Publications by authors named "Mohit Kumar Jolly"

104 Publications

Countries with high deaths due to flu and tuberculosis demonstrate lower COVID-19 mortality: roles of vaccinations.

Hum Vaccin Immunother 2021 Apr 15:1-12. Epub 2021 Apr 15.

Department of Biochemistry, Indian Institute of Science, Bangalore, India.

Deaths due to the ongoing COVID-19 pandemic vary (3-1681 deaths/million and mortality rates 0.71-14.54%) and are far greater in some countries compared to others. This observation led us to perform epidemiological analysis, using data in the public domain, to study the correlation of COVID-19 with the prevalence and vaccination strategies for two respiratory pathogens: flu and tuberculosis (TB). Countries showing more than 1000 COVID-19 deaths were selected at three time points during the ongoing pandemic: 17 May, 1 October and 31 December 2020. The major findings of this study that are broadly consistent at all three time points are: First, countries with high flu deaths negatively correlate with COVID-19 deaths/million. Second, TB incidences and deaths negatively correlate with COVID-19 deaths/million. Countries displaying high TB and flu deaths (Nigeria, Ethiopia, Myanmar, Indonesia, India) display lower COVID-19 deaths/million compared to countries with low TB and flu deaths (Italy, Spain, USA, France). Third, countries with greater flu vaccination display lower flu incidences but higher COVID-19 deaths/million and mortality rates. On the other hand, Bacillus Calmette Guerin (BCG) vaccination negatively correlates with Covid-19 deaths/million. Fourth, countries with only BCG, but no flu, vaccination show delayed and lower number of COVID-19 deaths/million compared to countries with flu, but no BCG, vaccination. Fifth, countries with high BCG vaccination coverage as well as high TB deaths display the lowest COVID-19 deaths/million. The implications of this global study are discussed with respect to the roles of respiratory infections and vaccinations in lowering COVID-19 deaths.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21645515.2021.1908058DOI Listing
April 2021

A Theoretical Approach to Coupling the Epithelial-Mesenchymal Transition (EMT) to Extracellular Matrix (ECM) Stiffness via LOXL2.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Center for Theoretical Biological Physics and Departments of Physics and Bioengineering, Northeastern University, Boston, MA 02115, USA.

The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as extracellular matrix (ECM) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state. The spatial-temporal heterogeneity of the LOXL2 concentration and thus the mechanical stiffness also has direct implications for migrating cells that attempt to escape the primary tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13071609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037024PMC
March 2021

Identifying "more equal than others" edges in diverse biochemical networks.

Proc Natl Acad Sci U S A 2021 Apr;118(16)

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2103698118DOI Listing
April 2021

Operating principles of circular toggle polygons.

Phys Biol 2021 Mar 17. Epub 2021 Mar 17.

Indian Institute of Science, Biological Sciences Building, 3rd floor, C-Wing, Bangalore, 560012, INDIA.

Decoding the dynamics of cellular decision-making and cell differentiation is a central question in cell and developmental biology. A common network motif involved in many cell-fate decisions is a mutually inhibitory feedback loop between two self-activating 'master regulators' A and B, also called as toggle switch. Typically, it can allow for three stable states - (high A, low B), (low A, high B) and (medium A, medium B). A toggle triad - three mutually repressing regulators A, B and C, i.e. three toggle switches arranged circularly (between A and B, between B and C, and between A and C) - can allow for six stable states: three 'single positive' and three 'double positive' ones. However, the operating principles of larger toggle polygons, i.e. toggle switches arranged circularly to form a polygon, remain unclear. Here, we simulate using both discrete and continuous methods the dynamics of different sized toggle polygons. We observed a pattern in their steady state frequency depending on whether the polygon was an even or odd numbered one. The even-numbered toggle polygons result in two dominant states with consecutive components of the network expressing alternating high and low levels. The odd- numbered toggle polygons, on the other hand, enable more number of states, usually twice the number of components with the states that follow 'circular permutation' patterns in their composition. Incorporating self-activations preserved these trends while increasing the frequency of multistability in the corresponding network. Our results offer insights into design principles of circular arrangement of regulatory units involved in cell-fate decision making, and can offer design strategies for synthesizing genetic circuits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1478-3975/abef79DOI Listing
March 2021

Topological signatures in regulatory network enable phenotypic heterogeneity in small cell lung cancer.

