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|  | | | |  | TABLE OF CONTENTS
| July 2015 Volume 47, Issue 7 |  | | |  |  Editorial
Commentary
News and Views
Analysis
Articles
Letters
Technical Report
Corrigendum
| | | | | | | Advertisement | | Presented by Adaptive Biotechnologies, Nature Immunology, Nature Medicine, Nature Biotechnology, and Nature Genetics
IMMUNE PROFILING IN HEALTH AND DISEASE
September 9-11, 2015 | Seattle, WA, USA
REGISTER NOW! |  | | | | | | Editorial |  Top | |  | | No impact without data access p691
doi:10.1038/ng.3351
A considerable proportion of the usefulness and interest of research publications in our field comes from the data and associated metadata. We therefore insist that data be available for peer reviewers to see and readers to use. Authors should use public permanent repositories designed for appropriately consented data.
| | Commentary | Top | | | | The European Genome-phenome Archive of human data consented for biomedical research OPEN pp692 - 695
Ilkka Lappalainen, Jeff Almeida-King, Vasudev Kumanduri, Alexander Senf, John Dylan Spalding, Saif ur-Rehman, Gary Saunders, Jag Kandasamy, Mario Caccamo, Rasko Leinonen, Brendan Vaughan, Thomas Laurent, Francis Rowland, Pablo Marin-Garcia, Jonathan Barker, Petteri Jokinen, Angel Carreño Torres, Jordi Rambla de Argila, Oscar Martinez Llobet, Ignacio Medina, Marc Sitges Puy, Mario Alberich, Sabela de la Torre, Arcadi Navarro, Justin Paschall & Paul Flicek
doi:10.1038/ng.3312
Paul Flicek and colleagues provide an update on the European Genome-phenome Archive (EGA), a service of the European Bioinformatics Institute (EMBL-EBI) and the Center for Genome Regulation (CRG). The authors describe the EGA policies and infrastructure, how access decisions are made, methods for data submission and future plans for expansion of this database.
| | News and Views | Top | | | | Double trouble in human aneuploidy pp696 - 698
Miguel A Brieño-Enríquez & Paula E Cohen
doi:10.1038/ng.3344
Crossing over, or reciprocal recombination, is essential for accurate segregation of homologous chromosomes at the first meiotic division, resulting in gametes containing the correct chromosome number. A new study in human oocytes analyzes the genome-wide recombination and segregation patterns in all the products of female meiosis, providing experimental support for existing theories about the origin of human aneuploidies and highlighting a novel reverse segregation mechanism of chromosome segregation during meiosis.
See also: Article by Ottolini et al. | | | | Sweet size control in tomato pp698 - 699
Andrew Fleming
doi:10.1038/ng.3345
All cells of an adult plant are ultimately derived from divisions that occur in small groups of cells distributed throughout the plant, termed meristems. A new study shows that carbohydrate post-translational modification of a peptide signal influences meristem and, as a consequence, fruit size in tomato.
See also: Article by Xu et al. | | | | Lipid transport and human brain development pp699 - 701
Christer Betsholtz
doi:10.1038/ng.3348
How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma.
See also: Letter by Guemez-Gamboa et al. | Letter by Alakbarzade et al. | | | | |
| | Analysis | Top | | | | Meta-analysis of the heritability of human traits based on fifty years of twin studies pp702 - 709
Tinca J C Polderman, Beben Benyamin, Christiaan A de Leeuw, Patrick F Sullivan, Arjen van Bochoven, Peter M Visscher & Danielle Posthuma
doi:10.1038/ng.3285
Danielle Posthuma, Peter Visscher and colleagues report a meta-analysis of 17,804 traits based on virtually all twin studies from the last 50 years. For a majority of traits, twin resemblance seems solely due to additive genetic variation and lacks evidence for a substantial influence of shared environment or non-additive genetic variation.
