Laboratory of Molecular Biology, Cambridge, UK.

Phosphatidylinositol-3-phosphate (PtdIns3P) is essential for generating autophagosomes and regulating endocytic trafficking. Recently, we have shown that the activities of human PIK3C3/VPS34-containing complexes I and II, which synthesize PtdIns3P, are greatly affected by three membrane physicochemical parameters: lipid unsaturation, membrane curvature, and negative charge. Both complexes are more active on membranes composed of unsaturated lipids than saturated lipids, and high membrane curvature can compensate for the negative effect of high lipid saturation. Negatively charged phosphatidylserine (PS) activates the complexes, as well as PIK3C3/VPS34 alone. The kinase activity of complex I depends critically on the ATG14 BATS domain, whereas complex II relies on the BECN1 BARA domain. Our findings highlight the importance of the membrane character as sensed by the unique membrane binding motifs/domain of the complexes for regulating PIK3C3/VPS34 activity.
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http://dx.doi.org/10.1080/15548627.2021.1872190DOI Listing
March 2021

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment.

Front Immunol 2020 11;11:574276. Epub 2020 Nov 11.

Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.

Chronic liver disease when accompanied by underlying fibrosis, is characterized by an accumulation of extracellular matrix (ECM) proteins and chronic inflammation. Although traditionally considered as a passive and largely architectural structure, the ECM is now being recognized as a source of potent damage-associated molecular pattern (DAMP)s with immune-active peptides and domains. In parallel, the ECM anchors a range of cytokines, chemokines and growth factors, all of which are capable of modulating immune responses. A growing body of evidence shows that ECM proteins themselves are capable of modulating immunity either directly ligation with immune cell receptors including integrins and TLRs, or indirectly through release of immunoactive molecules such as cytokines which are stored within the ECM structure. Notably, ECM deposition and remodeling during injury and fibrosis can result in release or formation of ECM-DAMPs within the tissue, which can promote local inflammatory immune response and chemotactic immune cell recruitment and inflammation. It is well described that the ECM and immune response are interlinked and mutually participate in driving fibrosis, although their precise interactions in the context of chronic liver disease are poorly understood. This review aims to describe the known pro-/anti-inflammatory and fibrogenic properties of ECM proteins and DAMPs, with particular reference to the immunomodulatory properties of the ECM in the context of chronic liver disease. Finally, we discuss the importance of developing novel biotechnological platforms based on decellularized ECM-scaffolds, which provide opportunities to directly explore liver ECM-immune cell interactions in greater detail.
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http://dx.doi.org/10.3389/fimmu.2020.574276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686550PMC
November 2020

Gβγ is a direct regulator of endogenous p101/p110γ and p84/p110γ PI3Kγ complexes in mouse neutrophils.

Sci Signal 2020 11 3;13(656). Epub 2020 Nov 3.

Signalling Programme, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.

The PI3Kγ isoform is activated by Gi-coupled GPCRs in myeloid cells, but the extent to which the two endogenous complexes of PI3Kγ, p101/p110γ and p84/p110γ, receive direct regulation through Gβγ or indirect regulation through RAS and the sufficiency of those inputs is controversial or unclear. We generated mice with point mutations that prevent Gβγ binding to p110γ (RK552DD) or to p101 (VVKR777AAAA) and investigated the effects of these mutations in primary neutrophils and in mouse models of neutrophilic inflammation. Loss of Gβγ binding to p110γ substantially reduced the activation of both p101/p110γ and p84/p110γ in neutrophils by various GPCR agonists. Loss of Gβγ binding to p101 caused more variable effects, depending on both the agonist and cellular response, with the biggest reductions seen in PIP production by primary neutrophils in response to LTB4 and MIP-2 and in the migration of neutrophils during thioglycolate-induced peritonitis or MIP2-induced ear pouch inflammation. We also observed that p101 neutrophils showed enhanced p84-dependent ROS responses to MLP and C5a, suggesting that competition may exist between p101/p110γ and p84/p110γ for Gβγ subunits downstream of GPCR activation. GPCRs did not activate p110γ in neutrophils from mice lacking both the p101 and p84 regulatory subunits, indicating that RAS binding to p110γ is insufficient to support GPCR activation in this cell type. These findings define a direct role for Gβγ subunits in activating both of the endogenous PI3Kγ complexes and indicate that the regulatory PI3Kγ subunit biases activation toward different GPCRs.
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http://dx.doi.org/10.1126/scisignal.aaz4003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610408PMC
November 2020

The G-Protein Rab5A Activates VPS34 Complex II, a Class III PI3K, by a Dual Regulatory Mechanism.

