Browsing by Author "He, You-Wen"
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Item Open Access An entirely cell-based system to generate single-chain antibodies against cell surface receptors.(2008) Chen, Yu-Hsun JasonThe generation of recombinant antibodies (Abs) using phage display is a proven method to obtain a large variety of Abs that bind with high affinity to a given antigen (Ag). Traditionally, the generation of single chain Abs depends on the use of recombinant proteins in several stages of the procedure. This can be a problem, especially in the case of cell surface receptors, because Abs generated and selected against recombinant proteins may not bind the same protein expressed on a cell surface in its native form and because the expression of some receptors as recombinant proteins is problematic. To overcome these difficulties, we developed a strategy to generate single chain Abs that does not require the use of purified protein at any stage of the procedure. In this strategy, stably transfected cells are used for the immunization of mice, measuring Ab responses to immunization, panning the phage library, high throughputs creening of arrayed phage clones, and characterization of recombinant single chain variable regions(scFvs). This strategy was used to generate a panel of single chain Abs specific for the innate immunity receptor Toll‐like receptor2 (TLR2). Once generated, individual scFvs were subcloned into an expression vector allowing the production of recombinant antibodies in insect cells, thus avoiding the contamination of recombinant Abs with microbial products. This cell‐based system efficiently generates Abs that bind native molecules displayed on cell surfaces, bypasses the requirement of recombinant protein production, and avoids risks of microbial component contamination. However, an inconvenience of this strategy is that it requires construction of a new library for each target TLR. This problem might be solved by using non‐immune antibody libraries to obtain antibodies against multiple TLRs. Non‐immune libraries contain a wide variety of antibodies but these are often low affinity, while immune libraries, derived from immunized animals, containa high frequency of high affinity antibodies, but are typically limited to a single antigen. In addition, it can be difficult to produce non‐immune libraries with sufficient complexity to select Abs against multiple Ags. Because the re‐assortment of VH and VL regions that occurs during antibody library construction greatly increases library complexity, we hypothesized that an immune antibody library produced against one member of a protein family would contain antibodies specific for other members of the same protein family. Here, we tested this hypothesis by mining an existing anti‐hTLR2 antibody library for antibodies specific for other members of the TLR family. This procedure, which we refer to as homolog mining, proved to be effective. Using a cell‐based system to pan and screen our anti‐hTLR2 library, we identified single chain antibodies specific for three of the four hTLR2 homologs we targeted. The antibodies identified, anti‐murine TLR2, anti‐hTLR5, and anti‐hTLR6, bind specifically to their target, with no cross‐reactivity to hTLR2 or other TLRs tested. These results demonstrate that combinatorial re‐assortment of VH and VL fragments during Ab library construction increases Ab repertoire complexity, allowing antibody libraries produced by immunization with one antigen to be used to obtain antibodies specific to related antigens. The principle of homolog mining may be extended to other protein families and will facilitate and accelerate antibody production processes. In conclusion, we developed an entirely cell‐based method to generate antibodies that bind to native molecules on the cell surface, while eliminating the requirement of recombinant proteins and the risk of microbial component contamination. With homolog mining, this system is capable of generating antibodies not only against the original immunized Ag, but also against homologous Ags. In combination, this system proved to be an effective and efficient means for generating multiple antibodies that bind to multiple related Ags as they are displayed on cell surfaces.Item Open Access B-lymphocyte effector functions in health and disease.(2010) DiLillo, David JohnB cells and humoral immunity make up an important component of the immune system and play a vital role in preventing and fighting off infection by various pathogens. B cells also have been implicated in the pathogenesis of autoimmune disease. However, the various functions that B cells perform during the development and maintenance of autoimmune conditions remain unclear. Therefore, the overall goal of this dissertation was to determine what roles B cells play during autoimmune disease. In the Chapter 3 of this dissertation, the function of B cells was assessed during tumor immunity, a model of immune system activation and cellular immunity. To quantify B cell contributions to T cell-mediated anti-tumor immune responses, mature B cells were depleted from wild type adult mice using CD20 monoclonal antibody (mAb) prior to syngeneic B16 melanoma tumor transfers. Remarkably, subcutaneous (s.c.) tumor volume and lung metastasis were increased two-fold in B cell-depleted mice. Effector-memory and interferon (IFN)γ or tumor necrosis factor (TNF)α-secreting CD4+ and CD8+ T cell induction was significantly impaired in B cell-depleted mice with tumors. Tumor antigen (Ag)-specific CD8+ T cell proliferation was also impaired in tumor-bearing mice that lacked B cells. Thus, B cells were required for optimal T cell activation and cellular immunity in this in vivo non-lymphoid tumor model. In Chapter 4 of this dissertation, the roles that B cells play during immune responses elicited by different allografts were assessed, since allograft rejection is thought to be T cell-mediated. The effects of B cell-depletion on acute cardiac rejection, chronic renal rejection, and skin graft rejection were compared using CD20 or CD19 mAbs. Both CD20 and CD19 mAbs effectively depleted mature B cells, while CD19 mAb treatment depleted plasmablasts and some plasma cells. B cell depletion did not affect acute cardiac allograft rejection, although CD19 mAb treatment prevented allograft-specific IgG production. Nonetheless, CD19 mAb treatment significantly reduced renal allograft rejection and abrogated allograft-specific IgG development, while CD20 mAb treatment did not. By contrast, B cell depletion exacerbated skin allograft rejection and augmented the proliferation of adoptively transferred alloAg-specific CD4+ T cells, demonstrating that B cells can also negatively regulate allograft rejection. Thereby, B cells can either positively or negatively regulate allograft rejection depending on the nature of the allograft and the intensity of the rejection response. Serum antibody (Ab) is, at least in part, responsible for protection against pathogens and tissue destruction during autoimmunity. In Chapter 5 of this dissertation, the mechanisms responsible for the maintenance of long-lived serum Ab levels were examined, since the relationship between memory B cells, long-lived plasma cells, and long-lived humoral immunity remains controversial. To address the roles of B cell subsets in the longevity of humoral responses, mature B cells were depleted in mice using CD20 mAb. CD20+ B cell depletion prevented humoral immune responses and class switching, and depleted existing and adoptively-transferred B cell memory. Nonetheless, B cell depletion did not affect serum Ig levels, Ag-specific Ab titers, or bone marrow (BM) Ab-secreting plasma cell numbers. Co-blockade of LFA-1 and VLA-4 adhesion molecules temporarily depleted long-lived plasma cells from the BM. CD20+ B cell depletion plus LFA-1/VLA-4 mAb treatment significantly prolonged Ag-specific plasma cell depletion from the BM, with a significant decrease in Ag-specific serum IgG. Collectively, these results indicate that BM plasma cells are intrinsically long-lived. Further, these studies now demonstrate that mature and memory B cells are not required for maintaining BM plasma cell numbers, but are required for repopulation of plasma cell-deficient BM. Thereby, depleting mature and memory B cells does not have a dramatic negative effect on pre-existing Ab levels. Collectively, the studies described in this dissertation demonstrate that B cells function through multiple effector mechanisms to influence the course and intensity of normal and autoreactive immune responses: the promotion of cellular immune responses and CD4+ T cell activation, the negative regulation of cellular immune responses, and the production and maintenance of long-lived Ag-specific serum Ab titers. Therefore, each of these three B cell effector mechanisms can contribute independently or in concert with the other mechanisms to clear pathogens or cause tissue damage during autoimmunity.Item Open Access Cellular and Molecular Mediators of Bronchiolitis Obliterans-like Pathological Changes in a Murine Model of Chlorine Gas Inhalation(2013) O'Koren, Emily GraceBronchiolitis Obliterans (BO) is a major cause of chronic airway dysfunction after toxic chemical inhalation. The pathophysiology of BO is not well understood, but epithelial cell injury has been closely associated with the development of fibrotic lesions in human studies and in animal models of both toxin- and transplant-induced BO. However, while almost all cases and models of BO include epithelial injury, not all instances of epithelial injury result in BO, suggesting that epithelial damage per se is not the critical event leading to the development of BO. In this dissertation, we describe a model of chlorine (Cl2)-induced BO in which mice develop tracheal and large airway obliterative lesions within 10 days of exposure to high (350 ppm), but not low (200 ppm), concentrations of Cl2 gas. Lesions develop in a series of well-demarcated pathological changes that include epithelial denudation, inflammatory cell infiltration by day 2 after exposure, fibroblast infiltration and collagen deposition by day 5, and in-growth of blood vessels by day 7, ultimately leading to lethal airway obstruction by days 9-12. Using this model, we were able to test our hypothesis that loss of epithelial progenitor cells is a critical factor leading to the development of obliterative airway lesions after chemical inhalation. Indeed, these lesions arise only under conditions and in areas in which basal cells, the resident progenitor cells for large airway epithelium, are eliminated by Cl2 exposure.
The molecular pathways contributing to BO development are not well understood. Mechanisms of epithelial injury differ across BO models, but we hypothesized that after the inciting injury, BO models share common pathways. We compared microarray analysis from day 5 non-BO- and BO-inducing chemical injuries and subsequently identified biological pathways that may contribute to BO pathogenesis. Our findings add support to pathways previously implicated in BO development and more importantly, suggest potential new pathways and molecular mediators of BO. Furthermore, we evaluated the efficacy of therapeutic inhibition of neovascularization or inflammation to prevent Cl2-induced BO. To date, our therapeutic interventions were ineffective. Nonetheless, our findings suggest that in the context of Cl2-induced BO, vascular endothelial growth factor receptor 2 (a mediator of neovascularization) and inducible nitric oxide synthase (a mediator of inflammation) are not critical in BO pathogenesis.
In sum, our work introduces and characterizes a novel Cl2-induced murine model of BO. Using this model we demonstrated that in the absence of basal cells, epithelial regeneration does not occur and regions of epithelial denudation persist from which an aberrant repair process is initiated, leading to obliterative airway lesions. Our findings suggest that, irrespective of the cause, loss of epithelial progenitor cells may be a critical factor leading to the development of BO. Furthermore, our gene expression analysis implicates novel mediators and signaling pathways in the development of BO. Our analysis lays the foundation for more rigorous exploration of these targets in the pathogenesis of BO.