| | | | Recurrent somatic mutations in regulatory regions of human cancer genomes pp710 - 716
Collin Melton, Jason A Reuter, Damek V Spacek & Michael Snyder
doi:10.1038/ng.3332
Michael Snyder and colleagues analyze whole-genome sequencing data from eight cancer subtypes and identify recurrent mutations in regulatory regions. They find evidence for positive selection of mutations in transcription factor binding sites near cancer-related genes.
| | Articles | Top | | | | Factors influencing success of clinical genome sequencing across a broad spectrum of disorders pp717 - 726
Jenny C Taylor, Hilary C Martin, Stefano Lise, John Broxholme, Jean-Baptiste Cazier, Andy Rimmer, Alexander Kanapin, Gerton Lunter, Simon Fiddy, Chris Allan, A Radu Aricescu, Moustafa Attar, Christian Babbs, Jennifer Becq, David Beeson, Celeste Bento, Patricia Bignell, Edward Blair, Veronica J Buckle, Katherine Bull, Ondrej Cais, Holger Cario, Helen Chapel, Richard R Copley, Richard Cornall, Jude Craft, Karin Dahan, Emma E Davenport, Calliope Dendrou, Olivier Devuyst, Aimée L Fenwick, Jonathan Flint, Lars Fugger, Rodney D Gilbert, Anne Goriely, Angie Green, Ingo H Greger, Russell Grocock, Anja V Gruszczyk, Robert Hastings, Edouard Hatton, Doug Higgs, Adrian Hill, Chris Holmes, Malcolm Howard, Linda Hughes, Peter Humburg, David Johnson, Fredrik Karpe, Zoya Kingsbury, Usha Kini, Julian C Knight, Jonathan Krohn, Sarah Lamble, Craig Langman, Lorne Lonie, Joshua Luck, Davis McCarthy, Simon J McGowan, Mary Frances McMullin, Kerry A Miller, Lisa Murray, Andrea H Németh, M Andrew Nesbit, David Nutt, Elizabeth Ormondroyd, Annette Bang Oturai, Alistair Pagnamenta, Smita Y Patel, Melanie Percy, Nayia Petousi, Paolo Piazza, Sian E Piret, Guadalupe Polanco-Echeverry, Niko Popitsch, Fiona Powrie, Chris Pugh, Lynn Quek, Peter A Robbins, Kathryn Robson, Alexandra Russo, Natasha Sahgal, Pauline A van Schouwenburg, Anna Schuh, Earl Silverman, Alison Simmons, Per Soelberg Sørensen, Elizabeth Sweeney, John Taylor, Rajesh V Thakker, Ian Tomlinson, Amy Trebes, Stephen R F Twigg, Holm H Uhlig, Paresh Vyas, Tim Vyse, Steven A Wall, Hugh Watkins, Michael P Whyte, Lorna Witty, Ben Wright, Chris Yau, David Buck, Sean Humphray, Peter J Ratcliffe, John I Bell, Andrew O M Wilkie, David Bentley, Peter Donnelly & Gilean McVean
doi:10.1038/ng.3304
Gilean McVean and colleagues report the results of a large-scale clinical genome sequencing project spanning a broad spectrum of disorders. They identify factors influencing successful genetic diagnosis and highlight the challenges of interpreting findings for genetically heterogeneous disorders.
| | | | Genome-wide maps of recombination and chromosome segregation in human oocytes and embryos show selection for maternal recombination rates pp727 - 735
Christian S Ottolini, Louise J Newnham, Antonio Capalbo, Senthilkumar A Natesan, Hrishikesh A Joshi, Danilo Cimadomo, Darren K Griffin, Karen Sage, Michael C Summers, Alan R Thornhill, Elizabeth Housworth, Alex D Herbert, Laura Rienzi, Filippo M Ubaldi, Alan H Handyside & Eva R Hoffmann
doi:10.1038/ng.3306
Eva Hoffman, Alan Handyside and colleagues generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female human meioses. They detect a reverse chromosome segregation pattern and selection for higher recombination rates in the female germ line and report chromosomal drive against non-recombinant chromatids at meiosis II.