Biophys J 2020 12 31;119(11):2205-2218. Epub 2020 Oct 31.

Molecular Biophysics Program, Department of Biochemistry, University of Colorado, Boulder, Colorado. Electronic address:

VPS34 complex II (VPS34CII) is a 386-kDa assembly of the lipid kinase subunit VPS34 and three regulatory subunits that altogether function as a prototypical class III phosphatidylinositol-3-kinase (PI3K). When the active VPS34CII complex is docked to the cytoplasmic surface of endosomal membranes, it phosphorylates its substrate lipid (phosphatidylinositol, PI) to generate the essential signaling lipid phosphatidylinositol-3-phosphate (PI3P). In turn, PI3P recruits an array of signaling proteins containing PI3P-specific targeting domains (including FYVE, PX, and PROPPINS) to the membrane surface, where they initiate key cell processes. In endocytosis and early endosome development, net VPS34CII-catalyzed PI3P production is greatly amplified by Rab5A, a small G protein of the Ras GTPase superfamily. Moreover, VPS34CII and Rab5A are each strongly linked to multiple human diseases. Thus, a molecular understanding of the mechanism by which Rab5A activates lipid kinase activity will have broad impacts in both signaling biology and medicine. Two general mechanistic models have been proposed for small G protein activation of PI3K lipid kinases. 1) In the membrane recruitment mechanism, G protein association increases the density of active kinase on the membrane. And 2) in the allosteric activation mechanism, G protein allosterically triggers an increase in the specific activity (turnover rate) of the membrane-bound kinase molecule. This study employs an in vitro single-molecule approach to elucidate the mechanism of GTP-Rab5A-associated VPS34CII kinase activation in a reconstituted GTP-Rab5A-VPS34CII-PI3P-PX signaling pathway on a target membrane surface. The findings reveal that both membrane recruitment and allosteric mechanisms make important contributions to the large increase in VPS34CII kinase activity and PI3P production triggered by membrane-anchored GTP-Rab5A. Notably, under near-physiological conditions in the absence of other activators, membrane-anchored GTP-Rab5A provides strong, virtually binary on-off switching and is required for VPS34CII membrane binding and PI3P production.
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http://dx.doi.org/10.1016/j.bpj.2020.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732812PMC
December 2020

The Effect of Aloe Vera Juice on Liver Enzymes and Hepatic Structure in a Healthy Population.

Integr Med (Encinitas) 2020 Jun;19(3):30-34

Department of Surgery and Cancer, Imperial College London, St Mary's Hospital, London, United Kingdom.

Background: There have been isolated reports of hepatotoxicity, usually manifested by transient liver function test abnormalities. While the European Food Safety Authority has recommended that whole leaf products containing the rind of the plant should not be used for human oral consumption, those gels made of the treated plant pulp alone are considered safe for daily consumption, provided recommended quantities are not exceeded. We aimed to assess hepatic function in healthy volunteers consuming the purified plant pulp gel over a 60 day period.

Methods: 35 healthy volunteers consumed the maximum recommended daily dose of 2 oz (57 mL) of gel twice daily for a total of 60 days. The participants attended an initial baseline visit where biochemical measurements of hepatic synthetic function were obtained, and each volunteer underwent hepatic ultrasound with elastography, superb microvascular imaging and image quantification. Further visits were undertaken at days 30 and 60 to undergo the same biochemical and imaging measurements of liver function to monitor if there were any changes in the parameters measured.

Results: Seven volunteers failed to complete the study, citing unspecified gastrointestinal upset and/or an inability to tolerate the taste of the gel. None of these individuals had disturbance of biochemical or imaging parameters of hepatic function. Of the remaining 27 healthy volunteers, none had a change in either biochemical indices of liver function, or of ultrasound markers of hepatic blood flow or liver tissue elasticity after 60 days of gel consumption. However, there was a non-significant reduction in serum homocysteine levels as the only detectable change in the cohort.