Item Open Access Clinically approved combination immunotherapy: Current status, limitations, and future perspective.(Current research in immunology, 2022-01) Lu, Ligong; Zhan, Meixiao; Li, Xian-Yang; Zhang, Hui; Dauphars, Danielle J; Jiang, Jun; Yin, Hua; Li, Shi-You; Luo, Sheng; Li, Yong; He, You-WenImmune-checkpoint inhibitor-based combination immunotherapy has become a first-line treatment for several major types of cancer including hepatocellular carcinoma (HCC), renal cell carcinoma, lung cancer, cervical cancer, and gastric cancer. Combination immunotherapy counters several immunosuppressive elements in the tumor microenvironment and activates multiple steps of the cancer-immunity cycle. The anti-PD-L1 antibody, atezolizumab, plus the anti-vascular endothelial growth factor antibody, bevacizumab, represents a promising class of combination immunotherapy. This combination has produced unprecedented clinical efficacy in unresectable HCC and become a landmark in HCC therapy. Advanced HCC patients treated with atezolizumab plus bevacizumab demonstrated impressive improvements in multiple clinical endpoints including overall survival, progress-free survival, objective response rate, and patient-reported quality of life when compared to current first-line treatment with sorafenib. However, atezolizumab plus bevacizumab first-line therapy has limitations. First, cancer patients falling into the criteria for the combination therapy may need to be further selected to reap benefits while avoiding some potential pitfalls. Second, the treatment regimen of atezolizumab plus bevacizumab at a fixed dose may require adjustment for optimal normalization of the tumor microenvironment to obtain maximum efficacy and reduce adverse events. Third, utilization of predictive biomarkers is urgently needed to guide the entire treatment process. Here we review the current status of clinically approved combination immunotherapies and the underlying immune mechanisms. We further provide a perspective analysis of the limitations for combination immunotherapies and potential approaches to overcome the limitations.Item Open Access Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).(Autophagy, 2016-01) Klionsky, Daniel J; Abdelmohsen, Kotb; Abe, Akihisa; Abedin, Md Joynal; Abeliovich, Hagai; Acevedo Arozena, Abraham; Adachi, Hiroaki; Adams, Christopher M; Adams, Peter D; Adeli, Khosrow; Adhihetty, Peter J; Adler, Sharon G; Agam, Galila; Agarwal, Rajesh; Aghi, Manish K; Agnello, Maria; Agostinis, Patrizia; Aguilar, Patricia V; Aguirre-Ghiso, Julio; Airoldi, Edoardo M; Ait-Si-Ali, Slimane; Akematsu, Takahiko; Akporiaye, Emmanuel T; Al-Rubeai, Mohamed; Albaiceta, Guillermo M; Albanese, Chris; Albani, Diego; Albert, Matthew L; Aldudo, Jesus; Algül, Hana; Alirezaei, Mehrdad; Alloza, Iraide; Almasan, Alexandru; Almonte-Beceril, Maylin; Alnemri, Emad S; Alonso, Covadonga; Altan-Bonnet, Nihal; Altieri, Dario C; Alvarez, Silvia; Alvarez, Silvia; Alvarez-Erviti, Lydia; Alves, Sandro; Amadoro, Giuseppina; Amano, Atsuo; Amantini, Consuelo; Ambrosio, Santiago; Amelio, Ivano; Amer, Amal O; Amessou, Mohamed; Amon, Angelika; An, Zhenyi; Anania, Frank A; Andersen, Stig U; Andley, Usha P; Andreadi, Catherine K; Andrieu-Abadie, Nathalie; Anel, Alberto; Ann, David K; Anoopkumar-Dukie, Shailendra; Antonioli, Manuela; Aoki, Hiroshi; Apostolova, Nadezda; Aquila, Saveria; Aquilano, Katia; Araki, Koichi; Arama, Eli; Aranda, Agustin; Araya, Jun; Arcaro, Alexandre; Arias, Esperanza; Arimoto, Hirokazu; Ariosa, Aileen R; Armstrong, Jane L; Arnould, Thierry; Arsov, Ivica; Asanuma, Katsuhiko; Askanas, Valerie; Asselin, Eric; Atarashi, Ryuichiro; Atherton, Sally S; Atkin, Julie D; Attardi, Laura D; Auberger, Patrick; Auburger, Georg; Aurelian, Laure; Autelli, Riccardo; Avagliano, Laura; Avantaggiati, Maria Laura; Avrahami, Limor; Awale, Suresh; Azad, Neelam; Bachetti, Tiziana; Backer, Jonathan M; Bae, Dong-Hun; Bae, Jae-Sung; Bae, Ok-Nam; Bae, Soo Han; Baehrecke, Eric H; Baek, Seung-Hoon; Baghdiguian, Stephen; Bagniewska-Zadworna, Agnieszka; Bai, Hua; Bai, Jie; Bai, Xue-Yuan; Bailly, Yannick; Balaji, Kithiganahalli Narayanaswamy; Balduini, Walter; Ballabio, Andrea; Balzan, Rena; Banerjee, Rajkumar; Bánhegyi, Gábor; Bao, Haijun; Barbeau, Benoit; Barrachina, Maria D; Barreiro, Esther; Bartel, Bonnie; Bartolomé, Alberto; Bassham, Diane C; Bassi, Maria Teresa; Bast, Robert C; Basu, Alakananda; Batista, Maria Teresa; Batoko, Henri; Battino, Maurizio; Bauckman, Kyle; Baumgarner, Bradley L; Bayer, K Ulrich; Beale, Rupert; Beaulieu, Jean-François; Beck, George R; Becker, Christoph; Beckham, J David; Bédard, Pierre-André; Bednarski, Patrick J; Begley, Thomas J; Behl, Christian; Behrends, Christian; Behrens, Georg Mn; Behrns, Kevin E; Bejarano, Eloy; Belaid, Amine; Belleudi, Francesca; Bénard, Giovanni; Berchem, Guy; Bergamaschi, Daniele; Bergami, Matteo; Berkhout, Ben; Berliocchi, Laura; Bernard, Amélie; Bernard, Monique; Bernassola, Francesca; Bertolotti, Anne; Bess, Amanda S; Besteiro, Sébastien; Bettuzzi, Saverio; Bhalla, Savita; Bhattacharyya, Shalmoli; Bhutia, Sujit K; Biagosch, Caroline; Bianchi, Michele Wolfe; Biard-Piechaczyk, Martine; Billes, Viktor; Bincoletto, Claudia; Bingol, Baris; Bird, Sara W; Bitoun, Marc; Bjedov, Ivana; Blackstone, Craig; Blanc, Lionel; Blanco, Guillermo A; Blomhoff, Heidi Kiil; Boada-Romero, Emilio; Böckler, Stefan; Boes, Marianne; Boesze-Battaglia, Kathleen; Boise, Lawrence H; Bolino, Alessandra; Boman, Andrea; Bonaldo, Paolo; Bordi, Matteo; Bosch, Jürgen; Botana, Luis M; Botti, Joelle; Bou, German; Bouché, Marina; Bouchecareilh, Marion; Boucher, Marie-Josée; Boulton, Michael E; Bouret, Sebastien G; Boya, Patricia; Boyer-Guittaut, Michaël; Bozhkov, Peter V; Brady, Nathan; Braga, Vania Mm; Brancolini, Claudio; Braus, Gerhard H; Bravo-San Pedro, José M; Brennan, Lisa A; Bresnick, Emery H; Brest, Patrick; Bridges, Dave; Bringer, Marie-Agnès; Brini, Marisa; Brito, Glauber C; Brodin, Bertha; Brookes, Paul S; Brown, Eric J; Brown, Karen; Broxmeyer, Hal E; Bruhat, Alain; Brum, Patricia Chakur; Brumell, John H; Brunetti-Pierri, Nicola; Bryson-Richardson, Robert J; Buch, Shilpa; Buchan, Alastair M; Budak, Hikmet; Bulavin, Dmitry V; Bultman, Scott J; Bultynck, Geert; Bumbasirevic, Vladimir; Burelle, Yan; Burke, Robert E; Burmeister, Margit; Bütikofer, Peter; Caberlotto, Laura; Cadwell, Ken; Cahova, Monika; Cai, Dongsheng; Cai, Jingjing; Cai, Qian; Calatayud, Sara; Camougrand, Nadine; Campanella, Michelangelo; Campbell, Grant R; Campbell, Matthew; Campello, Silvia; Candau, Robin; Caniggia, Isabella; Cantoni, Lavinia; Cao, Lizhi; Caplan, Allan B; Caraglia, Michele; Cardinali, Claudio; Cardoso, Sandra Morais; Carew, Jennifer S; Carleton, Laura A; Carlin, Cathleen R; Carloni, Silvia; Carlsson, Sven R; Carmona-Gutierrez, Didac; Carneiro, Leticia Am; Carnevali, Oliana; Carra, Serena; Carrier, Alice; Carroll, Bernadette; Casas, Caty; Casas, Josefina; Cassinelli, Giuliana; Castets, Perrine; Castro-Obregon, Susana; Cavallini, Gabriella; Ceccherini, Isabella; Cecconi, Francesco; Cederbaum, Arthur I; Ceña, Valentín; Cenci, Simone; Cerella, Claudia; Cervia, Davide; Cetrullo, Silvia; Chaachouay, Hassan; Chae, Han-Jung; Chagin, Andrei S; Chai, Chee-Yin; Chakrabarti, Gopal; Chamilos, Georgios; Chan, Edmond Yw; Chan, Matthew Tv; Chandra, Dhyan; Chandra, Pallavi; Chang, Chih-Peng; Chang, Raymond Chuen-Chung; Chang, Ta Yuan; Chatham, John C; Chatterjee, Saurabh; Chauhan, Santosh; Che, Yongsheng; Cheetham, Michael E; Cheluvappa, Rajkumar; Chen, Chun-Jung; Chen, Gang; Chen, Guang-Chao; Chen, Guoqiang; Chen, Hongzhuan; Chen, Jeff W; Chen, Jian-Kang; Chen, Min; Chen, Mingzhou; Chen, Peiwen; Chen, Qi; Chen, Quan; Chen, Shang-Der; Chen, Si; Chen, Steve S-L; Chen, Wei; Chen, Wei-Jung; Chen, Wen Qiang; Chen, Wenli; Chen, Xiangmei; Chen, Yau-Hung; Chen, Ye-Guang; Chen, Yin; Chen, Yingyu; Chen, Yongshun; Chen, Yu-Jen; Chen, Yue-Qin; Chen, Yujie; Chen, Zhen; Chen, Zhong; Cheng, Alan; Cheng, Christopher Hk; Cheng, Hua; Cheong, Heesun; Cherry, Sara; Chesney, Jason; Cheung, Chun Hei Antonio; Chevet, Eric; Chi, Hsiang Cheng; Chi, Sung-Gil; Chiacchiera, Fulvio; Chiang, Hui-Ling; Chiarelli, Roberto; Chiariello, Mario; Chieppa, Marcello; Chin, Lih-Shen; Chiong, Mario; Chiu, Gigi Nc; Cho, Dong-Hyung; Cho, Ssang-Goo; Cho, William C; Cho, Yong-Yeon; Cho, Young-Seok; Choi, Augustine Mk; Choi, Eui-Ju; Choi, Eun-Kyoung; Choi, Jayoung; Choi, Mary E; Choi, Seung-Il; Chou, Tsui-Fen; Chouaib, Salem; Choubey, Divaker; Choubey, Vinay; Chow, Kuan-Chih; Chowdhury, Kamal; Chu, Charleen T; Chuang, Tsung-Hsien; Chun, Taehoon; Chung, Hyewon; Chung, Taijoon; Chung, Yuen-Li; Chwae, Yong-Joon; Cianfanelli, Valentina; Ciarcia, Roberto; Ciechomska, Iwona A; Ciriolo, Maria Rosa; Cirone, Mara; Claerhout, Sofie; Clague, Michael