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Development and evaluation of an automated atlas-based data analysis method for dynamic microPET mouse brain studies [Meeting Abstract]

Mikheev, A; Logan, J; Baron, M; Malik, N; Mendoza, S; Tuchman, D; Rajamohamed, S; Hameetha, B; Herline, K; Sigurdsson, E M; Wisniewski, T; Fieremans, E; Rusinek, H; Ding, Y -S
Objectives: MicroPET imaging has been increasingly performed on mouse models for a variety of human CNS disorders. Despite high demand, digital mouse brain atlases based on PET are still lacking. Further, most microPET systems do not provide means of mapping mouse brain with atlas. For quantitative data analysis and accurate anatomical localization, the development and evaluation of an automated atlas-based data analysis on microPET mouse brain studies is presented. Methods: MicroPET imaging studies were performed after injection of F-18 labeled Amyvid (a tracer for imaging amyloid (Aa) plaques) in isoflurane-anesthetized adult mice using Inveon PET/CT (Siemens). The list mode dynamic PET data were collected for 30-60 min and rebinned using a Fourier rebinning algorithm. A CT scan was also performed for attenuation correction and anatomical co-registration. A 3D digital magnetic resonance microscopy (MRM)-based volume of interest (VOI) atlas generated from live C57BL/6J adult mouse brain was used for brain mapping (Ma et al., 2008). Landmarks, including left and right centroids of midears and eyes (4 landmarks), were generated on atlas template and individual mouse CT images. Co-registration of atlas, CT and PET was performed using Firevoxel (FVX) (https://urldefense.proofpoint.com/v2/url?u=https- 3A__wp.nyu.edu_Firevoxel&d=DgIBAg&c=j5oPpO0eBH1iio48DtsedbOBGmuw5jHLjgvtN2r4ehE&r=KRXe NoRy5_8lkSwAJG5vjS1yT0aFSItfe494dmkdSVs&m=B4bFtJccWjUzJ- dbK1qURkxJmihDqjf87yIgZlYKTMk&s=soyp2V3_QGPs--q8qXcfkDHjv7kMngxeekpEknOQoi8&e= ) and time-activity curves (TAC) for 20 specific 3D brain regions were generated. For comparison, an expert in mouse neuroanatomy manually drew corresponding VOIs on PET-CT co-registered images derived from IRW (Inveon data analysis software without atlas). The TACs thus generated via both methods were compared. For further evaluation, the tracer uptake and kinetics in both tau and Aa transgenic mouse models were also compared. Results: Using FVX, single step co-registration of atlas, CT and PET was accomplished in seconds (by one-button pressing) and the TACs for specific ROIs of mouse brain were automatically generated after co-registration. In contrast, it took an average of 15 min to manually draw a single VOI (total 5 hours/mouse for 20 VOIs) directly on CT images using Inveon IRW without an atlas, a process that required an expert in mouse neuroanatomy. Overall, the TACs for the corresponding VOIs derived from IRW and FVX were similar in counts and shapes. Most importantly, this VOI atlas-based method can provide unbiased measures of radioactivity concentration from PET studies. The results from studies of tau vs. Aa transgenic mouse models after injection of Amyvid showed an apparent difference in the tracer uptake and kinetics (Fig. 1). Conclusions: We have demonstrated the feasibility to map mouse brain with an automated atlas-based co-registration for data analysis of microPET brain studies using FVX. This novel time-saving data analysis methodology, unachievable with current microPET imaging systems, will facilitate accurate assessment and spatial localization of brain signals in mouse model studies for a variety of human CNS disorders
EMBASE:613981705
ISSN: 1860-2002
CID: 2415632

Affinity of Tau antibodies for solubilized pathological Tau species but not their immunogen or insoluble Tau aggregates predicts in vivo and ex vivo efficacy