Conclusions: Despite reports of potential hepatotoxicity with some products, in this healthy cohort, extended consumption of purified plant-pulp gel did not have any detectable effects on hepatic function, blood flow or tissue elasticity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572145PMC
June 2020

Acute Liver Failure.

Clin Liver Dis (Hoboken) 2020 Oct 7;16(Suppl 1):45-55. Epub 2020 Oct 7.

Institute of Hepatology London Foundation for Liver Research London United Kingdom.

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http://dx.doi.org/10.1002/cld.957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538923PMC
October 2020

Faecal cytokine profiling as a marker of intestinal inflammation in acutely decompensated cirrhosis.

JHEP Rep 2020 Dec 30;2(6):100151. Epub 2020 Jul 30.

Institute of Hepatology London, Foundation for Liver Research, London, UK.

Background & Aims: Gut dysbiosis and inflammation perpetuate loss of gut barrier integrity (GBI) and pathological bacterial translocation (BT) in cirrhosis, contributing to infection risk. Little is known about gut inflammation in cirrhosis and how this differs in acute decompensation (AD). We developed a novel approach to characterise intestinal immunopathology by quantifying faecal cytokines (FCs) and GBI markers.

Methods: Faeces and plasma were obtained from patients with stable cirrhosis (SC; n = 16), AD (n = 47), and healthy controls (HCs; n = 31). A panel of 15 cytokines and GBI markers, including intestinal fatty-acid-binding protein-2 (FABP2), d-lactate, and faecal calprotectin (FCAL), were quantified by electrochemiluminescence/ELISA. Correlations between analytes and clinical metadata with univariate and multivariate analyses were performed.

Results: Faecal (F) IL-1β, interferon gamma, tumour necrosis factor alpha, IL-21, IL-17A/F, and IL-22 were significantly elevated in AD SC ( <0.01). F-IL-23 was significantly elevated in AD HC ( = 0.0007). FABP2/d-lactate were significantly increased in faeces in AD SC and AD HC ( <0.0001) and in plasma ( = 0.0004;  = 0.011). F-FABP2 correlated most strongly with disease severity (Spearman's rho: Child-Pugh 0.466; <0.0001; model for end-stage liver disease 0.488; <0.0001). FCAL correlated with plasma IL-21, IL-1β, and IL-17F only and none of the faecal analytes. F-cytokines and F-GBI markers were more accurate than plasma in discriminating AD from SC.

Conclusions: FC profiling represents an innovative approach to investigating the localised intestinal cytokine micro-environment in cirrhosis. These data reveal that AD is associated with a highly inflamed and permeable gut barrier. FC profiles are very different from the classical innate-like features of systemic inflammation. There is non-specific upregulation of T1/T17 effector cytokines and those known to mediate intestinal barrier damage. This prevents mucosal healing in AD and further propagates BT and systemic inflammation.

Lay Summary: The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.
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http://dx.doi.org/10.1016/j.jhepr.2020.100151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391986PMC
December 2020

Membrane characteristics tune activities of endosomal and autophagic human VPS34 complexes.

Elife 2020 06 30;9. Epub 2020 Jun 30.

MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, United Kingdom.

The lipid kinase VPS34 orchestrates diverse processes, including autophagy, endocytic sorting, phagocytosis, anabolic responses and cell division. VPS34 forms various complexes that help adapt it to specific pathways, with complexes I and II being the most prominent ones. We found that physicochemical properties of membranes strongly modulate VPS34 activity. Greater unsaturation of both substrate and non-substrate lipids, negative charge and curvature activate VPS34 complexes, adapting them to their cellular compartments. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) of complexes I and II on membranes elucidated structural determinants that enable them to bind membranes. Among these are the Barkor/ATG14L autophagosome targeting sequence (BATS), which makes autophagy-specific complex I more active than the endocytic complex II, and the Beclin1 BARA domain. Interestingly, even though Beclin1 BARA is common to both complexes, its membrane-interacting loops are critical for complex II, but have only a minor role for complex I.
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http://dx.doi.org/10.7554/eLife.58281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326497PMC
June 2020

Is the increased risk for MAFLD patients to develop severe COVID-19 linked to perturbation of the gut-liver axis?