J; Clària, Joan; Clarke, Peter Gh; Clarke, Robert; Clementi, Emilio; Cleyrat, Cédric; Cnop, Miriam; Coccia, Eliana M; Cocco, Tiziana; Codogno, Patrice; Coers, Jörn; Cohen, Ezra Ew; Colecchia, David; Coletto, Luisa; Coll, Núria S; Colucci-Guyon, Emma; Comincini, Sergio; Condello, Maria; Cook, Katherine L; Coombs, Graham H; Cooper, Cynthia D; Cooper, J Mark; Coppens, Isabelle; Corasaniti, Maria Tiziana; Corazzari, Marco; Corbalan, Ramon; Corcelle-Termeau, Elisabeth; Cordero, Mario D; Corral-Ramos, Cristina; Corti, Olga; Cossarizza, Andrea; Costelli, Paola; Costes, Safia; Cotman, Susan L; Coto-Montes, Ana; Cottet, Sandra; Couve, Eduardo; Covey, Lori R; Cowart, L Ashley; Cox, Jeffery S; Coxon, Fraser P; Coyne, Carolyn B; Cragg, Mark S; Craven, Rolf J; Crepaldi, Tiziana; Crespo, Jose L; Criollo, Alfredo; Crippa, Valeria; Cruz, Maria Teresa; Cuervo, Ana Maria; Cuezva, Jose M; Cui, Taixing; Cutillas, Pedro R; Czaja, Mark J; Czyzyk-Krzeska, Maria F; Dagda, Ruben K; Dahmen, Uta; Dai, Chunsun; Dai, Wenjie; Dai, Yun; Dalby, Kevin N; Dalla Valle, Luisa; Dalmasso, Guillaume; D'Amelio, Marcello; Damme, Markus; Darfeuille-Michaud, Arlette; Dargemont, Catherine; Darley-Usmar, Victor M; Dasarathy, Srinivasan; Dasgupta, Biplab; Dash, Srikanta; Dass, Crispin R; Davey, Hazel Marie; Davids, Lester M; Dávila, David; Davis, Roger J; Dawson, Ted M; Dawson, Valina L; Daza, Paula; de Belleroche, Jackie; de Figueiredo, Paul; de Figueiredo, Regina Celia Bressan Queiroz; de la Fuente, José; De Martino, Luisa; De Matteis, Antonella; De Meyer, Guido Ry; De Milito, Angelo; De Santi, Mauro; de Souza, Wanderley; De Tata, Vincenzo; De Zio, Daniela; Debnath, Jayanta; Dechant, Reinhard; Decuypere, Jean-Paul; Deegan, Shane; Dehay, Benjamin; Del Bello, Barbara; Del Re, Dominic P; Delage-Mourroux, Régis; Delbridge, Lea Md; Deldicque, Louise; Delorme-Axford, Elizabeth; Deng, Yizhen; Dengjel, Joern; Denizot, Melanie; Dent, Paul; Der, Channing J; Deretic, Vojo; Derrien, Benoît; Deutsch, Eric; Devarenne, Timothy P; Devenish, Rodney J; Di Bartolomeo, Sabrina; Di Daniele, Nicola; Di Domenico, Fabio; Di Nardo, Alessia; Di Paola, Simone; Di Pietro, Antonio; Di Renzo, Livia; DiAntonio, Aaron; Díaz-Araya, Guillermo; Díaz-Laviada, Ines; Diaz-Meco, Maria T; Diaz-Nido, Javier; Dickey, Chad A; Dickson, Robert C; Diederich, Marc; Digard, Paul; Dikic, Ivan; Dinesh-Kumar, Savithrama P; Ding, Chan; Ding, Wen-Xing; Ding, Zufeng; Dini, Luciana; Distler, Jörg Hw; Diwan, Abhinav; Djavaheri-Mergny, Mojgan; Dmytruk, Kostyantyn; Dobson, Renwick Cj; Doetsch, Volker; Dokladny, Karol; Dokudovskaya, Svetlana; Donadelli, Massimo; Dong, X Charlie; Dong, Xiaonan; Dong, Zheng; Donohue, Terrence M; Doran, Kelly S; D'Orazi, Gabriella; Dorn, Gerald W; Dosenko, Victor; Dridi, Sami; Drucker, Liat; Du, Jie; Du, Li-Lin; Du, Lihuan; du Toit, André; Dua, Priyamvada; Duan, Lei; Duann, Pu; Dubey, Vikash Kumar; Duchen, Michael R; Duchosal, Michel A; Duez, Helene; Dugail, Isabelle; Dumit, Verónica I; Duncan, Mara C; Dunlop, Elaine A; Dunn, William A; Dupont, Nicolas; Dupuis, Luc; Durán, Raúl V; Durcan, Thomas M; Duvezin-Caubet, Stéphane; Duvvuri, Umamaheswar; Eapen, Vinay; Ebrahimi-Fakhari, Darius; Echard, Arnaud; Eckhart, Leopold; Edelstein, Charles L; Edinger, Aimee L; Eichinger, Ludwig; Eisenberg, Tobias; Eisenberg-Lerner, Avital; Eissa, N Tony; El-Deiry, Wafik S; El-Khoury, Victoria; Elazar, Zvulun; Eldar-Finkelman, Hagit; Elliott, Chris Jh; Emanuele, Enzo; Emmenegger, Urban; Engedal, Nikolai; Engelbrecht, Anna-Mart; Engelender, Simone; Enserink, Jorrit M; Erdmann, Ralf; Erenpreisa, Jekaterina; Eri, Rajaraman; Eriksen, Jason L; Erman, Andreja; Escalante, Ricardo; Eskelinen, Eeva-Liisa; Espert, Lucile; Esteban-Martínez, Lorena; Evans, Thomas J; Fabri, Mario; Fabrias, Gemma; Fabrizi, Cinzia; Facchiano, Antonio; Færgeman, Nils J; Faggioni, Alberto; Fairlie, W Douglas; Fan, Chunhai; Fan, Daping; Fan, Jie; Fang, Shengyun; Fanto, Manolis; Fanzani, Alessandro; Farkas, Thomas; Faure, Mathias; Favier, Francois B; Fearnhead, Howard; Federici, Massimo; Fei, Erkang; Felizardo, Tania C; Feng, Hua; Feng, Yibin; Feng, Yuchen; Ferguson, Thomas A; Fernández, Álvaro F; Fernandez-Barrena, Maite G; Fernandez-Checa, Jose C; Fernández-López, Arsenio; Fernandez-Zapico, Martin E; Feron, Olivier; Ferraro, Elisabetta; Ferreira-Halder, Carmen Veríssima; Fesus, Laszlo; Feuer, Ralph; Fiesel, Fabienne C; Filippi-Chiela, Eduardo C; Filomeni, Giuseppe; Fimia, Gian Maria; Fingert, John H; Finkbeiner, Steven; Finkel, Toren; Fiorito, Filomena; Fisher, Paul B; Flajolet, Marc; Flamigni, Flavio; Florey, Oliver; Florio, Salvatore; Floto, R Andres; Folini, Marco; Follo, Carlo; Fon, Edward A; Fornai, Francesco; Fortunato, Franco; Fraldi, Alessandro; Franco, Rodrigo; Francois, Arnaud; François, Aurélie; Frankel, Lisa B; Fraser, Iain Dc; Frey, Norbert; Freyssenet, Damien G; Frezza, Christian; Friedman, Scott L; Frigo, Daniel E; Fu, Dongxu; Fuentes, José M; Fueyo, Juan; Fujitani, Yoshio; Fujiwara, Yuuki; Fujiya, Mikihiro; Fukuda, Mitsunori; Fulda, Simone; Fusco, Carmela; Gabryel, Bozena; Gaestel, Matthias; Gailly, Philippe; Gajewska, Malgorzata; Galadari, Sehamuddin; Galili, Gad; Galindo, Inmaculada; Galindo, Maria F; Galliciotti, Giovanna; Galluzzi, Lorenzo; Galluzzi, Luca; Galy, Vincent; Gammoh, Noor; Gandy, Sam; Ganesan, Anand K; Ganesan, Swamynathan; Ganley, Ian G; Gannagé, Monique; Gao, Fen-Biao; Gao, Feng; Gao, Jian-Xin; García Nannig, Lorena; García Véscovi, Eleonora; Garcia-Macía, Marina; Garcia-Ruiz, Carmen; Garg, Abhishek D; Garg, Pramod Kumar; Gargini, Ricardo; Gassen, Nils Christian; Gatica, Damián; Gatti, Evelina; Gavard, Julie; Gavathiotis, Evripidis; Ge, Liang; Ge, Pengfei; Ge, Shengfang; Gean, Po-Wu; Gelmetti, Vania; Genazzani, Armando A; Geng, Jiefei; Genschik, Pascal; Gerner, Lisa; Gestwicki, Jason E; Gewirtz, David A; Ghavami, Saeid; Ghigo, Eric; Ghosh, Debabrata; Giammarioli, Anna Maria; Giampieri, Francesca; Giampietri, Claudia; Giatromanolaki, Alexandra; Gibbings, Derrick J; Gibellini, Lara; Gibson, Spencer B; Ginet, Vanessa; Giordano, Antonio; Giorgini, Flaviano; Giovannetti, Elisa; Girardin, Stephen E; Gispert, Suzana; Giuliano, Sandy; Gladson, Candece L; Glavic, Alvaro; Gleave, Martin; Godefroy, Nelly; Gogal, Robert M; Gokulan, Kuppan; Goldman, Gustavo H; Goletti, Delia; Goligorsky, Michael S; Gomes, Aldrin V; Gomes, Ligia C; Gomez, Hernando; Gomez-Manzano, Candelaria; Gómez-Sánchez, Rubén; Gonçalves, Dawit Ap; Goncu, Ebru; Gong, Qingqiu; Gongora, Céline; Gonzalez, Carlos B; Gonzalez-Alegre, Pedro; Gonzalez-Cabo, Pilar; González-Polo, Rosa Ana; Goping, Ing Swie; Gorbea, Carlos; Gorbunov, Nikolai V; Goring, Daphne R; Gorman, Adrienne M; Gorski, Sharon M; Goruppi, Sandro; Goto-Yamada, Shino; Gotor, Cecilia; Gottlieb, Roberta A; Gozes, Illana; Gozuacik, Devrim; Graba, Yacine; Graef, Martin; Granato, Giovanna E; Grant, Gary Dean; Grant, Steven; Gravina, Giovanni Luca; Green, Douglas R; Greenhough, Alexander; Greenwood, Michael T; Grimaldi, Benedetto; Gros, Frédéric; Grose, Charles; Groulx, Jean-Francois; Gruber, Florian; Grumati, Paolo; Grune, Tilman; Guan, Jun-Lin; Guan, Kun-Liang; Guerra, Barbara; Guillen, Carlos; Guillen, Carlos; Gulshan, Kailash; Gunst, Jan; Guo, Chuanyong; Guo, Lei; Guo, Ming; Guo, Wenjie; Guo, Xu-Guang; Gust, Andrea A; Gustafsson, Åsa B; Gutierrez, Elaine; Gutierrez, Maximiliano G; Gwak, Ho-Shin; Haas, Albert; Haber, James E; Hadano, Shinji; Hagedorn, Monica; Hahn, David R; Halayko, Andrew J; Hamacher-Brady, Anne; Hamada, Kozo; Hamai, Ahmed; Hamann, Andrea; Hamasaki, Maho; Hamer, Isabelle; Hamid, Qutayba; Hammond, Ester M; Han, Feng; Han, Weidong; Handa, James T; Hanover, John A; Hansen, Malene; Harada, Masaru; Harhaji-Trajkovic, Ljubica; Harper, J Wade; Harrath, Abdel Halim; Harris, Adrian L; Harris, James; Hasler, Udo; Hasselblatt, Peter; Hasui, Kazuhisa; Hawley, Robert G; Hawley, Teresa S; He, Congcong; He, Cynthia Y; He, Fengtian; He, Gu; He, Rong-Rong; He, Xian-Hui; He, You-Wen; He, Yu-Ying; Heath, Joan K; Hébert, Marie-Josée; Heinzen, Robert A; Helgason, Gudmundur Vignir; Hensel, Michael; Henske, Elizabeth P; Her, Chengtao; Herman, Paul K; Hernández, Agustín; Hernandez, Carlos; Hernández-Tiedra, Sonia; Hetz, Claudio; Hiesinger, P Robin; Higaki, Katsumi; Hilfiker, Sabine; Hill, Bradford G; Hill, Joseph A; Hill, William D; Hino, Keisuke; Hofius, Daniel; Hofman, Paul; Höglinger, Günter U; Höhfeld, Jörg; Holz, Marina K; Hong, Yonggeun; Hood, David A; Hoozemans, Jeroen Jm; Hoppe, Thorsten; Hsu, Chin; Hsu, Chin-Yuan; Hsu, Li-Chung; Hu, Dong; Hu, Guochang; Hu, Hong-Ming; Hu, Hongbo; Hu, Ming Chang; Hu, Yu-Chen; Hu, Zhuo-Wei; Hua, Fang; Hua, Ya; Huang, Canhua; Huang, Huey-Lan; Huang, Kuo-How; Huang, Kuo-Yang; Huang, Shile; Huang, Shiqian; Huang, Wei-Pang; Huang, Yi-Ran; Huang, Yong; Huang, Yunfei; Huber, Tobias