Elife 2021 03 17;10. Epub 2021 Mar 17.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India.

Phenotypic (non-genetic) heterogeneity has significant implications for the development and evolution of organs, organisms, and populations. Recent observations in multiple cancers have unraveled the role of phenotypic heterogeneity in driving metastasis and therapy recalcitrance. However, the origins of such phenotypic heterogeneity are poorly understood in most cancers. Here, we investigate a regulatory network underlying phenotypic heterogeneity in small cell lung cancer, a devastating disease with no molecular targeted therapy. Discrete and continuous dynamical simulations of this network reveal its multistable behavior that can explain co-existence of four experimentally observed phenotypes. Analysis of the network topology uncovers that multistability emerges from two teams of players that mutually inhibit each other, but members of a team activate one another, forming a 'toggle switch' between the two teams. Deciphering these topological signatures in cancer-related regulatory networks can unravel their 'latent' design principles and offer a rational approach to characterize phenotypic heterogeneity in a tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.64522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012062PMC
March 2021

Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-genetic Heterogeneity in Prostate Cancer Cells.

Entropy (Basel) 2021 Feb 26;23(3). Epub 2021 Feb 26.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.

Non-genetic heterogeneity is emerging as a crucial factor underlying therapy resistance in multiple cancers. However, the design principles of regulatory networks underlying non-genetic heterogeneity in cancer remain poorly understood. Here, we investigate the coupled dynamics of feedback loops involving (a) oscillations in androgen receptor (AR) signaling mediated through an intrinsically disordered protein PAGE4, (b) multistability in epithelial-mesenchymal transition (EMT), and c) Notch-Delta-Jagged signaling mediated cell-cell communication, each of which can generate non-genetic heterogeneity through multistability and/or oscillations. Our results show how different coupling strengths between AR and EMT signaling can lead to monostability, bistability, or oscillations in the levels of AR, as well as propagation of oscillations to EMT dynamics. These results reveal the emergent dynamics of coupled oscillatory and multi-stable systems and unravel mechanisms by which non-genetic heterogeneity in AR levels can be generated, which can act as a barrier to most existing therapies for prostate cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/e23030288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996788PMC
February 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Group Behavior and Emergence of Cancer Drug Resistance.

Trends Cancer 2021 Apr 20;7(4):323-334. Epub 2021 Feb 20.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA. Electronic address:

Drug resistance is a major impediment in cancer. Although it is generally thought that acquired drug resistance is due to genetic mutations, emerging evidence indicates that nongenetic mechanisms also play an important role. Resistance emerges through a complex interplay of clonal groups within a heterogeneous tumor and the surrounding microenvironment. Traits such as phenotypic plasticity, intercellular communication, and adaptive stress response, act in concert to ensure survival of intermediate reversible phenotypes, until permanent, resistant clones can emerge. Understanding the role of group behavior, and the underlying nongenetic mechanisms, can lead to more efficacious treatment designs and minimize or delay emergence of resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trecan.2021.01.009DOI Listing
April 2021

A Computational Systems Biology Approach Identifies SLUG as a Mediator of Partial Epithelial-Mesenchymal Transition (EMT).