J Hepatol 2021 02 20;74(2):487-488. Epub 2020 Jun 20.

The Institute of Hepatology, Foundation for Liver Research, London, UK; Faculty of Life Sciences and Medicine, King's College London, London, UK; School of medical Sciences, UNSW Sydney, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.05.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305888PMC
February 2021

A Double-Blind, Randomized Placebo-Controlled Trial of Probiotic Shirota in Stable Cirrhotic Patients.

Nutrients 2020 Jun 2;12(6). Epub 2020 Jun 2.

UCL Institute for Liver and Digestive Health, Division of Medicine, University College London, London NW3 2PF, UK.

Background In cirrhosis, a pathological gut microbiome has been linked with immune dysfunction. A pilot study of probiotic Shirota (LcS) in alcoholic cirrhosis demonstrated significant improvement in neutrophil function. This study aimed to evaluate the efficacy of LcS on neutrophil function and significant infection rates in patients with cirrhosis. Methods 92 cirrhotic patients (Child-Pugh score ≤10) were randomized to receive LcS or placebo, three times daily for six months. Primary end-points were incidence of significant infection and neutrophil function. Secondary end-points were cytokine profile, endotoxin, bacterial DNA positivity, intestinal permeability and quality of life. Results Rates of infection, decompensation or neutrophil function did not differ between placebo and probiotic groups. LcS significantly reduced plasma monocyte chemotactic protein-1 and, on subgroup analysis, plasma interleukin-1β (alcoholic cirrhosis), interleukin-17a and macrophage inflammatory protein-1β (non-alcoholic cirrhosis), compared with placebo. No significant differences in intestinal permeability, bacterial translocation or metabolomic profile were observed. Conclusion LcS supplementation in patients with early cirrhosis is safe. Although no significant infections were observed in either group, LcS improved cytokine profile towards an anti-inflammatory phenotype, an effect which appears to be independent of bacterial translocation.
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http://dx.doi.org/10.3390/nu12061651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352321PMC
June 2020

Moral Injury in Times of COVID-19.

J Health Serv Psychol 2020 May 2:1-5. Epub 2020 May 2.

Milwaukee, WI USA.

Health care providers are facing increased risk of moral distress during the COVID-19 pandemic because of changes in clinical practice and resource allocation procedures. Health care systems that employ a proactive approach in mitigating the lasting effects of moral distress will fare better in the long run. Psychologists are well poised to apply timely psychological first aid to the crisis needs of patients, colleagues, and even themselves. Key interventions are detailed, including creating and promoting safety, calmness, connectedness, self-efficacy, and hope.
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http://dx.doi.org/10.1007/s42843-020-00011-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195905PMC
May 2020

Astrocyte swelling in hepatic encephalopathy: molecular perspective of cytotoxic edema.

Metab Brain Dis 2020 04 7;35(4):559-578. Epub 2020 Mar 7.

The Institute of Hepatology London and Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK.

Hepatic encephalopathy (HE) may occur in patients with liver failure. The most critical pathophysiologic mechanism of HE is cerebral edema following systemic hyperammonemia. The dysfunctional liver cannot eliminate circulatory ammonia, so its plasma and brain levels rise sharply. Astrocytes, the only cells that are responsible for ammonia detoxification in the brain, are dynamic cells with unique phenotypic properties that enable them to respond to small changes in their environment. Any pathological changes in astrocytes may cause neurological disturbances such as HE. Astrocyte swelling is the leading cause of cerebral edema, which may cause brain herniation and death by increasing intracranial pressure. Various factors may have a role in astrocyte swelling. However, the exact molecular mechanism of astrocyte swelling is not fully understood. This article discusses the possible mechanisms of astrocyte swelling which related to hyperammonia, including the possible roles of molecules like glutamine, lactate, aquaporin-4 water channel, 18 KDa translocator protein, glial fibrillary acidic protein, alanine, glutathione, toll-like receptor 4, epidermal growth factor receptor, glutamate, and manganese, as well as inflammation, oxidative stress, mitochondrial permeability transition, ATP depletion, and astrocyte senescence. All these agents and factors may be targeted in therapeutic approaches to HE.
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http://dx.doi.org/10.1007/s11011-020-00549-8DOI Listing
April 2020

Acute-on-Chronic Liver Failure: A New Disease or an Old One Hiding in Plain Sight?