B; Huebbe, Patricia; Huh, Won-Ki; Hulmi, Juha J; Hur, Gang Min; Hurley, James H; Husak, Zvenyslava; Hussain, Sabah Na; Hussain, Salik; Hwang, Jung Jin; Hwang, Seungmin; Hwang, Thomas Is; Ichihara, Atsuhiro; Imai, Yuzuru; Imbriano, Carol; Inomata, Megumi; Into, Takeshi; Iovane, Valentina; Iovanna, Juan L; Iozzo, Renato V; Ip, Nancy Y; Irazoqui, Javier E; Iribarren, Pablo; Isaka, Yoshitaka; Isakovic, Aleksandra J; Ischiropoulos, Harry; Isenberg, Jeffrey S; Ishaq, Mohammad; Ishida, Hiroyuki; Ishii, Isao; Ishmael, Jane E; Isidoro, Ciro; Isobe, Ken-Ichi; Isono, Erika; Issazadeh-Navikas, Shohreh; Itahana, Koji; Itakura, Eisuke; Ivanov, Andrei I; Iyer, Anand Krishnan V; Izquierdo, José M; Izumi, Yotaro; Izzo, Valentina; Jäättelä, Marja; Jaber, Nadia; Jackson, Daniel John; Jackson, William T; Jacob, Tony George; Jacques, Thomas S; Jagannath, Chinnaswamy; Jain, Ashish; Jana, Nihar Ranjan; Jang, Byoung Kuk; Jani, Alkesh; Janji, Bassam; Jannig, Paulo Roberto; Jansson, Patric J; Jean, Steve; Jendrach, Marina; Jeon, Ju-Hong; Jessen, Niels; Jeung, Eui-Bae; Jia, Kailiang; Jia, Lijun; Jiang, Hong; Jiang, Hongchi; Jiang, Liwen; Jiang, Teng; Jiang, Xiaoyan; Jiang, Xuejun; Jiang, Xuejun; Jiang, Ying; Jiang, Yongjun; Jiménez, Alberto; Jin, Cheng; Jin, Hongchuan; Jin, Lei; Jin, Meiyan; Jin, Shengkan; Jinwal, Umesh Kumar; Jo, Eun-Kyeong; Johansen, Terje; Johnson, Daniel E; Johnson, Gail Vw; Johnson, James D; Jonasch, Eric; Jones, Chris; Joosten, Leo Ab; Jordan, Joaquin; Joseph, Anna-Maria; Joseph, Bertrand; Joubert, Annie M; Ju, Dianwen; Ju, Jingfang; Juan, Hsueh-Fen; Juenemann, Katrin; Juhász, Gábor; Jung, Hye Seung; Jung, Jae U; Jung, Yong-Keun; Jungbluth, Heinz; Justice, Matthew J; Jutten, Barry; Kaakoush, Nadeem O; Kaarniranta, Kai; Kaasik, Allen; Kabuta, Tomohiro; Kaeffer, Bertrand; Kågedal, Katarina; Kahana, Alon; Kajimura, Shingo; Kakhlon, Or; Kalia, Manjula; Kalvakolanu, Dhan V; Kamada, Yoshiaki; Kambas, Konstantinos; Kaminskyy, Vitaliy O; Kampinga, Harm H; Kandouz, Mustapha; Kang, Chanhee; Kang, Rui; Kang, Tae-Cheon; Kanki, Tomotake; Kanneganti, Thirumala-Devi; Kanno, Haruo; Kanthasamy, Anumantha G; Kantorow, Marc; Kaparakis-Liaskos, Maria; Kapuy, Orsolya; Karantza, Vassiliki; Karim, Md Razaul; Karmakar, Parimal; Kaser, Arthur; Kaushik, Susmita; Kawula, Thomas; Kaynar, A Murat; Ke, Po-Yuan; Ke, Zun-Ji; Kehrl, John H; Keller, Kate E; Kemper, Jongsook Kim; Kenworthy, Anne K; Kepp, Oliver; Kern, Andreas; Kesari, Santosh; Kessel, David; Ketteler, Robin; Kettelhut, Isis do Carmo; Khambu, Bilon; Khan, Muzamil Majid; Khandelwal, Vinoth Km; Khare, Sangeeta; Kiang, Juliann G; Kiger, Amy A; Kihara, Akio; Kim, Arianna L; Kim, Cheol Hyeon; Kim, Deok Ryong; Kim, Do-Hyung; Kim, Eung Kweon; Kim, Hye Young; Kim, Hyung-Ryong; Kim, Jae-Sung; Kim, Jeong Hun; Kim, Jin Cheon; Kim, Jin Hyoung; Kim, Kwang Woon; Kim, Michael D; Kim, Moon-Moo; Kim, Peter K; Kim, Seong Who; Kim, Soo-Youl; Kim, Yong-Sun; Kim, Yonghyun; Kimchi, Adi; Kimmelman, Alec C; Kimura, Tomonori; King, Jason S; Kirkegaard, Karla; Kirkin, Vladimir; Kirshenbaum, Lorrie A; Kishi, Shuji; Kitajima, Yasuo; Kitamoto, Katsuhiko; Kitaoka, Yasushi; Kitazato, Kaio; Kley, Rudolf A; Klimecki, Walter T; Klinkenberg, Michael; Klucken, Jochen; Knævelsrud, Helene; Knecht, Erwin; Knuppertz, Laura; Ko, Jiunn-Liang; Kobayashi, Satoru; Koch, Jan C; Koechlin-Ramonatxo, Christelle; Koenig, Ulrich; Koh, Young Ho; Köhler, Katja; Kohlwein, Sepp D; Koike, Masato; Komatsu, Masaaki; Kominami, Eiki; Kong, Dexin; Kong, Hee Jeong; Konstantakou, Eumorphia G; Kopp, Benjamin T; Korcsmaros, Tamas; Korhonen, Laura; Korolchuk, Viktor I; Koshkina, Nadya V; Kou, Yanjun; Koukourakis, Michael I; Koumenis, Constantinos; Kovács, Attila L; Kovács, Tibor; Kovacs, Werner J; Koya, Daisuke; Kraft, Claudine; Krainc, Dimitri; Kramer, Helmut; Kravic-Stevovic, Tamara; Kravic-Stevovic, Tamara; Krek, Wilhelm; Kretz-Remy, Carole; Krick, Roswitha; Krishnamurthy, Malathi; Kriston-Vizi, Janos; Kroemer, Guido; Kruer, Michael C; Kruger, Rejko; Ktistakis, Nicholas T; Kuchitsu, Kazuyuki; Kuhn, Christian; Kumar, Addanki Pratap; Kumar, Anuj; Kumar, Ashok; Kumar, Deepak; Kumar, Dhiraj; Kumar, Rakesh; Kumar, Sharad; Kundu, Mondira; Kung, Hsing-Jien; Kuno, Atsushi; Kuo, Sheng-Han; Kuret, Jeff; Kurz, Tino; Kwok, Terry; Kwon, Taeg Kyu; Kwon, Yong Tae; Kyrmizi, Irene; La Spada, Albert R; Lafont, Frank; Lahm, Tim; Lakkaraju, Aparna; Lam, Truong; Lamark, Trond; Lancel, Steve; Landowski, Terry H; Lane, Darius JR; Lane, Jon D; Lanzi, Cinzia; Lapaquette, Pierre; Lapierre, Louis R; Laporte, Jocelyn; Laukkarinen, Johanna; Laurie, Gordon W; Lavandero, Sergio; Lavie, Lena; LaVoie, Matthew J; Law, Betty Yuen Kwan; Law, Helen Ka-Wai; Law, Kelsey B; Layfield, Robert; Lazo, Pedro A; Le Cam, Laurent; Le Roch, Karine G; Le Stunff, Hervé; Leardkamolkarn, Vijittra; Lecuit, Marc; Lee, Byung-Hoon; Lee, Che-Hsin; Lee, Erinna F; Lee, Gyun Min; Lee, He-Jin; Lee, Hsinyu; Lee, Jae Keun; Lee, Jongdae; Lee, Ju-Hyun; Lee, Jun Hee; Lee, Michael; Lee, Myung-Shik; Lee, Patty J; Lee, Sam W; Lee, Seung-Jae; Lee, Shiow-Ju; Lee, Stella Y; Lee, Sug Hyung; Lee, Sung Sik; Lee, Sung-Joon; Lee, Sunhee; Lee, Ying-Ray; Lee, Yong J; Lee, Young H; Leeuwenburgh, Christiaan; Lefort, Sylvain; Legouis, Renaud; Lei, Jinzhi; Lei, Qun-Ying; Leib, David A; Leibowitz, Gil; Lekli, Istvan; Lemaire, Stéphane D; Lemasters, John J; Lemberg, Marius K; Lemoine, Antoinette; Leng, Shuilong; Lenz, Guido; Lenzi, Paola; Lerman, Lilach O; Lettieri Barbato, Daniele; Leu, Julia I-Ju; Leung, Hing Y; Levine, Beth; Lewis, Patrick A; Lezoualc'h, Frank; Li, Chi; Li, Faqiang; Li, Feng-Jun; Li, Jun; Li, Ke; Li, Lian; Li, Min; Li, Min; Li, Qiang; Li, Rui; Li, Sheng; Li, Wei; Li, Wei; Li, Xiaotao; Li, Yumin; Lian, Jiqin; Liang, Chengyu; Liang, Qiangrong; Liao, Yulin; Liberal, Joana; Liberski, Pawel P; Lie, Pearl; Lieberman, Andrew P; Lim, Hyunjung Jade; Lim, Kah-Leong; Lim, Kyu; Lima, Raquel T; Lin, Chang-Shen; Lin, Chiou-Feng; Lin, Fang; Lin, Fangming; Lin, Fu-Cheng; Lin, Kui; Lin, Kwang-Huei; Lin, Pei-Hui; Lin, Tianwei; Lin, Wan-Wan; Lin, Yee-Shin; Lin, Yong; Linden, Rafael; Lindholm, Dan; Lindqvist, Lisa M; Lingor, Paul; Linkermann, Andreas; Liotta, Lance A; Lipinski, Marta M; Lira, Vitor A; Lisanti, Michael P; Liton, Paloma B; Liu, Bo; Liu, Chong; Liu, Chun-Feng; Liu, Fei; Liu, Hung-Jen; Liu, Jianxun; Liu, Jing-Jing; Liu, Jing-Lan; Liu, Ke; Liu, Leyuan; Liu, Liang; Liu, Quentin; Liu, Rong-Yu; Liu, Shiming; Liu, Shuwen; Liu, Wei; Liu, Xian-De; Liu, Xiangguo; Liu, Xiao-Hong; Liu, Xinfeng; Liu, Xu; Liu, Xueqin; Liu, Yang; Liu, Yule; Liu, Zexian; Liu, Zhe; Liuzzi, Juan P; Lizard, Gérard; Ljujic, Mila; Lodhi, Irfan J; Logue, Susan E; Lokeshwar, Bal L; Long, Yun Chau; Lonial, Sagar; Loos, Benjamin; López-Otín, Carlos; López-Vicario, Cristina; Lorente, Mar; Lorenzi, Philip L; Lõrincz, Péter; Los, Marek; Lotze, Michael T; Lovat, Penny E; Lu, Binfeng; Lu, Bo; Lu, Jiahong; Lu, Qing; Lu, She-Min; Lu, Shuyan; Lu, Yingying; Luciano, Frédéric; Luckhart, Shirley; Lucocq, John Milton; Ludovico, Paula; Lugea, Aurelia; Lukacs, Nicholas W; Lum, Julian J; Lund, Anders H; Luo, Honglin; Luo, Jia; Luo, Shouqing; Luparello, Claudio; Lyons, Timothy; Ma, Jianjie; Ma, Yi; Ma, Yong; Ma, Zhenyi; Machado, Juliano; Machado-Santelli, Glaucia M; Macian, Fernando; MacIntosh, Gustavo C; MacKeigan, Jeffrey P; Macleod, Kay F; MacMicking, John D; MacMillan-Crow, Lee Ann; Madeo, Frank; Madesh, Muniswamy; Madrigal-Matute, Julio; Maeda, Akiko; Maeda, Tatsuya; Maegawa, Gustavo; Maellaro, Emilia; Maes, Hannelore; Magariños, Marta; Maiese, Kenneth; Maiti, Tapas K; Maiuri, Luigi; Maiuri, Maria Chiara; Maki, Carl G; Malli, Roland; Malorni, Walter; Maloyan, Alina; Mami-Chouaib, Fathia; Man, Na; Mancias, Joseph D; Mandelkow, Eva-Maria; Mandell, Michael A; Manfredi, Angelo A; Manié, Serge N; Manzoni, Claudia; Mao, Kai; Mao, Zixu; Mao, Zong-Wan; Marambaud, Philippe; Marconi, Anna Maria; Marelja, Zvonimir; Marfe, Gabriella; Margeta, Marta; Margittai, Eva; Mari, Muriel; Mariani, Francesca V; Marin, Concepcio; Marinelli, Sara; Mariño, Guillermo; Markovic, Ivanka; Marquez, Rebecca; Martelli, Alberto M; Martens, Sascha; Martin, Katie R; Martin, Seamus J; Martin, Shaun; Martin-Acebes, Miguel A; Martín-Sanz, Paloma; Martinand-Mari, Camille; Martinet, Wim; Martinez, Jennifer; Martinez-Lopez, Nuria; Martinez-Outschoorn, Ubaldo; Martínez-Velázquez, Moisés; Martinez-Vicente, Marta; Martins, Waleska Kerllen; Mashima, Hirosato; Mastrianni, James A; Matarese, Giuseppe; Matarrese, Paola; Mateo, Roberto; Matoba, Satoaki; Matsumoto, Naomichi; Matsushita, Takehiko; Matsuura, Akira; Matsuzawa, Takeshi; Mattson, Mark P; Matus, Soledad; Maugeri, Norma; Mauvezin, Caroline; Mayer, Andreas; Maysinger, Dusica; Mazzolini, Guillermo D; McBrayer, Mary Kate; McCall, Kimberly; McCormick, Craig; McInerney, Gerald