Congdon, Erin E; Lin, Yan; Rajamohamedsait, Hameetha B; Shamir, Dov B; Krishnaswamy, Senthilkumar; Rajamohamedsait, Wajitha J; Rasool, Suhail; Gonzalez, Veronica; Levenga, Josien; Gu, Jiaping; Hoeffer, Charles; Sigurdsson, Einar M
BACKGROUND: A few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures. RESULTS: Surprisingly, we here show that one antibody, 4E6, which has low affinity for most forms of tau acutely improved cognition and reduced soluble phospho-tau, whereas another antibody, 6B2, which has high affinity for various tau species was ineffective. Concurrently, we confirmed and clarified these efficacy differences in an ex vivo model of tauopathy. Alzheimer's paired helical filaments (PHF) were toxic to the neurons and increased tau levels in remaining neurons. Both toxicity and tau seeding were prevented by 4E6 but not by 6B2. Furthermore, 4E6 reduced PHF spreading between neurons. Interestingly, 4E6's efficacy relates to its high affinity binding to solubilized PHF, whereas the ineffective 6B2 binds mainly to aggregated PHF. Blocking 4E6's uptake into neurons prevented its protective effects if the antibody was administered after PHF had been internalized. When 4E6 and PHF were administered at the same time, the antibody was protective extracellularly. CONCLUSIONS: Overall, these findings indicate that high antibody affinity for solubilized PHF predicts efficacy, and that acute antibody-mediated improvement in cognition relates to clearance of soluble phospho-tau. Importantly, both intra- and extracellular clearance pathways are in play. Together, these results have major implications for understanding the pathogenesis of tauopathies and for development of immunotherapies.
PMCID:5006503
PMID: 27578006
ISSN: 1750-1326
CID: 2232012

Sex and Immunogen-Specific Benefits of Immunotherapy Targeting Islet Amyloid Polypeptide in Transgenic and Wild-Type Mice

Krishnamurthy, Pavan K; Rajamohamedsait, Hameetha B; Gonzalez, Veronica; Rajamohamedsait, Wajitha J; Ahmed, Nawal; Krishnaswamy, Senthilkumar; Sigurdsson, Einar M
Type 2 diabetes mellitus is characterized by the deposition of islet amyloid polypeptide (IAPP) as amyloid in islets, a process thought to be toxic to beta-cells. To determine the feasibility of targeting these aggregates therapeutically, we vaccinated transgenic (Tg) mice that overexpress human IAPP and were fed a high-fat diet to promote their diabetic phenotype. Our findings indicate that prophylactic vaccination with IAPP and its derivative IAPP7-19-TT, protects wild-type female mice, but not males, from obesity-induced early mortality, and the derivative showed a strong trend for prolonging the lifespan of Tg females but not males. Furthermore, IAPP7-19-TT-immunized Tg females cleared a glucose bolus more efficiently than controls, while IAPP-immunized Tg females showed an impaired ability to clear a glucose bolus compared to their adjuvant injected Tg controls. Interestingly, IAPP or IAPP7-19-TT treatments had no effect on glucose clearance in Tg males. Overall, these beneficial effects of IAPP targeted immunization depend on Tg status, sex, and immunogen. Hence, future studies in this field should carefully consider these variables that clearly affect the therapeutic outcome. In conclusion, IAPP targeting immunotherapy may have benefits in patients with type 2 diabetes.
PMCID:4907063
PMID: 27379014
ISSN: 1664-2392
CID: 2175782

Internalization of tau antibody and pathological tau protein detected with a flow cytometry multiplexing approach

Shamir, Dov B; Rosenqvist, Nina; Rasool, Suhail; Pedersen, Jan T; Sigurdsson, Einar M
INTRODUCTION: Tau immunotherapy has emerged as a promising approach to clear tau aggregates from the brain. Our previous findings suggest that tau antibodies may act outside and within neurons to promote such clearance. METHODS: We have developed an approach using flow cytometry, a human neuroblastoma cell model overexpressing tau with the P301L mutation, and paired helical filament (PHF)-enriched pathologic tau to effectively screen uptake and retention of tau antibodies in conjunction with PHF. RESULTS: The flow cytometry approach correlates well with Western blot analysis to detect internalized antibodies in naive and transfected SH-SY5Y cells (r2 = 0.958, and r2 = 0.968, P = .021 and P = .016, respectively). In transfected cells, more antibodies are taken up/retained as pathologic tau load increases, both under co-treated conditions and when the cells are pretreated with PHF before antibody administration (r2 = 0.999 and r2 = 0.999, P = .013 and P = .011, respectively). DISCUSSION: This approach allows rapid in vitro screening of antibody uptake and retention in conjunction with pathologic tau protein before more detailed studies in animals or other more complex model systems.
PMCID:5383206
PMID: 27016263
ISSN: 1552-5279
CID: 2052302

Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory

Fa, M; Puzzo, D; Piacentini, R; Staniszewski, A; Zhang, H; Baltrons, M A; Li Puma, D D; Chatterjee, I; Li, J; Saeed, F; Berman, H L; Ripoli, C; Gulisano, W; Gonzalez, J; Tian, H; Costa, J A; Lopez, P; Davidowitz, E; Yu, W H; Haroutunian, V; Brown, L M; Palmeri, A; Sigurdsson, E M; Duff, K E; Teich, A F; Honig, L S; Sierks, M; Moe, J G; D'Adamio, L; Grassi, C; Kanaan, N M; Fraser, P E; Arancio, O
Non-fibrillar soluble oligomeric forms of amyloid-beta peptide (oAbeta) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAbeta initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Abeta, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAbeta levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAbeta to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Abeta on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Abeta and tau pathology.
PMCID:4726138
PMID: 26786552
ISSN: 2045-2322
CID: 1921462

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) [Guideline]

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; Algul, Hana; Alirezaei, Mehrdad; Alloza, Iraide; Almasan, Alexandru; Almonte-Beceril, Maylin; Alnemri, Emad S; Alonso, Covadonga; Altan-Bonnet, Nihal; Altieri, Dario C; 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; Banhegyi, Gabor; Bao, Haijun; Barbeau, Benoit; Barrachina, Maria D; Barreiro, Esther; Bartel, Bonnie; Bartolome, Alberto; Bassham, Diane C; Bassi, Maria Teresa; Bast, Robert C Jr; Basu, Alakananda; Batista, Maria Teresa; Batoko, Henri; Battino, Maurizio; Bauckman, Kyle; Baumgarner, Bradley L; Bayer, K Ulrich; Beale, Rupert; Beaulieu, Jean-Francois; Beck, George R Jr; Becker, Christoph; Beckham, J David; Bedard, Pierre-Andre; Bednarski, Patrick J; Begley, Thomas J; Behl, Christian; Behrends, Christian; Behrens, Georg Mn; Behrns, Kevin E; Bejarano, Eloy; Belaid, Amine; Belleudi, Francesca; Benard, Giovanni; Berchem, Guy; Bergamaschi, Daniele; Bergami, Matteo; Berkhout, Ben; Berliocchi, Laura; Bernard, Amelie; Bernard, Monique; Bernassola, Francesca; Bertolotti, Anne; Bess, Amanda S; Besteiro, Sebastien; 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; Bockler, Stefan; Boes, Marianne; Boesze-Battaglia, Kathleen; Boise, Lawrence H; Bolino, Alessandra; Boman, Andrea; Bonaldo, Paolo; Bordi, Matteo; Bosch, Jurgen; Botana, Luis M; Botti, Joelle; Bou, German; Bouche, Marina; Bouchecareilh, Marion; Boucher, Marie-Josee; Boulton, Michael E; Bouret, Sebastien G; Boya, Patricia; Boyer-Guittaut, Michael; Bozhkov, Peter V; Brady, Nathan; Braga, Vania Mm; Brancolini, Claudio; Braus, Gerhard H; Bravo-San Pedro, Jose M; Brennan, Lisa A; Bresnick, Emery H; Brest, Patrick; Bridges, Dave; Bringer, Marie-Agnes; 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; Butikofer, 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; Cena, Valentin; 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; Claria, Joan; Clarke, Peter Gh; Clarke, Robert; Clementi, Emilio; Cleyrat, Cedric; Cnop, Miriam; Coccia, Eliana M; Cocco, Tiziana; Codogno, Patrice; Coers, Jorn; Cohen, Ezra Ew; Colecchia, David; Coletto, Luisa; Coll, Nuria 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; Davila, 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, Jose; 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, Regis; Delbridge, Lea Md; Deldicque, Louise; Delorme-Axford, Elizabeth; Deng, Yizhen; Dengjel, Joern; Denizot, Melanie; Dent, Paul; Der, Channing J; Deretic, Vojo; Derrien, Benoit; 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; Diaz-Araya, Guillermo; Diaz-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, Jorg 