Clin Liver Dis (Hoboken) 2020 Feb 2;15(Suppl 1):S45-S51. Epub 2020 Mar 2.

Institute of Hepatology Foundation for Liver Research London United Kingdom.

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http://dx.doi.org/10.1002/cld.859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050950PMC
February 2020

Patient-Derived Scaffolds of Colorectal Cancer Metastases as an Organotypic 3D Model of the Liver Metastatic Microenvironment.

Cancers (Basel) 2020 Feb 5;12(2). Epub 2020 Feb 5.

First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.

The liver is the most common site for colorectal cancer (CRC) metastasis and there is an urgent need for new tissue culture models to study colorectal cancer liver metastasis (CRLM) as current models do not mimic the biological, biochemical, and structural characteristics of the metastatic microenvironment. Decellularization provides a novel approach for the study of the cancer extracellular matrix (ECM) as decellularized scaffolds retain tissue-specific features and biological properties. In the present study, we created a 3D model of CRC and matched CRLM using patient-derived decellularized ECM scaffolds seeded with the HT-29 CRC cell line. Here, we show an increased HT-29 cell proliferation and migration capability when cultured in cancer-derived scaffolds compared to same-patient healthy colon and liver tissues. HT-29 cells cultured in CRLM scaffolds also displayed an indication of epithelial-mesenchymal transition (EMT), with a loss of E-cadherin and increased Vimentin expression. EMT was confirmed by gene expression profiling, with the most represented biological processes in CRLM-seeded scaffolds involving demethylation, deacetylation, a cellular response to stress metabolic processes, and a response to the oxygen level and starvation. HT-29 cells cultured in cancer-specific 3D microenvironments showed a reduced response to treatment with 5-fluorouracil and 5-fluorouracil combined with Irinotecan when used at a standard IC (as determined in the 2D culture). Our 3D culture system with patient-derived tissue-specific decellularized ECM better recapitulates the metastatic microenvironment compared to conventional 2D culture conditions and represents a relevant approach for the study of CRLM progression and assessing the response to chemotherapy agents.
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http://dx.doi.org/10.3390/cancers12020364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072130PMC
February 2020

Characterisation of the Serum Metabolic Signature of Cholangiocarcinoma in a United Kingdom Cohort.

J Clin Exp Hepatol 2020 Jan-Feb;10(1):17-29. Epub 2019 Jun 15.

Division of Surgery and Cancer, Imperial College London, London, W2 INY, United Kingdom.

Background: A distinct serum metabonomic pattern has been previously revealed to be associated with various forms of liver disease. Here, we aimed to apply mass spectrometry to obtain serum metabolomic profiles from individuals with cholangiocarcinoma and benign hepatobiliary diseases to gain an insight into pathogenesis and search for potential early-disease biomarkers.

Methods: Serum samples were profiled using a hydrophilic interaction liquid chromatography platform, coupled to a mass spectrometer. A total of 47 serum specimens from 8 cholangiocarcinoma cases, 20 healthy controls, 8 benign disease controls (bile duct strictures) and 11 patients with hepatocellular carcinoma (as malignant disease controls) were included. Data analysis was performed using univariate and multivariate statistics.

Results: The serum metabolome disparities between the metabolite profiles from healthy controls and patients with hepatobiliary disease were predominantly related to changes in lipid and lipid-derived compounds (phospholipids, bile acids and steroids) and amino acid metabolites (phenylalanine). A metabolic pattern indicative of inflammatory response due to cirrhosis and cholestasis was associated with the disease groups. The abundance of phospholipid metabolites was altered in individuals with liver disease, particularly cholangiocarcinoma, but no significant difference was seen between profiles from patients with benign biliary strictures and cholangiocarcinoma.