M; McIver, Skye C; McKenna, Sharon; McMahon, John J; McNeish, Iain A; Mechta-Grigoriou, Fatima; Medema, Jan Paul; Medina, Diego L; Megyeri, Klara; Mehrpour, Maryam; Mehta, Jawahar L; Mei, Yide; Meier, Ute-Christiane; Meijer, Alfred J; Meléndez, Alicia; Melino, Gerry; Melino, Sonia; de Melo, Edesio Jose Tenorio; Mena, Maria A; Meneghini, Marc D; Menendez, Javier A; Menezes, Regina; Meng, Liesu; Meng, Ling-Hua; Meng, Songshu; Menghini, Rossella; Menko, A Sue; Menna-Barreto, Rubem Fs; Menon, Manoj B; Meraz-Ríos, Marco A; Merla, Giuseppe; Merlini, Luciano; Merlot, Angelica M; Meryk, Andreas; Meschini, Stefania; Meyer, Joel N; Mi, Man-Tian; Miao, Chao-Yu; Micale, Lucia; Michaeli, Simon; Michiels, Carine; Migliaccio, Anna Rita; Mihailidou, Anastasia Susie; Mijaljica, Dalibor; Mikoshiba, Katsuhiko; Milan, Enrico; Miller-Fleming, Leonor; Mills, Gordon B; Mills, Ian G; Minakaki, Georgia; Minassian, Berge A; Ming, Xiu-Fen; Minibayeva, Farida; Minina, Elena A; Mintern, Justine D; Minucci, Saverio; Miranda-Vizuete, Antonio; Mitchell, Claire H; Miyamoto, Shigeki; Miyazawa, Keisuke; Mizushima, Noboru; Mnich, Katarzyna; Mograbi, Baharia; Mohseni, Simin; Moita, Luis Ferreira; Molinari, Marco; Molinari, Maurizio; Møller, Andreas Buch; Mollereau, Bertrand; Mollinedo, Faustino; Mongillo, Marco; Monick, Martha M; Montagnaro, Serena; Montell, Craig; Moore, Darren J; Moore, Michael N; Mora-Rodriguez, Rodrigo; Moreira, Paula I; Morel, Etienne; Morelli, Maria Beatrice; Moreno, Sandra; Morgan, Michael J; Moris, Arnaud; Moriyasu, Yuji; Morrison, Janna L; Morrison, Lynda A; Morselli, Eugenia; Moscat, Jorge; Moseley, Pope L; Mostowy, Serge; Motori, Elisa; Mottet, Denis; Mottram, Jeremy C; Moussa, Charbel E-H; Mpakou, Vassiliki E; Mukhtar, Hasan; Mulcahy Levy, Jean M; Muller, Sylviane; Muñoz-Moreno, Raquel; Muñoz-Pinedo, Cristina; Münz, Christian; Murphy, Maureen E; Murray, James T; Murthy, Aditya; Mysorekar, Indira U; Nabi, Ivan R; Nabissi, Massimo; Nader, Gustavo A; Nagahara, Yukitoshi; Nagai, Yoshitaka; Nagata, Kazuhiro; Nagelkerke, Anika; Nagy, Péter; Naidu, Samisubbu R; Nair, Sreejayan; Nakano, Hiroyasu; Nakatogawa, Hitoshi; Nanjundan, Meera; Napolitano, Gennaro; Naqvi, Naweed I; Nardacci, Roberta; Narendra, Derek P; Narita, Masashi; Nascimbeni, Anna Chiara; Natarajan, Ramesh; Navegantes, Luiz C; Nawrocki, Steffan T; Nazarko, Taras Y; Nazarko, Volodymyr Y; Neill, Thomas; Neri, Luca M; Netea, Mihai G; Netea-Maier, Romana T; Neves, Bruno M; Ney, Paul A; Nezis, Ioannis P; Nguyen, Hang Tt; Nguyen, Huu Phuc; Nicot, Anne-Sophie; Nilsen, Hilde; Nilsson, Per; Nishimura, Mikio; Nishino, Ichizo; Niso-Santano, Mireia; Niu, Hua; Nixon, Ralph A; Njar, Vincent Co; Noda, Takeshi; Noegel, Angelika A; Nolte, Elsie Magdalena; Norberg, Erik; Norga, Koenraad K; Noureini, Sakineh Kazemi; 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Paludan, Søren R; Palumbo, Camilla; Palumbo, Silvia; Pampliega, Olatz; Pan, Hongming; Pan, Wei; Panaretakis, Theocharis; Pandey, Aseem; Pantazopoulou, Areti; Papackova, Zuzana; Papademetrio, Daniela L; Papassideri, Issidora; Papini, Alessio; Parajuli, Nirmala; Pardo, Julian; Parekh, Vrajesh V; Parenti, Giancarlo; Park, Jong-In; Park, Junsoo; Park, Ohkmae K; Parker, Roy; Parlato, Rosanna; Parys, Jan B; Parzych, Katherine R; Pasquet, Jean-Max; Pasquier, Benoit; Pasumarthi, Kishore Bs; Patschan, Daniel; Patterson, Cam; Pattingre, Sophie; Pattison, Scott; Pause, Arnim; Pavenstädt, Hermann; Pavone, Flaminia; Pedrozo, Zully; Peña, Fernando J; Peñalva, Miguel A; Pende, Mario; Peng, Jianxin; Penna, Fabio; Penninger, Josef M; Pensalfini, Anna; Pepe, Salvatore; Pereira, Gustavo Js; Pereira, Paulo C; Pérez-de la Cruz, Verónica; Pérez-Pérez, María Esther; Pérez-Rodríguez, Diego; Pérez-Sala, Dolores; Perier, Celine; Perl, Andras; Perlmutter, David H; Perrotta, Ida; Pervaiz, Shazib; Pesonen, Maija; Pessin, Jeffrey E; Peters, Godefridus J; Petersen, Morten; Petrache, Irina; Petrof, Basil J; Petrovski, Goran; Phang, James M; Piacentini, Mauro; Pierdominici, Marina; Pierre, Philippe; Pierrefite-Carle, Valérie; Pietrocola, Federico; Pimentel-Muiños, Felipe X; Pinar, Mario; Pineda, Benjamin; Pinkas-Kramarski, Ronit; Pinti, Marcello; Pinton, Paolo; Piperdi, Bilal; Piret, James M; Platanias, Leonidas C; Platta, Harald W; Plowey, Edward D; Pöggeler, Stefanie; Poirot, Marc; Polčic, Peter; Poletti, Angelo; Poon, Audrey H; Popelka, Hana; Popova, Blagovesta; Poprawa, Izabela; Poulose, Shibu M; Poulton, Joanna; Powers, Scott K; Powers, Ted; Pozuelo-Rubio, Mercedes; Prak, Krisna; Prange, Reinhild; Prescott, Mark; Priault, Muriel; Prince, Sharon; Proia, Richard L; Proikas-Cezanne, Tassula; Prokisch, Holger; Promponas, Vasilis J; Przyklenk, Karin; Puertollano, Rosa; Pugazhenthi, Subbiah; Puglielli, Luigi; Pujol, Aurora; Puyal, Julien; Pyeon, Dohun; Qi, Xin; Qian, Wen-Bin; Qin, Zheng-Hong; Qiu, Yu; Qu, Ziwei; Quadrilatero, Joe; Quinn, Frederick; Raben, Nina; Rabinowich, Hannah; Radogna, Flavia; Ragusa, Michael J; Rahmani, Mohamed; Raina, Komal; Ramanadham, Sasanka; Ramesh, Rajagopal; Rami, Abdelhaq; Randall-Demllo, Sarron; Randow, Felix; Rao, Hai; Rao, V Ashutosh; Rasmussen, Blake B; Rasse, Tobias M; Ratovitski, Edward A; Rautou, Pierre-Emmanuel; Ray, Swapan K; Razani, Babak; Reed, Bruce H; Reggiori, Fulvio; Rehm, Markus; Reichert, Andreas S; Rein, Theo; Reiner, David J; Reits, Eric; Ren, Jun; Ren, Xingcong; Renna, Maurizio; Reusch, Jane Eb; Revuelta, Jose L; Reyes, Leticia; Rezaie, Alireza R; Richards, Robert I; Richardson, Des R; Richardson, Des R; Richetta, Clémence; Riehle, Michael A; Rihn, Bertrand H; Rikihisa, Yasuko; Riley, Brigit E; Rimbach, Gerald; Rippo, Maria Rita; Ritis, Konstantinos; Rizzi, Federica; Rizzo, Elizete; Roach, Peter J; Robbins, Jeffrey; Roberge, Michel; Roca, Gabriela; Roccheri, Maria Carmela; Rocha, Sonia; Rodrigues, Cecilia MP; Rodríguez, Clara I; de Cordoba, Santiago Rodriguez; Rodriguez-Muela, Natalia; Roelofs, Jeroen; Rogov, Vladimir V; Rohn, Troy T; Rohrer, Bärbel; Romanelli, Davide; Romani, Luigina; Romano, Patricia Silvia; Roncero, M Isabel G; Rosa, Jose Luis; Rosello, Alicia; Rosen, Kirill V; Rosenstiel, Philip; Rost-Roszkowska, Magdalena; Roth, Kevin A; Roué, Gael; Rouis, Mustapha; Rouschop, Kasper M; Ruan, Daniel T; Ruano, Diego; Rubinsztein, David C; Rucker, Edmund B; Rudich, Assaf; Rudolf, Emil; Rudolf, Ruediger; Ruegg, Markus A; Ruiz-Roldan, Carmen; Ruparelia, Avnika Ashok; Rusmini, Paola; Russ, David W; Russo, Gian Luigi; Russo, Giuseppe; Russo, Rossella; Rusten, Tor Erik; Ryabovol, Victoria; Ryan, Kevin M; Ryter, Stefan W; Sabatini, David M; Sacher, Michael; Sachse, Carsten; Sack, Michael N; Sadoshima, Junichi; Saftig, Paul; Sagi-Eisenberg, Ronit; Sahni, Sumit; Saikumar, Pothana; Saito, Tsunenori; Saitoh, Tatsuya; Sakakura, Koichi; Sakoh-Nakatogawa, Machiko; Sakuraba, Yasuhito; Salazar-Roa, María; Salomoni, Paolo; Saluja, Ashok K; Salvaterra, Paul M; Salvioli, Rosa; Samali, Afshin; Sanchez, Anthony Mj; Sánchez-Alcázar, José A; Sanchez-Prieto, Ricardo; Sandri, Marco; Sanjuan, Miguel A; Santaguida, Stefano; Santambrogio, Laura; Santoni, Giorgio; Dos Santos, Claudia Nunes; Saran, Shweta; Sardiello, Marco; Sargent, Graeme; Sarkar, Pallabi; Sarkar, Sovan; Sarrias, Maria Rosa; Sarwal, Minnie M; Sasakawa, Chihiro; Sasaki, Motoko; Sass, Miklos; Sato, Ken; Sato, Miyuki; Satriano, Joseph; Savaraj, Niramol; Saveljeva, Svetlana; Schaefer, Liliana; Schaible, Ulrich E; Scharl, Michael; Schatzl, Hermann M; Schekman, Randy; Scheper, Wiep; Schiavi, Alfonso; Schipper, Hyman M; Schmeisser, Hana; Schmidt, Jens; Schmitz, Ingo; Schneider, Bianca E; Schneider, E Marion; Schneider, Jaime L; Schon, Eric A; Schönenberger, Miriam J; Schönthal, Axel H; Schorderet, Daniel F; Schröder, Bernd; Schuck, Sebastian; Schulze, Ryan J; Schwarten, Melanie; Schwarz, Thomas L; Sciarretta, Sebastiano; Scotto, Kathleen; Scovassi, A Ivana; Screaton, Robert A; Screen, Mark; Seca, Hugo; Sedej, Simon; Segatori, Laura; Segev, Nava; Seglen, Per O; Seguí-Simarro, Jose M; Segura-Aguilar, Juan; Seki, Ekihiro; Sell, Christian; Seiliez, Iban; Semenkovich, Clay F; Semenza, Gregg L; Sen, Utpal; Serra, Andreas L; Serrano-Puebla, Ana; Sesaki, Hiromi; Setoguchi, Takao; Settembre, Carmine; Shacka, John J; Shajahan-Haq, Ayesha N; Shapiro, Irving M; Sharma, Shweta; She, Hua; Shen, C-K James; Shen, Chiung-Chyi; Shen, Han-Ming; Shen, Sanbing; Shen, Weili; Sheng, Rui; Sheng, Xianyong; Sheng, Zu-Hang; Shepherd, Trevor G; Shi, Junyan; Shi, Qiang; Shi, Qinghua; Shi, Yuguang; Shibutani, Shusaku; Shibuya, Kenichi; Shidoji, Yoshihiro; Shieh, Jeng-Jer; Shih, Chwen-Ming; Shimada, Yohta; Shimizu, Shigeomi; Shin, Dong Wook; Shinohara, Mari L; Shintani, Michiko; Shintani, Takahiro; Shioi, Tetsuo; Shirabe, Ken; Shiri-Sverdlov, Ronit; Shirihai, Orian; Shore, Gordon