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 Jr; Doran, Kelly S; D'Orazi, Gabriella; Dorn, Gerald W 2nd; Dosenko, Victor; Dridi, Sami; Drucker, Liat; Du, Jie; Du, Li-Lin; Du, Lihuan; du Toit, Andre; Dua, Priyamvada; Duan, Lei; Duann, Pu; Dubey, Vikash Kumar; Duchen, Michael R; Duchosal, Michel A; Duez, Helene; Dugail, Isabelle; Dumit, Veronica I; Duncan, Mara C; Dunlop, Elaine A; Dunn, William A Jr; Dupont, Nicolas; Dupuis, Luc; Duran, Raul V; Durcan, Thomas M; Duvezin-Caubet, Stephane; 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-Martinez, Lorena; Evans, Thomas J; Fabri, Mario; Fabrias, Gemma; Fabrizi, Cinzia; Facchiano, Antonio; Faergeman, 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; Fernandez, Alvaro F; Fernandez-Barrena, Maite G; Fernandez-Checa, Jose C; Fernandez-Lopez, Arsenio; Fernandez-Zapico, Martin E; Feron, Olivier; Ferraro, Elisabetta; Ferreira-Halder, Carmen Verissima; 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; Francois, Aurelie; Frankel, Lisa B; Fraser, Iain Dc; Frey, Norbert; Freyssenet, Damien G; Frezza, Christian; Friedman, Scott L; Frigo, Daniel E; Fu, Dongxu; Fuentes, Jose 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; Gannage, Monique; Gao, Fen-Biao; Gao, Feng; Gao, Jian-Xin; Garcia Nannig, Lorena; Garcia Vescovi, Eleonora; Garcia-Macia, Marina; Garcia-Ruiz, Carmen; Garg, Abhishek D; Garg, Pramod Kumar; Gargini, Ricardo; Gassen, Nils Christian; Gatica, Damian; 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 Jr; Gokulan, Kuppan; Goldman, Gustavo H; Goletti, Delia; Goligorsky, Michael S; Gomes, Aldrin V; Gomes, Ligia C; Gomez, Hernando; Gomez-Manzano, Candelaria; Gomez-Sanchez, Ruben; Goncalves, Dawit Ap; Goncu, Ebru; Gong, Qingqiu; Gongora, Celine; Gonzalez, Carlos B; Gonzalez-Alegre, Pedro; Gonzalez-Cabo, Pilar; Gonzalez-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, Frederic; Grose, Charles; Groulx, Jean-Francois; Gruber, Florian; Grumati, Paolo; Grune, Tilman; Guan, Jun-Lin; Guan, Kun-Liang; Guerra, Barbara; Guillen, Carlos; Gulshan, Kailash; Gunst, Jan; Guo, Chuanyong; Guo, Lei; Guo, Ming; Guo, Wenjie; Guo, Xu-Guang; Gust, Andrea A; Gustafsson, Asa 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; Hebert, Marie-Josee; Heinzen, Robert A; Helgason, Gudmundur Vignir; Hensel, Michael; Henske, Elizabeth P; Her, Chengtao; Herman, Paul K; Hernandez, Agustin; Hernandez, Carlos; Hernandez-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; Hoglinger, Gunter U; Hohfeld, Jorg; 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, Jose M; Izumi, Yotaro; Izzo, Valentina; Jaattela, 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; Jimenez, 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; Juhasz, Gabor; 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; Kagedal, 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; Knaevelsrud, Helene; Knecht, Erwin; Knuppertz, Laura; Ko, Jiunn-Liang; Kobayashi, Satoru; Koch, Jan C; Koechlin-Ramonatxo, Christelle; Koenig, Ulrich; Koh, Young Ho; Kohler, 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; Kovacs, Attila L; Kovacs, Tibor; Kovacs, Werner J; Koya, Daisuke; Kraft, Claudine; Krainc, Dimitri; Kramer, Helmut; 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, Herve; 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, Stephane 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, Gerard; Ljujic, Mila; Lodhi, Irfan J; Logue, Susan E; Lokeshwar, Bal L; Long, Yun Chau; Lonial, Sagar; Loos, Benjamin; Lopez-Otin, Carlos; Lopez-Vicario, Cristina; Lorente, Mar; Lorenzi, Philip L; Lorincz, Peter; Los, Marek; Lotze, Michael