Cells Tissues Organs 2021 Feb 10:1-14. Epub 2021 Feb 10.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India,

Epithelial-mesenchymal plasticity comprises reversible transitions among epithelial, hybrid epithelial/mesenchymal (E/M) and mesenchymal phenotypes, and underlies various aspects of aggressive tumor progression such as metastasis, therapy resistance, and immune evasion. The process of cells attaining one or more hybrid E/M phenotypes is termed as partial epithelial mesenchymal transition (EMT). Cells in hybrid E/M phenotype(s) can be more aggressive than those in either fully epithelial or mesenchymal state. Thus, identifying regulators of hybrid E/M phenotypes is essential to decipher the rheostats of phenotypic plasticity and consequent accelerators of metastasis. Here, using a computational systems biology approach, we demonstrate that SLUG (SNAIL2) - an EMT-inducing transcription factor - can inhibit cells from undergoing a complete EMT and thus stabilize them in hybrid E/M phenotype(s). It expands the parametric range enabling the existence of a hybrid E/M phenotype, thereby behaving as a phenotypic stability factor. Our simulations suggest that this specific property of SLUG emerges from the topology of the regulatory network it forms with other key regulators of epithelial-mesenchymal plasticity. Clinical data suggest that SLUG associates with worse patient prognosis across multiple carcinomas. Together, our results indicate that SLUG can stabilize hybrid E/M phenotype(s).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000512520DOI Listing
February 2021

Editorial: Characterizing the Multi-Faceted Dynamics of Tumor Cell Plasticity.

Front Mol Biosci 2020 20;7:630276. Epub 2021 Jan 20.

Center for Theoretical Biological Physics, Northeastern University, Boston MA, United States.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmolb.2020.630276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855584PMC
January 2021

Gene expression profiles of inflammatory breast cancer reveal high heterogeneity across the epithelial-hybrid-mesenchymal spectrum.

Transl Oncol 2021 Apr 31;14(4):101026. Epub 2021 Jan 31.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India. Electronic address:

Inflammatory breast cancer (IBC) is a highly aggressive breast cancer that metastasizes largely via tumor emboli, and has a 5-year survival rate of less than 30%. No unique genomic signature has yet been identified for IBC nor has any specific molecular therapeutic been developed to manage the disease. Thus, identifying gene expression signatures specific to IBC remains crucial. Here, we compare various gene lists that have been proposed as molecular footprints of IBC using different clinical samples as training and validation sets and using independent training algorithms, and determine their accuracy in identifying IBC samples in three independent datasets. We show that these gene lists have little to no mutual overlap, and have limited predictive accuracy in identifying IBC samples. Despite this inconsistency, single-sample gene set enrichment analysis (ssGSEA) of IBC samples correlate with their position on the epithelial-hybrid-mesenchymal spectrum. This positioning, together with ssGSEA scores, improves the accuracy of IBC identification across the three independent datasets. Finally, we observed that IBC samples robustly displayed a higher coefficient of variation in terms of EMT scores, as compared to non-IBC samples. Pending verification that this patient-to-patient variability extends to intratumor heterogeneity within a single patient, these results suggest that higher heterogeneity along the epithelial-hybrid-mesenchymal spectrum can be regarded to be a hallmark of IBC and a possibly useful biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tranon.2021.101026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851345PMC
April 2021

Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells.

J Clin Med 2021 Jan 26;10(3). Epub 2021 Jan 26.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.

Adaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK (AMP-activated protein kinase) and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can significantly generate two phenotypes or cell states: matrix detachment-triggered pAMPK/ pAkt state, and matrix (re)attachment-triggered pAkt/ pAMPK state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkt/ pAMPK and pAMPK/pAkt) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of The Cancer Genome Atlas (TCGA) breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multi-stability and drive phenotypic switching and heterogeneity in a cancer cell population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10030472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865639PMC
January 2021

Hybrid E/M Phenotype(s) and Stemness: A Mechanistic Connection Embedded in Network Topology.

J Clin Med 2020 Dec 26;10(1). Epub 2020 Dec 26.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.