C; Shu, Chih-Wen; Shukla, Deepak; Sibirny, Andriy A; Sica, Valentina; Sigurdson, Christina J; Sigurdsson, Einar M; Sijwali, Puran Singh; Sikorska, Beata; Silveira, Wilian A; Silvente-Poirot, Sandrine; Silverman, Gary A; Simak, Jan; Simmet, Thomas; Simon, Anna Katharina; Simon, Hans-Uwe; Simone, Cristiano; Simons, Matias; Simonsen, Anne; Singh, Rajat; Singh, Shivendra V; Singh, Shrawan K; Sinha, Debasish; Sinha, Sangita; Sinicrope, Frank A; Sirko, Agnieszka; Sirohi, Kapil; Sishi, Balindiwe Jn; Sittler, Annie; Siu, Parco M; Sivridis, Efthimios; Skwarska, Anna; Slack, Ruth; Slaninová, Iva; Slavov, Nikolai; Smaili, Soraya S; Smalley, Keiran Sm; Smith, Duncan R; Soenen, Stefaan J; Soleimanpour, Scott A; Solhaug, Anita; Somasundaram, Kumaravel; Son, Jin H; Sonawane, Avinash; Song, Chunjuan; Song, Fuyong; Song, Hyun Kyu; Song, Ju-Xian; Song, Wei; Soo, Kai Y; Sood, Anil K; Soong, Tuck Wah; Soontornniyomkij, Virawudh; Sorice, Maurizio; Sotgia, Federica; Soto-Pantoja, David R; Sotthibundhu, Areechun; Sousa, Maria João; Spaink, Herman P; Span, Paul N; Spang, Anne; Sparks, Janet D; Speck, Peter G; Spector, Stephen A; Spies, Claudia D; Springer, Wolfdieter; Clair, Daret St; Stacchiotti, Alessandra; Staels, Bart; Stang, Michael T; Starczynowski, Daniel T; Starokadomskyy, Petro; Steegborn, Clemens; Steele, John W; Stefanis, Leonidas; Steffan, Joan; Stellrecht, Christine M; Stenmark, Harald; Stepkowski, Tomasz M; Stern, Stęphan T; Stevens, Craig; Stockwell, Brent R; Stoka, Veronika; Storchova, Zuzana; Stork, Björn; Stratoulias, Vassilis; Stravopodis, Dimitrios J; Strnad, Pavel; Strohecker, Anne Marie; Ström, Anna-Lena; Stromhaug, Per; Stulik, Jiri; Su, Yu-Xiong; Su, Zhaoliang; Subauste, Carlos S; Subramaniam, Srinivasa; Sue, Carolyn M; Suh, Sang Won; Sui, Xinbing; Sukseree, Supawadee; Sulzer, David; Sun, Fang-Lin; Sun, Jiaren; Sun, Jun; Sun, Shi-Yong; Sun, Yang; Sun, Yi; Sun, Yingjie; Sundaramoorthy, Vinod; Sung, Joseph; Suzuki, Hidekazu; Suzuki, Kuninori; Suzuki, Naoki; Suzuki, Tadashi; Suzuki, Yuichiro J; Swanson, Michele S; Swanton, Charles; Swärd, Karl; Swarup, Ghanshyam; Sweeney, Sean T; Sylvester, Paul W; Szatmari, Zsuzsanna; Szegezdi, Eva; Szlosarek, Peter W; Taegtmeyer, Heinrich; Tafani, Marco; Taillebourg, Emmanuel; Tait, Stephen Wg; Takacs-Vellai, Krisztina; Takahashi, Yoshinori; Takáts, Szabolcs; Takemura, Genzou; Takigawa, Nagio; Talbot, Nicholas J; Tamagno, Elena; Tamburini, Jerome; Tan, Cai-Ping; Tan, Lan; Tan, Mei Lan; Tan, Ming; Tan, Yee-Joo; Tanaka, Keiji; Tanaka, Masaki; Tang, Daolin; Tang, Dingzhong; Tang, Guomei; Tanida, Isei; Tanji, Kunikazu; Tannous, Bakhos A; Tapia, Jose A; Tasset-Cuevas, Inmaculada; Tatar, Marc; Tavassoly, Iman; Tavernarakis, Nektarios; Taylor, Allen; Taylor, Graham S; Taylor, Gregory A; Taylor, J Paul; Taylor, Mark J; Tchetina, Elena V; Tee, Andrew R; Teixeira-Clerc, Fatima; Telang, Sucheta; Tencomnao, Tewin; Teng, Ba-Bie; Teng, Ru-Jeng; Terro, Faraj; Tettamanti, Gianluca; Theiss, Arianne L; Theron, Anne E; Thomas, Kelly Jean; Thomé, Marcos P; Thomes, Paul G; Thorburn, Andrew; Thorner, Jeremy; Thum, Thomas; Thumm, Michael; Thurston, Teresa Lm; Tian, Ling; Till, Andreas; Ting, Jenny Pan-Yun; Titorenko, Vladimir I; Toker, Lilach; Toldo, Stefano; Tooze, Sharon A; Topisirovic, Ivan; Torgersen, Maria Lyngaas; Torosantucci, Liliana; Torriglia, Alicia; Torrisi, Maria Rosaria; Tournier, Cathy; Towns, Roberto; Trajkovic, Vladimir; Travassos, Leonardo H; Triola, Gemma; Tripathi, Durga Nand; Trisciuoglio, Daniela; Troncoso, Rodrigo; Trougakos, Ioannis P; Truttmann, Anita C; Tsai, Kuen-Jer; Tschan, Mario P; Tseng, Yi-Hsin; Tsukuba, Takayuki; Tsung, Allan; Tsvetkov, Andrey S; Tu, Shuiping; Tuan, Hsing-Yu; Tucci, Marco; Tumbarello, David A; Turk, Boris; Turk, Vito; Turner, Robin Fb; Tveita, Anders A; Tyagi, Suresh C; Ubukata, Makoto; Uchiyama, Yasuo; Udelnow, Andrej; Ueno, Takashi; Umekawa, Midori; Umemiya-Shirafuji, Rika; Underwood, Benjamin R; Ungermann, Christian; Ureshino, Rodrigo P; Ushioda, Ryo; Uversky, Vladimir N; Uzcátegui, Néstor L; Vaccari, Thomas; Vaccaro, Maria I; Váchová, Libuše; Vakifahmetoglu-Norberg, Helin; Valdor, Rut; Valente, Enza Maria; Vallette, Francois; Valverde, Angela M; Van den Berghe, Greet; Van Den Bosch, Ludo; van den Brink, Gijs R; van der Goot, F Gisou; van der Klei, Ida J; van der Laan, Luc Jw; van Doorn, Wouter G; van Egmond, Marjolein; van Golen, Kenneth L; Van Kaer, Luc; van Lookeren Campagne, Menno; Vandenabeele, Peter; Vandenberghe, Wim; Vanhorebeek, Ilse; Varela-Nieto, Isabel; Vasconcelos, M Helena; Vasko, Radovan; Vavvas, Demetrios G; Vega-Naredo, Ignacio; Velasco, Guillermo; Velentzas, Athanassios D; Velentzas, Panagiotis D; Vellai, Tibor; Vellenga, Edo; Vendelbo, Mikkel Holm; Venkatachalam, Kartik; Ventura, Natascia; Ventura, Salvador; Veras, Patrícia St; Verdier, Mireille; Vertessy, Beata G; Viale, Andrea; Vidal, Michel; Vieira, Helena LA; Vierstra, Richard D; Vigneswaran, Nadarajah; Vij, Neeraj; Vila, Miquel; Villar, Margarita; Villar, Victor H; Villarroya, Joan; Villarroya, Joan; Vindis, Cécile; Viola, Giampietro; Viscomi, Maria Teresa; Vitale, Giovanni; Vogl, Dan T; Voitsekhovskaja, Olga V; von Haefen, Clarissa; von Schwarzenberg, Karin; Voth, Daniel E; Vouret-Craviari, Valérie; Vuori, Kristina; Vyas, Jatin M; Waeber, Christian; Walker, Cheryl Lyn; Walker, Mark J; Walter, Jochen; Wan, Lei; Wan, Xiangbo; Wang, Bo; Wang, Caihong; Wang, Chao-Yung; Wang, Chengshu; Wang, Chenran; Wang, Chuangui; Wang, Dong; Wang, Fen; Wang, Fuxin; Wang, Guanghui; Wang, Hai-Jie; Wang, Haichao; Wang, Hong-Gang; Wang, Hongmin; Wang, Horng-Dar; Wang, Jing; Wang, Junjun; Wang, Mei; Wang, Mei-Qing; Wang, Pei-Yu; Wang, Peng; Wang, Richard C; Wang, Shuo; Wang, Ting-Fang; Wang, Xian; Wang, Xiao-Jia; Wang, Xiao-Wei; Wang, Xin; Wang, Xuejun; Wang, Yan; Wang, Yanming; Wang, Ying; Wang, Ying-Jan; Wang, Yipeng; Wang, Yu; Wang, Yu Tian; Wang, Yuqing; Wang, Zhi-Nong; Wappner, Pablo; Ward, Carl; Ward, Diane McVey; Warnes, Gary; Watada, Hirotaka; Watanabe, Yoshihisa; Watase, Kei; Weaver, Timothy E; Weekes, Colin D; Wei, Jiwu; Weide, Thomas; Weihl, Conrad C; Weindl, Günther; Weis, Simone Nardin; Wen, Longping; Wen, Xin; Wen, Yunfei; Westermann, Benedikt; Weyand, Cornelia M; White, Anthony R; White, Eileen; Whitton, J Lindsay; Whitworth, Alexander J; Wiels, Joëlle; Wild, Franziska; Wildenberg, Manon E; Wileman, Tom; Wilkinson, Deepti Srinivas; Wilkinson, Simon; Willbold, Dieter; Williams, Chris; Williams, Katherine; Williamson, Peter R; Winklhofer, Konstanze F; Witkin, Steven S; Wohlgemuth, Stephanie E; Wollert, Thomas; Wolvetang, Ernst J; Wong, Esther; Wong, G William; Wong, Richard W; Wong, Vincent Kam Wai; Woodcock, Elizabeth A; Wright, Karen L; Wu, Chunlai; Wu, Defeng; Wu, Gen Sheng; Wu, Jian; Wu, Junfang; Wu, Mian; Wu, Min; Wu, Shengzhou; Wu, William Kk; Wu, Yaohua; Wu, Zhenlong; Xavier, Cristina Pr; Xavier, Ramnik J; Xia, Gui-Xian; Xia, Tian; Xia, Weiliang; Xia, Yong; Xiao, Hengyi; Xiao, Jian; Xiao, Shi; Xiao, Wuhan; Xie, Chuan-Ming; Xie, Zhiping; Xie, Zhonglin; Xilouri, Maria; Xiong, Yuyan; Xu, Chuanshan; Xu, Congfeng; Xu, Feng; Xu, Haoxing; Xu, Hongwei; Xu, Jian; Xu, Jianzhen; Xu, Jinxian; Xu, Liang; Xu, Xiaolei; Xu, Yangqing; Xu, Ye; Xu, Zhi-Xiang; Xu, Ziheng; Xue, Yu; Yamada, Takahiro; Yamamoto, Ai; Yamanaka, Koji; Yamashina, Shunhei; Yamashiro, Shigeko; Yan, Bing; Yan, Bo; Yan, Xianghua; Yan, Zhen; Yanagi, Yasuo; Yang, Dun-Sheng; Yang, Jin-Ming; Yang, Liu; Yang, Minghua; Yang, Pei-Ming; Yang, Peixin; Yang, Qian; Yang, Wannian; Yang, Wei Yuan; Yang, Xuesong; Yang, Yi; Yang, Ying; Yang, Zhifen; Yang, Zhihong; Yao, Meng-Chao; Yao, Pamela J; Yao, Xiaofeng; Yao, Zhenyu; Yao, Zhiyuan; Yasui, Linda S; Ye, Mingxiang; Yedvobnick, Barry; Yeganeh, Behzad; Yeh, Elizabeth S; Yeyati, Patricia L; Yi, Fan; Yi, Long; Yin, Xiao-Ming; Yip, Calvin K; Yoo, Yeong-Min; Yoo, Young Hyun; Yoon, Seung-Yong; Yoshida, Ken-Ichi; Yoshimori, Tamotsu; Young, Ken H; Yu, Huixin; Yu, Jane J; Yu, Jin-Tai; Yu, Jun; Yu, Li; Yu, W Haung; Yu, Xiao-Fang; Yu, Zhengping; Yuan, Junying; Yuan, Zhi-Min; Yue, Beatrice Yjt; Yue, Jianbo; Yue, Zhenyu; Zacks, David N; Zacksenhaus, Eldad; Zaffaroni, Nadia; Zaglia, Tania; Zakeri, Zahra; Zecchini, Vincent; Zeng, Jinsheng; Zeng, Min; Zeng, Qi; Zervos, Antonis S; Zhang, Donna D; Zhang, Fan; Zhang, Guo; Zhang, Guo-Chang; Zhang, Hao; Zhang, Hong; Zhang, Hong; Zhang, Hongbing; Zhang, Jian; Zhang, Jian; Zhang, Jiangwei; Zhang, Jianhua; Zhang, Jing-Pu; Zhang, Li; Zhang, Lin; Zhang, Lin; Zhang, Long; Zhang, Ming-Yong; Zhang, Xiangnan; Zhang, Xu Dong; Zhang, Yan; Zhang, Yang; Zhang, Yanjin; Zhang, Yingmei; Zhang, Yunjiao; Zhao, Mei; Zhao, Wei-Li; Zhao, Xiaonan; Zhao, Yan G; Zhao, Ying; Zhao, Yongchao; Zhao, Yu-Xia; Zhao, Zhendong; Zhao, Zhizhuang J; Zheng, Dexian; Zheng, Xi-Long; Zheng, Xiaoxiang; Zhivotovsky, Boris; Zhong, Qing; Zhou, Guang-Zhou; Zhou, Guofei; Zhou, Huiping; Zhou, Shu-Feng; Zhou, Xu-Jie; Zhu, Hongxin; Zhu, Hua; Zhu, Wei-Guo; Zhu, Wenhua; Zhu, Xiao-Feng; Zhu, Yuhua; Zhuang, Shi-Mei; Zhuang, Xiaohong; Ziparo, Elio; Zois, Christos E; Zoladek, Teresa; Zong, Wei-Xing; Zorzano, Antonio; Zughaier, Susu MItem Open Access Bcl2l1 Deficiency in Osteoblasts Reduces the Trabecular Bone Due to Enhanced Osteoclastogenesis Likely through Osteoblast Apoptosis.