Conclusion: The serum metabolome in cholangiocarcinoma exhibited changes in metabolites related to inflammation, altered energy production and phospholipid metabolism. This study serves to highlight future avenues for biomarker research in large-scale studies.
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http://dx.doi.org/10.1016/j.jceh.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995894PMC
June 2019

Perturbations in Mitochondrial Dynamics Are Closely Involved in the Progression of Alcoholic Liver Disease.

Alcohol Clin Exp Res 2020 04 25;44(4):856-865. Epub 2020 Feb 25.

From the, Institute of Hepatology, (EP, AR, RW, SC), Foundation for Liver Research, London, UK.

Background: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria-shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown.

Methods: Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray (n = 15) and Reverse Transcription Polymerase Chain Reaction (n = 32). The activation of dynamin-1-like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients (n = 8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision-cut liver slices (PCLS) exposed for 24 hours to increasing doses of ethanol (EtOH; 50 to 250 mM).

Results: A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short-term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model.

Conclusions: The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD.
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http://dx.doi.org/10.1111/acer.14299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166173PMC
April 2020

Identifying Key Challenges Facing Healthcare Systems In Africa And Potential Solutions.

Int J Gen Med 2019 6;12:395-403. Epub 2019 Nov 6.

Liver Unit, Department of Surgery and Cancer, St Mary's Campus, Imperial College London, London W2 1PG, UK.

Introduction: Healthcare systems in Africa suffer from neglect and underfunding, leading to severe challenges across the six World Health Organization (WHO) pillars of healthcare delivery. We conducted this study to identify the principal challenges in the health sector in Africa and their solutions for evidence-based decisions, policy development and program prioritization.

Methods: The study was conducted as part of a recent African Epidemiological Association Meeting in Maputo, Mozambique with participants drawn from 11 African countries, Cuba, Portugal and the United Kingdom. Participants were divided into 10 groups, consisting of 7 to 10 persons each. Brainstorming approaches were used in a structured, modified nominal group process exercise to identify key challenges and strategies to mitigate healthcare service challenges in Africa. Identified challenges and solutions were prioritised by ranking 1-5, with 1 most important and 5 being least important.

Results: The first three challenges identified were inadequate human resources (34.29%), inadequate budgetary allocation to health (30%) and poor leadership and management (8.45%). The leading solutions suggested included training and capacity building for health workers (29.69%), increase budgetary allocation to health (20.31%) and advocacy for political support and commitment (12.31%).

Conclusion: The underdeveloped healthcare systems in Africa need radical solutions with innovative thought to break the current impasse in service delivery. For example, public-private initiatives should be sought, where multinational companies extracting resources from Africa might be encouraged to plough some of the profits back into healthcare for the communities providing the workforce for their commercial activities. Most problems and their solutions lie within human resources, budget allocation and management. These should be accorded the highest priority for better health outcomes.
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http://dx.doi.org/10.2147/IJGM.S223882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844097PMC
November 2019

Prime Time for Dimeric Cytohesins: Surveying the Membrane with One Foot at a Time.

Structure 2019 12;27(12):1739-1741

MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address:

In this issue of Structure, Das et al. (2019) probe the structure and dynamics of dimeric cytohesins (guanine nucleotide exchange factors for ADP-ribosylation factors), in solution and on membranes. Unleashing an arsenal of methods, they demonstrate that a pleckstrin-homology domain-mediated membrane recruitment promotes conformational changes that prime cytohesins for allosteric activation.
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http://dx.doi.org/10.1016/j.str.2019.11.009DOI Listing
December 2019

Antimicrobial resistance in chronic liver disease.

Hepatol Int 2020 Jan 3;14(1):24-34. Epub 2019 Dec 3.

The Institute of Hepatology London and Foundation for Liver Research, 111 Coldharbour Lane, London, SE5 9NT, UK.