Metastasis remains an unsolved clinical challenge. Two crucial features of metastasizing cancer cells are (a) their ability to dynamically move along the epithelial-hybrid-mesenchymal spectrum and (b) their tumor initiation potential or stemness. With increasing functional characterization of hybrid epithelial/mesenchymal (E/M) phenotypes along the spectrum, recent in vitro and in vivo studies have suggested an increasing association of hybrid E/M phenotypes with stemness. However, the mechanistic underpinnings enabling this association remain unclear. Here, we develop a mechanism-based mathematical modeling framework that interrogates the emergent nonlinear dynamics of the coupled network modules regulating E/M plasticity (miR-200/ZEB) and stemness (LIN28/let-7). Simulating the dynamics of this coupled network across a large ensemble of parameter sets, we observe that hybrid E/M phenotype(s) are more likely to acquire stemness relative to "pure" epithelial or mesenchymal states. We also integrate multiple "phenotypic stability factors" (PSFs) that have been shown to stabilize hybrid E/M phenotypes both in silico and in vitro-such as OVOL1/2, GRHL2, and NRF2-with this network, and demonstrate that the enrichment of hybrid E/M phenotype(s) with stemness is largely conserved in the presence of these PSFs. Thus, our results offer mechanistic insights into recent experimental observations of hybrid E/M phenotype(s) that are essential for tumor initiation and highlight how this feature is embedded in the underlying topology of interconnected EMT (Epithelial-Mesenchymal Transition) and stemness networks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10010060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794989PMC
December 2020

The Good, The Bad and The Ugly: A Mathematical Model Investigates the Differing Outcomes Among CoVID-19 Patients.

J Indian Inst Sci 2020 Oct 5:1-9. Epub 2020 Oct 5.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, 560012 India.

The disease caused by SARS-CoV-2-CoVID-19-is a global pandemic that has brought severe changes worldwide. Approximately 80% of the infected patients are largely asymptomatic or have mild symptoms such as fever or cough, while rest of the patients display varying degrees of severity of symptoms, with an average mortality rate of 3-4%. Severe symptoms such as pneumonia and acute respiratory distress syndrome may be caused by tissue damage, which is mostly due to aggravated and unresolved innate and adaptive immune response, often resulting from a cytokine storm. Here, we discuss how an intricate interplay among infected cells and cells of innate and adaptive immune system can lead to such diverse clinicopathological outcomes. Particularly, we discuss how the emergent nonlinear dynamics of interaction among the components of adaptive and immune system components and virally infected cells can drive different disease severity. Such minimalistic yet rigorous mathematical modeling approaches are helpful in explaining how various co-morbidity risk factors, such as age and obesity, can aggravate the severity of CoVID-19 in patients. Furthermore, such approaches can elucidate how a fine-tuned balance of infected cell killing and resolution of inflammation can lead to infection clearance, while disruptions can drive different severe phenotypes. These results can help further in a rational selection of drug combinations that can effectively balance viral clearance and minimize tissue damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s41745-020-00205-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533167PMC
October 2020

Anticipating the Novel Coronavirus Disease (COVID-19) Pandemic.

Front Public Health 2020 3;8:569669. Epub 2020 Sep 3.

Department of Mathematics, Indian Institute of Technology Ropar, Rupnagar, India.

The COVID-19 outbreak was first declared an international public health, and it was later deemed a pandemic. In most countries, the COVID-19 incidence curve rises sharply over a short period of time, suggesting a transition from a disease-free (or low-burden disease) equilibrium state to a sustained infected (or high-burden disease) state. Such a transition is often known to exhibit characteristics of "critical slowing down." Critical slowing down can be, in general, successfully detected using many statistical measures, such as variance, lag-1 autocorrelation, density ratio, and skewness. Here, we report an empirical test of this phenomena on the COVID-19 datasets of nine countries, including India, China, and the United States. For most of the datasets, increases in variance and autocorrelation predict the onset of a critical transition. Our analysis suggests two key features in predicting the COVID-19 incidence curve for a specific country: (a) the timing of strict social distancing and/or lockdown interventions implemented and (b) the fraction of a nation's population being affected by COVID-19 at that time. Furthermore, using satellite data of nitrogen dioxide as an indicator of lockdown efficacy, we found that countries where lockdown was implemented early and firmly have been successful in reducing COVID-19 spread. These results are essential for designing effective strategies to control the spread/resurgence of infectious pandemics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpubh.2020.569669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494973PMC
September 2020

NFATc Acts as a Non-Canonical Phenotypic Stability Factor for a Hybrid Epithelial/Mesenchymal Phenotype.