(International journal of molecular sciences, 2023-12) Moriishi, Takeshi; Kawai, Yosuke; Fukuyama, Ryo; Matsuo, Yuki; He, You-Wen; Akiyama, Haruhiko; Asahina, Izumi; Komori, ToshihisaBcl2l1 (Bcl-XL) belongs to the Bcl-2 family, Bcl2 and Bcl2-XL are major anti-apoptotic proteins, and the apoptosis of osteoblasts is a key event for bone homeostasis. As the functions of Bcl2l1 in osteoblasts and bone homeostasis remain unclear, we generated osteoblast-specific Bcl2l1-deficient (Bcl2l1fl/flCre) mice using 2.3-kb Col1a1 Cre. Trabecular bone volume and the trabecular number were lower in Bcl2l1fl/flCre mice of both sexes than in Bcl2l1fl/fl mice. In bone histomorphometric analysis, osteoclast parameters were increased in Bcl2l1fl/flCre mice, whereas osteoblast parameters and the bone formation rate were similar to those in Bcl2l1fl/fl mice. TUNEL-positive osteoblastic cells and serum TRAP5b levels were increased in Bcl2l1fl/flCre mice. The deletion of Bcl2l1 in osteoblasts induced Tnfsf11 expression, whereas the overexpression of Bcl-XL had no effect. In a co-culture of Bcl2l1-deficient primary osteoblasts and wild-type bone-marrow-derived monocyte/macrophage lineage cells, the numbers of multinucleated TRAP-positive cells and resorption pits increased. Furthermore, serum deprivation or the deletion of Bcl2l1 in primary osteoblasts increased apoptosis and ATP levels in the medium. Therefore, the reduction in trabecular bone in Bcl2l1fl/flCre mice may be due to enhanced bone resorption through osteoblast apoptosis and the release of ATP from apoptotic osteoblasts, and Bcl2l1 may inhibit bone resorption by preventing osteoblast apoptosis.Item Open Access Impact of HER2-low status for patients with early-stage breast cancer and non-pCR after neoadjuvant chemotherapy: a National Cancer Database Analysis.(Breast cancer research and treatment, 2023-12) Li, Huiyue; Plichta, Jennifer K; Li, Kan; Jin, Yizi; Thomas, Samantha M; Ma, Fei; Tang, Li; Wei, Qingyi; He, You-Wen; Chen, Qichen; Guo, Yuanyuan; Liu, Yueping; Zhang, Jian; Luo, ShengPurpose
To investigate potential differences in pathological complete response (pCR) rates and overall survival (OS) between HER2-low and HER2-zero patients with early-stage hormone receptor (HR)-positive and triple-negative breast cancer (TNBC), in the neoadjuvant chemotherapy setting.Methods
We identified early-stage invasive HER2-negative BC patients who received neoadjuvant chemotherapy diagnosed between 2010 and 2018 in the National Cancer Database. HER2-low was defined by immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, and HER2-zero by IHC0. All the methods were applied separately in the HR-positive and TNBC cohorts. Logistic regression was used to estimate the association of HER2 status with pCR (i.e. ypT0/Tis and ypN0). Kaplan-Meier method and Cox proportional hazards model were applied to estimate the association of HER2 status with OS. Inverse probability weighting and/or multivariable regression were applied to all analyses.Results
For HR-positive patients, 70.9% (n = 17,934) were HER2-low, whereas 51.1% (n = 10,238) of TNBC patients were HER2-low. For both HR-positive and TNBC cohorts, HER2-low status was significantly associated with lower pCR rates [HR-positive: 5.0% vs. 6.7%; weighted odds ratio (OR) = 0.81 (95% CI: 0.72-0.91), p < 0.001; TNBC: 21.6% vs. 24.4%; weighted OR = 0.91 (95% CI: 0.85-0.98), p = 0.007] and improved OS [HR-positive: weighted hazard ratio = 0.85 (95% CI: 0.79-0.91), p < 0.001; TNBC: weighted hazard ratio = 0.91 (95% CI: 0.86-0.96), p < 0.001]. HER2-low status was associated with favorable OS among patients not achieving pCR [HR-positive: adjusted hazard ratio = 0.83 (95% CI: 0.77-0.89), p < 0.001; TNBC: adjusted hazard ratio = 0.88 (95% CI 0.83-0.94), p < 0.001], while no significant difference in OS was observed in patients who achieved pCR [HR-positive: adjusted hazard ratio = 1.00 (95% CI: 0.61-1.63), p > 0.99; TNBC: adjusted hazard ratio = 1.11 (95% CI: 0.85-1.45), p = 0.44].Conclusion
In both early-stage HR-positive and TNBC patients, HER2-low status was associated with lower pCR rates. HER2-zero status might be considered an adverse prognostic factor for OS in patients not achieving pCR.Item Open Access MicroRNA-29 is an essential regulator of brain maturation through regulation of CH methylation.(Cell reports, 2021-04) Swahari, Vijay; Nakamura, Ayumi; Hollville, Emilie; Stroud, Hume; Simon, Jeremy M; Ptacek, Travis S; Beck, Matthew V; Flowers, Cornelius; Guo, Jiami; Plestant, Charlotte; Liang, Jie; Kurtz, C Lisa; Kanke, Matt; Hammond, Scott M; He, You-Wen; Anton, ES; Sethupathy, Praveen; Moy, Sheryl S; Greenberg, Michael E; Deshmukh, MohanishAlthough embryonic brain development and neurodegeneration have received considerable attention, the events that govern postnatal brain maturation are less understood. Here, we identify the miR-29 family to be strikingly induced during the late stages of brain maturation. Brain maturation is associated with a transient, postnatal period of de novo non-CG (CH) DNA methylation mediated by DNMT3A. We examine whether an important function of miR-29 during brain maturation is to restrict the period of CH methylation via its targeting of Dnmt3a. Deletion of miR-29 in the brain, or knockin mutations preventing miR-29 to specifically target Dnmt3a, result in increased DNMT3A expression, higher CH methylation, and repression of genes associated with neuronal activity and neuropsychiatric disorders. These mouse models also develop neurological deficits and premature lethality. Our results identify an essential role for miR-29 in restricting CH methylation in the brain and illustrate the importance of CH methylation regulation for normal brain maturation.Item Open Access Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation.(2010) Jin, CongIn recent years, the incidence of allergic asthma as well as the severity of disease has rapidly increased worldwide. Numerous epidemiological studies have related the exacerbation of allergic asthma with exposure to increased ambient particles from air pollutants. However, the mechanism by which particulate allergens (pAg) exacerbate allergic asthma remains undefined. To evaluate this, we modeled environmental pAg induced allergic asthma by exposing mice to polystyrene beads coated with natural allergen extracts. Compared to equal amounts of soluble allergen extracts (sAg), pAg triggered markedly enhanced airway hyper-responsiveness and pulmonary eosinophilia in allergen sensitized mice. The cellular basis for this effect was determined to be mast cells (MCs), as both airway allergic responses were attenuated in MC deficient KitWsh/KitW-sh mice compared to MC reconstituted KitW-sh/KitW-sh mice. The divergent responses of MCs to pAg versus sAg were due to differences in the termination rate of IgE/FcεRI initiated signaling. Following ligation of sAg, IgE/FcεRI rapidly shuttled into a degradative endosome/lysosome pathway. However, following ligation by pAg, IgE/FcεRI migrated into lipid raft enriched compartments and subsequently failed to follow a degradative pathway, which resulted in a prolonged signaling and heightened synthesis of proinflammatory mediators. These observations highlight the overlooked contributions of the particulate nature of allergens and mast cell endocytic circuitry to the aggravation of allergic asthma.Item Open Access Regulation of myeloid cell survival and homeostasis by c-FLIP(2011) Gordy, Claire LeeMacrophages play vital roles in pathogen clearance, initiation of immune responses, and maintenance of immune homeostasis; however, current understanding of the contributions of macrophages to these processes in vivo has been limited by the reagents and animal models available. Of the many macrophage-deficient mouse models that have been reported, none have specific, long-term loss of distinct macrophage populations, and most develop infections that complicate the study of immune homeostasis. By conditionally deleting the anti-apoptotic protein cellular FLICE-like inhibitory protein (c-FLIP) in myeloid cells, we have generated a novel mouse model that has proven useful in studying both the in vivo functions of macrophages under steady-state conditions and the requirements for macrophage survival at steady-state and during inflammation.