High levels of antimicrobial drug resistance deleteriously affecting the outcome of treatment with antibacterial agents are causing increasing concern worldwide. This is particularly worrying in patients with cirrhosis with a depressed immune system and heightened susceptibility to infection. Antibiotics have to be started early before results of microbiological culture are available. Current guidelines for the empirical choice of antibiotics in this situation are not very helpful, and embracing antimicrobial stewardship including rapid de-escalation of therapy are not sufficiently emphasised. Multi-drug resistant organism rates to quinolone drugs of up to 40% are recorded in patients with spontaneous bacterial peritonitis on prophylactic antibiotics, leading to a break-through recurrence of intra-peritoneal infection. Also considered in this review is the value of rifaximin-α, non-selective beta-blockers, and concerns around proton pump inhibitor drug use. Fecal microbial transplantation and other gut-targeting therapies in lessening gut bacterial translocation are a promising approach, and new molecular techniques for determining bacterial sensitivity will allow more specific targeted therapy.
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http://dx.doi.org/10.1007/s12072-019-10004-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994429PMC
January 2020

Unacceptable failures: the final report of the Lancet Commission into liver disease in the UK.

Lancet 2020 01 29;395(10219):226-239. Epub 2019 Nov 29.

Aneurin Bevan University Health Board, Newport, UK.

This final report of the Lancet Commission into liver disease in the UK stresses the continuing increase in burden of liver disease from excess alcohol consumption and obesity, with high levels of hospital admissions which are worsening in deprived areas. Only with comprehensive food and alcohol strategies based on fiscal and regulatory measures (including a minimum unit price for alcohol, the alcohol duty escalator, and an extension of the sugar levy on food content) can the disease burden be curtailed. Following introduction of minimum unit pricing in Scotland, alcohol sales fell by 3%, with the greatest effect on heavy drinkers of low-cost alcohol products. We also discuss the major contribution of obesity and alcohol to the ten most common cancers as well as measures outlined by the departing Chief Medical Officer to combat rising levels of obesity-the highest of any country in the west. Mortality of severely ill patients with liver disease in district general hospitals is unacceptably high, indicating the need to develop a masterplan for improving hospital care. We propose a plan based around specialist hospital centres that are linked to district general hospitals by operational delivery networks. This plan has received strong backing from the British Association for Study of the Liver and British Society of Gastroenterology, but is held up at NHS England. The value of so-called day-case care bundles to reduce high hospital readmission rates with greater care in the community is described, along with examples of locally derived schemes for the early detection of disease and, in particular, schemes to allow general practitioners to refer patients directly for elastography assessment. New funding arrangements for general practitioners will be required if these proposals are to be taken up more widely around the country. Understanding of the harm to health from lifestyle causes among the general population is low, with a poor knowledge of alcohol consumption and dietary guidelines. The Lancet Commission has serious doubts about whether the initiatives described in the Prevention Green Paper, with the onus placed on the individual based on the use of information technology and the latest in behavioural science, will be effective. We call for greater coordination between official and non-official bodies that have highlighted the unacceptable disease burden from liver disease in England in order to present a single, strong voice to the higher echelons of government.
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http://dx.doi.org/10.1016/S0140-6736(19)32908-3DOI Listing
January 2020

Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis.

JCI Insight 2019 12 19;4(24). Epub 2019 Dec 19.

Microbiome Analysis Center, George Mason University, Manassas, Virginia, USA.

BACKGROUNDHepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular fecal microbial transplant (FMT) in HE, with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. The aim of this study was to determine the effect of FMT on the gut-brain axis compared with placebo, using microbial function based on bile acids (BAs), inflammation (serum IL-6, LPS-binding protein [LBP]), and their association with EncephalApp.METHODSTwenty cirrhotic patients were randomized 1:1 into groups that received 1-time FMT capsules from a donor enriched in Lachnospiraceae and Ruminococcaceae or placebo capsules, with 5-month follow-up for safety outcomes. Stool microbiota and BA; serum IL-6, BA, and LBP; and EncephalApp were analyzed at baseline and 4 weeks after FMT/placebo. Correlation networks among microbiota, BAs, EncephalApp, IL-6, and LBP were performed before/after FMT.RESULTSFMT-assigned participants had 1 HE recurrence and 2 unrelated infections. Six placebo-assigned participants developed negative outcomes. FMT, but not placebo, was associated with reduced serum IL-6 and LBP and improved EncephalApp. FMT-assigned participants demonstrated higher deconjugation and secondary BA formation in feces and serum compared with baseline. No change was seen in placebo. Correlation networks showed greater complexity after FMT compared with baseline. Beneficial taxa, such as Ruminococcaceae, Verrucomicrobiaceae, and Lachnospiraceae, were correlated with cognitive improvement and decrease in inflammation after FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes.CONCLUSIONGut microbial function in cirrhosis is beneficially affected by capsular FMT, with improved inflammation and cognition. Lower secondary BAs in FMT recipients could select for participants who develop negative outcomes.TRIAL REGISTRATIONClinicaltrials.gov NCT03152188.FUNDINGNational Center for Advancing Translational Sciences NIH grant R21TR002024, VA Merit Review grant 2I0CX001076, the United Kingdom National Institute for Health Research Biomedical Facility at Imperial College London, the British Heart Foundation, Wellcome Trust, and King's College London.
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http://dx.doi.org/10.1172/jci.insight.133410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975263PMC
December 2019