Front Oncol 2020 8;10:553342. Epub 2020 Sep 8.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India.

Metastasis remains the cause of over 90% of cancer-related deaths. Cells undergoing metastasis use phenotypic plasticity to adapt to their changing environmental conditions and avoid therapy and immune response. Reversible transitions between epithelial and mesenchymal phenotypes - epithelial-mesenchymal transition (EMT) and its reverse mesenchymal-epithelial transition (MET) - form a key axis of phenotypic plasticity during metastasis and therapy resistance. Recent studies have shown that the cells undergoing EMT/MET can attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes, the process of which is termed as partial EMT/MET. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either epithelial or mesenchymal state. Thus, it is crucial to identify the factors and regulatory networks enabling such hybrid E/M phenotypes. Here, employing an integrated computational-experimental approach, we show that the transcription factor nuclear factor of activated T-cell (NFATc) can inhibit the process of complete EMT, thus stabilizing the hybrid E/M phenotype. It increases the range of parameters enabling the existence of a hybrid E/M phenotype, thus behaving as a phenotypic stability factor (PSF). However, unlike previously identified PSFs, it does not increase the mean residence time of the cells in hybrid E/M phenotypes, as shown by stochastic simulations; rather it enables the co-existence of epithelial, mesenchymal and hybrid E/M phenotypes and transitions among them. Clinical data suggests the effect of NFATc on patient survival in a tissue-specific or context-dependent manner. Together, our results indicate that NFATc behaves as a non-canonical PSF for a hybrid E/M phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.553342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506140PMC
September 2020

Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators.

J R Soc Interface 2020 09 30;17(170):20200631. Epub 2020 Sep 30.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India.

Identifying the design principles of complex regulatory networks driving cellular decision-making remains essential to decode embryonic development as well as enhance cellular reprogramming. A well-studied network motif involved in cellular decision-making is a toggle switch-a set of two opposing transcription factors A and B, each of which is a master regulator of a specific cell fate and can inhibit the activity of the other. A toggle switch can lead to two possible states-(high A, low B) and (low A, high B)-and drives the 'either-or' choice between these two cell fates for a common progenitor cell. However, the principles of coupled toggle switches remain unclear. Here, we investigate the dynamics of three master regulators A, B and C inhibiting each other, thus forming three-coupled toggle switches to form a toggle triad. Our simulations show that this toggle triad can lead to co-existence of cells into three differentiated 'single positive' phenotypes-(high A, low B, low C), (low A, high B, low C) and (low A, low B, high C). Moreover, the hybrid or 'double positive' phenotypes-(high A, high B, low C), (low A, high B, high C) and (high A, low B, high C)-can coexist together with 'single positive' phenotypes. Including self-activation loops on A, B and C can increase the frequency of 'double positive' states. Finally, we apply our results to understand cellular decision-making in terms of differentiation of naive CD4 T cells into Th1, Th2 and Th17 states, where hybrid Th1/Th2 and hybrid Th1/Th17 cells have been reported in addition to the Th1, Th2 and Th17 ones. Our results offer novel insights into the design principles of a multi-stable network topology and provide a framework for synthetic biology to design tristable systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rsif.2020.0631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536062PMC
September 2020

Single-Cell RNA-seq Identifies Cell Subsets in Human Placenta That Highly Expresses Factors Driving Pathogenesis of SARS-CoV-2.

Front Cell Dev Biol 2020 19;8:783. Epub 2020 Aug 19.