c-FLIPf/f Lysm-Cre mice specifically lack bone marrow macrophages and splenic marginal zone macrophages and develop severe neutrophilia, splenomegaly, extramedullary hematopoiesis, decreased body weight, and increased production of G-CSF and IL-1β, but not IL-17 secondary to the loss of these macrophage populations. c-FLIPf/f Lysm-Cre mice exhibit delayed clearance of circulating neutrophils, suggesting that failure of macrophages to efficiently clear apoptotic neutrophils causes production of cytokines that drive excess granulopoiesis. Further, blocking G-CSF, but not IL-1R signaling in vivo rescues this neutrophilia, suggesting that a G-CSF-dependent, IL-1β-independent pathway plays a role in promoting neutrophil production in mice with defective clearance of apoptotic cells.
Furthermore, using mice expressing only one c-FLIP isoform in myeloid cells (c-FLIPS or c-FLIPL), we have shown that although either isoform is sufficient to promote survival of macrophages under steady-state conditions, both c-FLIPS and c-FLIPL required for macrophage survival during inflammation. In contrast, c-FLIPL is sufficient to promote survival of eosinophils in inflammatory conditions in the absence of c-FLIPS. These data demonstrate distinct requirements for myeloid cell survival in the presence and absence of inflammation and point to a mechanism by which pathogenic organisms may target macrophages to evade the immune response.
Together, these findings demonstrate a critical role for c-FLIP in promoting macrophage survival, which is in turn required for neutrophil homeostasis, and provide an in vivo model system for continuing studies of the non-redundant functions of c-FLIPS and c-FLIPL in myeloid cells during infection and inflammation.
Item Open Access Targeting Tumor-Associated Antigens in Hepatocellular Carcinoma for Immunotherapy: Past Pitfalls and Future Strategies.(Hepatology (Baltimore, Md.), 2020-08-07) Lu, Ligong; Jiang, Jun; Zhan, Meixiao; Zhang, Hui; Wang, Qian-Ting; Sun, Sheng-Nan; Guo, Xiao-Kai; Yin, Hua; Wei, Yadong; Li, Shi-You; Liu, Jun O; Li, Yong; He, You-WenThere are few treatment options for advanced-stage hepatocellular carcinoma (HCC). Targeting tumor-associated antigens (TAAs) for HCC immunotherapy has been tested clinically for many years with limited success. Recent advances in applying mutated tumor-specific neoantigens as immunotherapeutic targets raise hope that this class of antigens may be used in HCC treatment. Accordingly, multiple clinical trials have been initiated to test this concept. However, recent findings demonstrate that mutated neoantigens are rarely detected while unmutated antigens derived from TAAs are represented in the HLA ligandomes of HCC patients, suggesting a requirement to target TAAs for HCC immunotherapy. Herein, we review the potential pitfalls of previous clinical applications of targeting TAAs in HCC immunotherapy. Based on further understanding of the roles of different arms of adaptive immunity in antitumor immunity, we provide a perspective on how to address the unsatisfactory previous immunotherapy attempts in HCC. We propose a new vaccine platform that enhances all three arms of the adaptive immune system to improve TAA-based cancer vaccination in HCC patients. As many solid tumors with low and intermediate mutation burdens have similar TAA and neoantigen expression and presentation patterns, the new vaccine platform is broadly applicable. In conclusion, targeting TAA in HCC for immunotherapy is necessary and new strategies are needed to improve clinical efficacy.Item Open Access The Complement Receptors C3aR and C5aR Are a New Class of Immune Checkpoint Receptor in Cancer Immunotherapy.(Frontiers in Immunology, 2019-01) Wang, Yu; Zhang, Hui; He, You-WenCancer immunotherapy has made remarkable clinical advances in recent years. Antibodies targeting the immune checkpoint receptors PD-1 and CTLA-4 and adoptive cell therapy (ACT) based on ex vivo expanded peripheral CTLs, tumor infiltrating lymphocytes (TILs), gene-engineered TCR- and chimeric antigen receptor (CAR)-T cells have all shown durable clinical efficacies in multiple types of cancers. However, these immunotherapeutic approaches only benefit a small fraction of cancer patients as various immune resistance mechanisms and limitations make their effective use a challenge in the majority of cancer patients. For example, adaptive resistance to therapeutic PD-1 blockade is associated with an upregulation of some additional immune checkpoint receptors. The efficacy of transferred tumor-specific T cells under the current clinical ACT protocol is often limited by their inefficient engraftment, poor persistence, and weak capability to attack tumor cells. Recent studies demonstrate that the complement receptor C3aR and C5aR function as a new class of immune checkpoint receptors. Complement signaling through C3aR and C5aR expressed on effector T lymphocytes prevent the production of the cytokine interleukin-10 (IL-10). Removing C3aR/C5aR-mediated transcriptional suppression of IL-10 expression results in endogenous IL-10 production by antitumor effector T cells, which drives T cell expansion and enhances T cell-mediated antitumor immunity. Importantly, preclinical, and clinical data suggest that a signaling axis consisting of complement/C3aR/C5aR/IL-10 critically regulates T cell mediated antitumor immunity and manipulation of the pathway ex vivo and in vivo is an effective strategy for cancer immunotherapy. Furthermore, a combination of treatment strategies targeting the complement/C3aR/C5aR/IL-10 pathway with other treatment modalities may improve cancer therapeutic efficacy.Item Open Access The Role of Phosphatidylinositol-3 Kinases and Phosphatidylinositol Phosphatases in T Cell Intracellular Homeostasis and Autophagy(2013) McLeod, Ian AlexanderThe homeostasis of naïve T lymphocytes is maintained by several mechanisms involving basal TCR and cytokine signaling, and nutrient factors. One of the common net results of these input signals is the production and stabilization of anti-apoptotic Bcl-2 family members. A second result of these processes is the induction of autophagy, an intracellular, catabolic, lysosomal targeting pathway. Autophagy induction in most systems involves the class III phosphatidylinositol-3 kinase (PI3K), Vps34, to produce phosphatidylinositol-3-phosphate (PI(3)P). To test this in T lymphocytes, I generated mice specifically lacking Vps34 in T cells (Vps34f/fLck-cre mice). However, Vps34-deficient T lymphocytes have normal levels of basal autophagy, and upregulate autophagy normally in response to cytokine or nutrient withdrawal, or TCR stimulation. Therefore I conclude that Vps34 activity is not required for autophagy induction in T lymphocytes. T lymphocytes lacking Vps34 do have enhanced rates of apoptosis, but this is due to defects in intracellular trafficking, specifically of the Interleukin-7 receptor alpha subunit (IL-7Rα). Additionally, multivesicular body (MVB) maturation is impaired in T cells lacking Vps34 such that extracellular ligands are not efficiently targeted to the lysosome.
Autophagy induction in Vps34-deficient T lymphocytes is still sensitive to pan-PI3K inhibitors, such as wortmannin and 3-methyladenine (3MA). Therefore, I hypothesized that other classes of PI3K are necessary to induce autophagy in T lymphocytes through the production of PI(3)P. Autophagy induction is sensitive to specific class I PI3K (PI3KI) inhibitors, such as PIK75. Additionally, T cells lacking the p85 regulatory subunit of PI3KI also have severe defects in T cell receptor (TCR) mediated autophagy induction. PI3KI activity results in the production of PI(3,4,5)P3, though, and not PI(3)P. Because of this specificity, I hypothesize that additional inositol polyphosphatases (Inpp) are required for autophagy induction downstream of PI3KI activity. Indeed, utilizing both inhibitors of pharmacological inhibition and siRNA-mediated knockdown of two classes of phosphatidylinositol phosphatases, inositol polyphosphate-4-phosphatase (Inpp4) and SH2 containing inositol phosphatase (SHIP), had dramatic impacts on autophagy induction. Furthermore, exogenous addition of PI(3,4)P2, a hypothesized intermediate in this pathway, positively regulates autophagy induction and leads to enhanced progression of autophagy. These observations indicate that PI3KI activity, linked to Inpp activity, are necessary and positive regulators of autophagy through the production of PI(3)P.
Item Open Access The Roles of the Bcl-2 Family Proteins in T Lymphocyte Development and Homeostasis(2011) Dunkle, Alexis DeHavenThroughout their development in the thymus and during their maintenance and the immunological response in the periphery, T cells rely on the regulation of classical apoptotic pathways to promote cell survival or death. Several proteins of the Bcl-2 family have been shown to be critical in thymocyte and T cell survival and consequently, in T cell function. Among these proteins, the antiapoptotic proteins Bcl-2 and Mcl-1 are critical for promoting T cell survival at multiple stages of the T cell "life cycle." While these proteins have been reported to interact with several of the proapoptotic members of the Bcl-2 family, the specific interactions by which Mcl-1 in particular promotes T cell survival in vivo were not well understood. Further, how different stimuli (for example, cytokine signaling and T cell activation) modulate the specific functions of Mcl-1 had also not been thoroughly explored.
We utilized mouse models to dissect the roles of Mcl-1 at multiple stages of T cell development and function. We utilized conditional knockout and double knockout strategies to build genetic pathways for Mcl-1 activity during thymocyte development and in peripheral T cells under a variety of conditions. In the thymus, the major role of Mcl-1 is to inhibit the activity of proapoptotic Bak because the loss of Bak, but not the loss of Bax or Bim, rescued the survival of Mcl-1-deficient thymocytes at both the double negative and single positive stages. Further, we concluded that this role is not shared with Bcl-2 because overexpression of Bcl-2 did not rescue DN or SP survival.
In peripheral T cells, the loss of Bak rescued T cell survival in the presence of IL 7, but not during conditions of cytokine withdrawal. Interestingly, the overexpression of Bcl-2 or the loss of Bim partially rescued the survival of T cells during cytokine withdrawal, indicating that Mcl-1 has dual roles in T cells: cytokine-dependent and cytokine independent. Additionally, we found that cytokines of the common gamma chain family have different effects on the activity of Mcl-1 due to the differential regulation of other proteins of the Bcl-2 family, most notably Bim.
Finally, we utilized a Bcl-2 reporter mouse model to examine the role of Bcl-2 in the establishment of CD8+ T cell memory to infection. Although it is known that Bcl-2 is dynamically regulated in response to activation, the importance of this regulation in the establishment of T cell memory is not yet clear. We show that a subset of effector T cells within a previously defined memory precursor population retained high Bcl-2 expression at the peak of the immune response. Using adoptive transfer of sorted effector T cells, we provide preliminary evidence that the cells with memory potential lie within a strict range of Bcl-2 expression. These studies indicate that the regulation of Bcl 2 is likely critical in establishing T cell memory and provide a platform for the future study of the factors that influence T cell memory.