The ribosomal P-stalk couples amino acid starvation to GCN2 activation in mammalian cells.

Elife 2019 11 21;8. Epub 2019 Nov 21.

Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.

The eukaryotic translation initiation factor 2α (eIF2α) kinase GCN2 is activated by amino acid starvation to elicit a rectifying physiological program known as the Integrated Stress Response (ISR). A role for uncharged tRNAs as activating ligands of yeast GCN2 is supported experimentally. However, mouse GCN2 activation has recently been observed in circumstances associated with ribosome stalling with no global increase in uncharged tRNAs. We report on a mammalian CHO cell-based CRISPR-Cas9 mutagenesis screen for genes that contribute to ISR activation by amino acid starvation. Disruption of genes encoding components of the ribosome P-stalk, uL10 and P1, selectively attenuated GCN2-mediated ISR activation by amino acid starvation or interference with tRNA charging without affecting the endoplasmic reticulum unfolded protein stress-induced ISR, mediated by the related eIF2α kinase PERK. Wildtype ribosomes isolated from CHO cells, but not those with P-stalk lesions, stimulated GCN2-dependent eIF2α phosphorylation in vitro. These observations support a model whereby lack of a cognate charged tRNA exposes a latent capacity of the ribosome P-stalk to activate GCN2 in cells and help explain the emerging link between ribosome stalling and ISR activation.
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http://dx.doi.org/10.7554/eLife.50149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919976PMC
November 2019

Structural Mechanisms of PTEN Regulation.

Cold Spring Harb Perspect Med 2020 03 2;10(3). Epub 2020 Mar 2.

Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.

The tumor suppressor (PTEN) is a tightly regulated enzyme responsible for dephosphorylating the progrowth lipid messenger molecule phosphatidylinositol 3,4,5-trisphosphate (PIP) on the plasma membrane. The carboxy-terminal tail (CTT) of PTEN is key for regulation of the enzyme. When phosphorylated, the unstructured CTT interacts with the phosphatase-C2 superdomain to inactivate the enzyme by preventing membrane association. PTEN mutations associated with cancer also inactivate the enzyme. Alternate translation-initiation sites generate extended isoforms of PTEN, such as PTEN-L that has multiple roles in cells. The extended amino-terminal region bears a signal sequence and a polyarginine sequence to facilitate exit from and entry into cells, respectively, and a membrane-binding helix that activates the enzyme. This amino-terminal region also facilitates mitochondrial and nucleolar localization. This review explores PTEN structure and its impact on localization and regulation.
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http://dx.doi.org/10.1101/cshperspect.a036152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050585PMC
March 2020

Architecture of human Rag GTPase heterodimers and their complex with mTORC1.

Science 2019 10;366(6462):203-210

MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.

The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagA/RagC nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.
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http://dx.doi.org/10.1126/science.aax3939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795536PMC
October 2019

Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology.

Nat Commun 2019 09 25;10(1):4364. Epub 2019 Sep 25.

Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.

Phosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations in PIK3CG resulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/β-dependent manner upon TLR stimulation. Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.
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http://dx.doi.org/10.1038/s41467-019-12311-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761123PMC
September 2019