T; Lovat, Penny E; Lu, Binfeng; Lu, Bo; Lu, Jiahong; Lu, Qing; Lu, She-Min; Lu, Shuyan; Lu, Yingying; Luciano, Frederic; 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; Magarinos, 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; Manie, 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; Marino, Guillermo; Markovic, Ivanka; Marquez, Rebecca; Martelli, Alberto M; Martens, Sascha; Martin, Katie R; Martin, Seamus J; Martin, Shaun; Martin-Acebes, Miguel A; Martin-Sanz, Paloma; Martinand-Mari, Camille; Martinet, Wim; Martinez, Jennifer; Martinez-Lopez, Nuria; Martinez-Outschoorn, Ubaldo; Martinez-Velazquez, Moises; 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; Melendez, 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-Rios, 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; Moller, 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; Munoz-Moreno, Raquel; Munoz-Pinedo, Cristina; Munz, 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, Peter; 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; Notomi, Shoji; Notterpek, Lucia; Nowikovsky, Karin; Nukina, Nobuyuki; Nurnberger, Thorsten; O'Donnell, Valerie B; O'Donovan, Tracey; O'Dwyer, Peter J; Oehme, Ina; Oeste, Clara L; Ogawa, Michinaga; Ogretmen, Besim; Ogura, Yuji; Oh, Young J; Ohmuraya, Masaki; Ohshima, Takayuki; Ojha, Rani; Okamoto, Koji; Okazaki, Toshiro; Oliver, F Javier; Ollinger, Karin; Olsson, Stefan; Orban, Daniel P; Ordonez, Paulina; Orhon, Idil; Orosz, Laszlo; O'Rourke, Eyleen J; Orozco, Helena; Ortega, Angel L; Ortona, Elena; Osellame, Laura D; Oshima, Junko; Oshima, Shigeru; Osiewacz, Heinz D; Otomo, Takanobu; Otsu, Kinya; Ou, Jing-Hsiung James; Outeiro, Tiago F; Ouyang, Dong-Yun; Ouyang, Hongjiao; Overholtzer, Michael; Ozbun, Michelle A; Ozdinler, P Hande; Ozpolat, Bulent; Pacelli, Consiglia; Paganetti, Paolo; Page, Guylene; Pages, Gilles; Pagnini, Ugo; Pajak, Beata; Pak, Stephen C; Pakos-Zebrucka, Karolina; Pakpour, Nazzy; Palkova, Zdena; Palladino, Francesca; Pallauf, Kathrin; Pallet, Nicolas; Palmieri, Marta; Paludan, Soren 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; Pavenstadt, Hermann; Pavone, Flaminia; Pedrozo, Zully; Pena, Fernando J; Penalva, Miguel A; Pende, Mario; Peng, Jianxin; Penna, Fabio; Penninger, Josef M; Pensalfini, Anna; Pepe, Salvatore; Pereira, Gustavo Js; Pereira, Paulo C; Perez-de la Cruz, Veronica; Perez-Perez, Maria Esther; Perez-Rodriguez, Diego; Perez-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, Valerie; Pietrocola, Federico; Pimentel-Muinos, 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; Poggeler, Stefanie; Poirot, Marc; Polcic, 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; 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Sishi, Balindiwe Jn; Sittler, Annie; Siu, Parco M; Sivridis, Efthimios; Skwarska, Anna; Slack, Ruth; Slaninova, 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 Joao; 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, Stephan T; Stevens, Craig; Stockwell, Brent R; Stoka, Veronika; Storchova, Zuzana; Stork, Bjorn; Stratoulias, Vassilis; Stravopodis, Dimitrios J; Strnad, Pavel; Strohecker, Anne Marie; Strom, 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; Sward, 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; Takats, 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; Thome, 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; Uzcategui, Nestor L; Vaccari, Thomas; Vaccaro, Maria I; Vachova, Libuse; 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; 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PMCID:4835977
PMID: 26799652
ISSN: 1554-8635
CID: 1922322