Molecular and Cellular Biology Laboratory, ICMR-National Institute for Research in Reproductive Health, Indian Council of Medical Research (ICMR), Mumbai, India.

Infection by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) results in the novel coronavirus disease COVID-19, which has posed a serious threat globally. Infection of SARS-CoV-2 during pregnancy is associated with complications such as preterm labor and premature rupture of membranes, and a proportion of neonates born to infected mothers are also positive for the virus. During pregnancy, the placental barrier protects the fetus from pathogens and ensures healthy development. To predict if the placenta is permissive to SARS-CoV-2, we utilized publicly available single-cell RNA-seq data to identify if the placental cells express the necessary factors required for infection. SARS-CoV-2 binding receptor and the S protein priming protease are co-expressed by a subset of syncytiotrophoblasts (STB) in the first trimester and extravillous trophoblasts (EVT) in the second trimester human placenta. In addition, the non-canonical receptor and other proteases (, and ) are detected in most of the placental cells. Other coronavirus family receptors ( and ) were also expressed in the first and second trimester placental cells. Additionally, the term placenta of multiple species including humans expressed , , and along with the viral S protein proteases. The - and -positive ( + +) placental subsets expressed mRNA for proteins involved in viral budding and replication. These cells also had the mRNA for proteins that physically interact with SARS-CoV-2 in host cells. Further, we discovered unique signatures of genes in + + STBs and EVTs. The + + STBs are highly differentiated cells and express genes involving mitochondrial metabolism and glucose transport. The second trimester + + EVTs are enriched for markers of endovascular trophoblasts. Both these subtypes abundantly expressed genes in the Toll-like receptor pathway. The second trimester EVTs are also enriched for components of the JAK-STAT pathway that drives inflammation. We carried out a systematic review and identified that in 12% of pregnant women with COVID-19, the placenta was infected with SARS-CoV-2, and the virus was detected in STBs. To conclude, herein we have uncovered the cellular targets for SARS-CoV-2 entry and have shown that these cells can potentially drive viremia in the developing human placenta. Our results provide a basic framework toward understanding the paraphernalia involved in SARS-CoV-2 infections in pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.00783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466449PMC
August 2020

A Non-genetic Mechanism Involving the Integrin β4/Paxillin Axis Contributes to Chemoresistance in Lung Cancer.

iScience 2020 Aug 22;23(9):101496. Epub 2020 Aug 22.

Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA. Electronic address:

Tumor heterogeneity and cisplatin resistance are major causes of tumor relapse and poor survival. Here, we show that in lung cancer, interaction between paxillin (PXN) and integrin β4 (ITGB4), components of the focal adhesion (FA) complex, contributes to cisplatin resistance. Knocking down PXN and ITGB4 attenuated cell growth and improved cisplatin sensitivity, both in 2D and 3D cultures. PXN and ITGB4 independently regulated expression of several genes. In addition, they also regulated expression of common genes including USP1 and VDAC1, which are required for maintaining genomic stability and mitochondrial function, respectively. Mathematical modeling suggested that bistability could lead to stochastic phenotypic switching between cisplatin-sensitive and resistant states in these cells. Consistently, purified subpopulations of sensitive and resistant cells re-created the mixed parental population when cultured separately. Altogether, these data point to an unexpected role of the FA complex in cisplatin resistance and highlight a novel non-genetic mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2020.101496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502350PMC
August 2020

Mathematical Modeling of Plasticity and Heterogeneity in EMT.

Methods Mol Biol 2021 ;2179:385-413

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, Karnataka, India.

The epithelial-mesenchymal transition (EMT) and the corresponding reverse process, mesenchymal-epithelial transition (MET), are dynamic and reversible cellular programs orchestrated by many changes at both biochemical and morphological levels. A recent surge in identifying the molecular mechanisms underlying EMT/MET has led to the development of various mathematical models that have contributed to our improved understanding of dynamics at single-cell and population levels: (a) multi-stability-how many phenotypes can cells attain during an EMT/MET?, (b) reversibility/irreversibility-what time and/or concentration of an EMT inducer marks the "tipping point" when cells induced to undergo EMT cannot revert?, (c) symmetry in EMT/MET-do cells take the same path when reverting as they took during the induction of EMT?, and (d) non-cell autonomous mechanisms-how does a cell undergoing EMT alter the tendency of its neighbors to undergo EMT? These dynamical traits may facilitate a heterogenous response within a cell population undergoing EMT/MET. Here, we present a few examples of designing different mathematical models that can contribute to decoding EMT/MET dynamics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-0716-0779-4_28DOI Listing
March 2021

OVOL1/2: Drivers of Epithelial Differentiation in Development, Disease, and Reprogramming.

Cells Tissues Organs 2020 Sep 15:1-10. Epub 2020 Sep 15.

Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, India,

OVOL proteins (OVOL1 and OVOL2), vertebrate homologs of Drosophila OVO, are critical regulators of epithelial lineage determination and differentiation during embryonic development in tissues such as kidney, skin, mammary epithelia, and testis. OVOL can inhibit epithelial-mesenchymal transition and/or can promote mesenchymal-epithelial transition. Moreover, they can regulate the stemness of cancer cells, thus playing an important role during cancer cell metastasis. Due to their central role in differentiation and maintenance of epithelial lineage, OVOL overexpression has been shown to be capable of reprogramming fibroblasts to epithelial cells. Here, we review the roles of OVOL-mediated epithelial differentiation across multiple contexts, including embryonic development, cancer progression, and cellular reprogramming.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000511383DOI Listing
September 2020

Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy.

Biomolecules 2020 09 8;10(9). Epub 2020 Sep 8.

Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Kerala 695014, India.

The basic helix-loop-helix (bHLH) transcription factors inhibitor of differentiation 1 () and inhibitor of differentiation 3 (referred to as ) have an important role in maintaining the cancer stem cell (CSC) phenotype in the triple-negative breast cancer (TNBC) subtype. In this study, we aimed to understand the molecular mechanism underlying control of CSC phenotype and exploit it for therapeutic purposes. We used two different TNBC tumor models marked by either depletion or expression in order to identify targets using a combinatorial analysis of RNA sequencing and microarray data. Phenotypically, Id protein depletion leads to cell cycle arrest in the G0/G1 phase, which we demonstrate is reversible. In order to understand the molecular underpinning of Id proteins on the cell cycle phenotype, we carried out a large-scale small interfering RNA (siRNA) screen of 61 putative targets identified by using genomic analysis of two Id TNBC tumor models. Kinesin Family Member 11 () and Aurora Kinase A (), which are critical cell cycle regulators, were further validated as Id targets. Interestingly, unlike in depletion conditions, and knockdown leads to a G2/M arrest, suggesting a novel cell cycle mechanism, which we will explore in further studies. Therapeutic targeting of to block the axis was carried out using small molecular inhibitor ispinesib. We finally leveraged our findings to target the pathway using the small molecule inhibitor ispinesib in the Id+ CSC results combined with chemotherapy for better response in TNBC subtypes. This work opens up exciting new possibilities of targeting targets such as in the TNBC subtype, which is currently refractory to chemotherapy. Targeting the molecular pathway in the Id1+ CSCs in combination with chemotherapy and small molecular inhibitor results in more effective debulking of TNBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom10091295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565337PMC
September 2020

Understanding the Principles of Pattern Formation Driven by Notch Signaling by Integrating Experiments and Theoretical Models.

Front Physiol 2020 31;11:929. Epub 2020 Jul 31.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India.