Tau Immunotherapy

Sigurdsson, Einar M
In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-beta (Abeta) pathology, greater clinical efficacy may be achieved by clearing tau than Abeta aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects.
PMCID:4777344
PMID: 26551002
ISSN: 1660-2862
CID: 1834672

Tau immunotherapy for Alzheimer's disease

Pedersen, Jan Torleif; Sigurdsson, Einar M
Targeting pathological tau protein in Alzheimer's disease (AD) and related tauopathies has shown great potential in animal models. Given that tau lesions correlate better with the degree of dementia than do amyloid-beta (Abeta) plaques, their clearance may be clinically more efficacious than removing Abeta when cognitive deficits become evident in AD. Several complementary mechanisms of antibody-mediated removal of tau aggregates are likely to act in concert and the importance of each one may depend on antibody properties, the disease, and its stage. Clinical trials of tau immunotherapy are already underway and several more are likely to be initiated in the near future.
PMID: 25846560
ISSN: 1471-499x
CID: 1644542

Specific Amyloid beta Clearance by a Catalytic Antibody Construct

Planque, Stephanie A; Nishiyama, Yasuhiro; Sonoda, Sari; Lin, Yan; Taguchi, Hiroaki; Hara, Mariko; Kolodziej, Steven; Mitsuda, Yukie; Gonzalez, Veronica; Sait, Hameetha B R; Fukuchi, Ken-Ichiro; Massey, Richard J; Friedland, Robert P; O'Nuallain, Brian; Sigurdsson, Einar M; Paul, Sudhir
Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid beta (Abeta)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Abeta C terminus noncovalently and hydrolyzed Abeta rapidly, with no reactivity to the Abeta precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive Abeta dipeptide unit. The catabody dissolved preformed Abeta aggregates and inhibited Abeta aggregation more potently than an Abeta-binding IgG. Intravenous catabody treatment reduced brain Abeta deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific Abeta hydrolysis appears to be an innate immune function that could be applied for therapeutic Abeta removal.
PMCID:4400338
PMID: 25724648
ISSN: 1083-351x
CID: 1544012

Antibody-derived in vivo imaging of tau pathology

Krishnaswamy, Senthilkumar; Lin, Yan; Rajamohamedsait, Wajitha J; Rajamohamedsait, Hameetha B; Krishnamurthy, Pavan; Sigurdsson, Einar M
Antibodies or their derivatives as imaging probes for pathological tau protein have great potential, but have not been well studied. In particular, smaller, single-chain-variable antibody fragments (scFv's) are attractive for detecting tau lesions in live subjects. Here, we generated libraries of scFv's and identified numerous phospho-tau-selective scFv's. Peripheral injection of one of these scFv's consistently resulted in a strong in vivo brain signal in transgenic tauopathy mice, but not in wild-type or amyloid-beta plaque mice. The parent tau antibody provided similar results, albeit with a weaker signal intensity. The imaging signal correlated very well with colocalization of the probe with intraneuronal tau aggregates. Both were associated with markers of endosomes, autophagosomes, and lysosomes, suggesting their interaction in these degradation pathways. Such specific antibody-derived imaging probes have great potential as diagnostic markers for Alzheimer's disease and related tauopathies.
PMCID:4261104
PMID: 25505335
ISSN: 0270-6474
CID: 1424802