Notch signaling is an evolutionary conserved cell-cell communication pathway. Besides regulating cell-fate decisions at an individual cell level, Notch signaling coordinates the emergent spatiotemporal patterning in a tissue through ligand-receptor interactions among transmembrane molecules of neighboring cells, as seen in embryonic development, angiogenesis, or wound healing. Due to its ubiquitous nature, Notch signaling is also implicated in several aspects of cancer progression, including tumor angiogenesis, stemness of cancer cells and cellular invasion. Here, we review experimental and computational models that help understand the operating principles of cell patterning driven by Notch signaling. First, we discuss the basic mechanisms of spatial patterning via canonical lateral inhibition and lateral induction mechanisms, including examples from angiogenesis, inner ear development and cancer metastasis. Next, we analyze additional layers of complexity in the Notch pathway, including the effect of varying cell sizes and shapes, ligand-receptor binding within the same cell, variable binding affinity of different ligand/receptor subtypes, and filopodia. Finally, we discuss some recent evidence of mechanosensitivity in the Notch pathway in driving collective epithelial cell migration and cardiovascular morphogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.00929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411240PMC
July 2020

Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis.

Transl Oncol 2020 Nov 8;13(11):100845. Epub 2020 Aug 8.

Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Electronic address:

Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the 'fittest' for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tranon.2020.100845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419667PMC
November 2020

A polycyclic aromatic hydrocarbon-enriched environmental chemical mixture enhances AhR, antiapoptotic signaling and a proliferative phenotype in breast cancer cells.

Carcinogenesis 2020 Dec;41(12):1648-1659

Department of Surgery, Division of Surgical Sciences, Durham, NC, USA.

Emerging evidence suggests the role of environmental chemicals, in particular endocrine-disrupting chemicals (EDCs), in progression of breast cancer and treatment resistance, which can impact survival outcomes. However, most research tends to focus on tumor etiology and the effect of single chemicals, offering little insight into the effects of realistic complex mixture exposures on tumor progression. Herein, we investigated the effect of a polycyclic aromatic hydrocarbon (PAH)-enriched EDC mixture in a panel of normal and breast cancer cells and in a tumor organoid model. Cells or organoids in culture were treated with EDC mixture at doses estimated from US adult intake of the top four PAH compounds within the mixture from the National Health and Nutrition Examination Survey database. We demonstrate that low-dose PAH mixture (6, 30 and 300 nM) increased aryl hydrocarbon receptor (AhR) expression and CYP activity in estrogen receptor (ER) positive but not normal mammary or ER-negative breast cancer cells, and that upregulated AhR signaling corresponded with increased cell proliferation and expression of antiapoptotic and antioxidant proteins XIAP and SOD1. We employed a mathematical model to validate PAH-mediated increases in AhR and XIAP expression in the MCF-7 ER-positive cell line. Furthermore, the PAH mixture caused significant growth increases in ER-negative breast cancer cell derived 3D tumor organoids, providing further evidence for the role of a natural-derived PAH mixture in enhancing a tumor proliferative phenotype. Together, our integrated cell signaling, computational and phenotype analysis reveals the underlying mechanisms of EDC mixtures in breast cancer progression and survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgaa047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791619PMC
December 2020

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT.

Oncotarget 2020 Jul 7;11(27):2611-2624. Epub 2020 Jul 7.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India.

Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343638PMC
July 2020

Author Correction: Identifying inhibitors of epithelial-mesenchymal plasticity using a network topology-based approach.

NPJ Syst Biol Appl 2020 06 12;6(1):19. Epub 2020 Jun 12.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, 560012, India.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41540-020-0139-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293276PMC
June 2020

Insights into the Multi-Dimensional Dynamic Landscape of Epithelial-Mesenchymal Plasticity through Inter-Disciplinary Approaches.

J Clin Med 2020 May 27;9(6). Epub 2020 May 27.

Cancer Research Program, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain.

Epithelial-mesenchymal transition (EMT), first described by Dr. Elizabeth (Betty) Hay in the 1980s during vertebrate embryonic development [1], has important implications in cancer aggressiveness [2]. [...].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9061624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356048PMC
May 2020