See also: News and Views by Brieno-Enriquez & Cohen | | | | Spatial genomic heterogeneity within localized, multifocal prostate cancer pp736 - 745
Paul C Boutros, Michael Fraser, Nicholas J Harding, Richard de Borja, Dominique Trudel, Emilie Lalonde, Alice Meng, Pablo H Hennings-Yeomans, Andrew McPherson, Veronica Y Sabelnykova, Amin Zia, Natalie S Fox, Julie Livingstone, Yu-Jia Shiah, Jianxin Wang, Timothy A Beck, Cherry L Have, Taryne Chong, Michelle Sam, Jeremy Johns, Lee Timms, Nicholas Buchner, Ada Wong, John D Watson, Trent T Simmons, Christine P'ng, Gaetano Zafarana, Francis Nguyen, Xuemei Luo, Kenneth C Chu, Stephenie D Prokopec, Jenna Sykes, Alan Dal Pra, Alejandro Berlin, Andrew Brown, Michelle A Chan-Seng-Yue, Fouad Yousif, Robert E Denroche, Lauren C Chong, Gregory M Chen, Esther Jung, Clement Fung, Maud H W Starmans, Hanbo Chen, Shaylan K Govind, James Hawley, Alister D'Costa, Melania Pintilie, Daryl Waggott, Faraz Hach, Philippe Lambin, Lakshmi B Muthuswamy, Colin Cooper, Rosalind Eeles, David Neal, Bernard Tetu, Cenk Sahinalp, Lincoln D Stein, Neil Fleshner, Sohrab P Shah, Colin C Collins, Thomas J Hudson, John D McPherson, Theodorus van der Kwast & Robert G Bristow
doi:10.1038/ng.3315
Paul Boutros, Robert Bristow and colleagues report a molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer. They find that multifocal tumors are highly heterogeneous, and they identify a novel recurrent amplification of MYCL1.
| | | | Whole-genome fingerprint of the DNA methylome during human B cell differentiation pp746 - 756
Marta Kulis, Angelika Merkel, Simon Heath, Ana C Queirós, Ronald P Schuyler, Giancarlo Castellano, Renée Beekman, Emanuele Raineri, Anna Esteve, Guillem Clot, Néria Verdaguer-Dot, Martí Duran-Ferrer, Nuria Russiñol, Roser Vilarrasa-Blasi, Simone Ecker, Vera Pancaldi, Daniel Rico, Lidia Agueda, Julie Blanc, David Richardson, Laura Clarke, Avik Datta, Marien Pascual, Xabier Agirre, Felipe Prosper, Diego Alignani, Bruno Paiva, Gersende Caron, Thierry Fest, Marcus O Muench, Marina E Fomin, Seung-Tae Lee, Joseph L Wiemels, Alfonso Valencia, Marta Gut, Paul Flicek, Hendrik G Stunnenberg, Reiner Siebert, Ralf Küppers, Ivo G Gut, Elías Campo & José I Martín-Subero
doi:10.1038/ng.3291
Jose Martin-Subero and colleagues report the whole-genome bisulfite sequencing of ten blood cell subpopulations representing the cellular stages during B cell differentiation. They find that early stages are characterized by enhancer demethylation and that neoplasms derived from B cell lineages undergo methylation changes in regions with dynamic methylation during normal differentiation.
| | | | Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia pp757 - 765
Susanne Kohl, Ditta Zobor, Wei-Chieh Chiang, Nicole Weisschuh, Jennifer Staller, Irene Gonzalez Menendez, Stanley Chang, Susanne C Beck, Marina Garcia Garrido, Vithiyanjali Sothilingam, Mathias W Seeliger, Franco Stanzial, Francesco Benedicenti, Francesca Inzana, Elise Héon, Ajoy Vincent, Jill Beis, Tim M Strom, Günther Rudolph, Susanne Roosing, Anneke I den Hollander, Frans P M Cremers, Irma Lopez, Huanan Ren, Anthony T Moore, Andrew R Webster, Michel Michaelides, Robert K Koenekoop, Eberhart Zrenner, Randal J Kaufman, Stephen H Tsang, Bernd Wissinger & Jonathan H Lin
doi:10.1038/ng.3319
Susanne Kohl and colleagues report mutations in ATF6, a regulator of the unfolded protein response pathway, that cause a familial form of achromatopsia. Their results indicate a role for ATF6 in foveal development rather than a direct role in the cone phototransduction pathway.
| | | | An allelic series of miR-17∼92-mutant mice uncovers functional specialization and cooperation among members of a microRNA polycistron pp766 - 775
Yoon-Chi Han, Joana A Vidigal, Ping Mu, Evelyn Yao, Irtisha Singh, Alvaro J González, Carla P Concepcion, Ciro Bonetti, Paul Ogrodowski, Brett Carver, Licia Selleri, Doron Betel, Christina Leslie & Andrea Ventura
doi:10.1038/ng.3321
Andrea Ventura and colleagues characterize an allelic series of genetically engineered mice harboring targeted deletions of individual members of the miR-17~92 cluster. They find evidence of functional cooperation and specialization among members of this cluster and show that the miR-17 seed family influences axial patterning.
| | | | Trbp regulates heart function through microRNA-mediated Sox6 repression pp776 - 783
Jian Ding, Jinghai Chen, Yanqun Wang, Masaharu Kataoka, Lixin Ma, Pingzhu Zhou, Xiaoyun Hu, Zhiqiang Lin, Mao Nie, Zhong-Liang Deng, William T Pu & Da-Zhi Wang
doi:10.1038/ng.3324
Da-Zhi Wang and colleagues knock out Trbp in mouse cardiomyocytes in vivo and investigate its requirement for normal heart function. They find that Trbp is necessary for the biogenesis of miR-208a, which targets and represses Sox6.
| | | | A cascade of arabinosyltransferases controls shoot meristem size in tomato pp784 - 792
Cao Xu, Katie L Liberatore, Cora A MacAlister, Zejun Huang, Yi-Hsuan Chu, Ke Jiang, Christopher Brooks, Mari Ogawa-Ohnishi, Guangyan Xiong, Markus Pauly, Joyce Van Eck, Yoshikatsu Matsubayashi, Esther van der Knaap & Zachary B Lippman
doi:10.1038/ng.3309
Zachary Lippman and colleagues report mutations in the tomato ortholog of CLV1 and a gene encoding a hydroxyproline O-arabinosyltransferase enzyme that modifies CLV3, both of which cause fasciated flowers and fruits owing to increased meristem size. They also find that a natural mutation in CLV3 was a major target of selection during tomato domestication.
See also: News and Views by Fleming | | Letters | Top | | | | Common variants at 10p12.31, 10q21.1 and 13q12.13 are associated with sporadic pituitary adenoma pp793 - 797
Zhao Ye, Zhiqiang Li, Yongfei Wang, Ying Mao, Ming Shen, Qilin Zhang, Shiqi Li, Liangfu Zhou, Xuefei Shou, Jianhua Chen, Zhijian Song, Zengyi Ma, Zhaoyun Zhang, Yiming Li, Hongying Ye, Chuanxin Huang, Tao Wang, Wenqiang He, Yichao Zhang, Rong Xie, Nidan Qiao, Huijia Qiu, Shan Huang, Meng Wang, Jiawei Shen, Zujia Wen, Wenjin Li, Ke Liu, Juan Zhou, Lin Wang, Jue Ji, Yin Wang, Hong Chen, Haixia Cheng, Zhifeng Shi, Yuqian Zhu, Daoying Geng, Zhenwei Yao, Weijun Tang, Bin Lu, Li Pan, Yi Zhang, Weimin Bao, Jinsong Wu, Kang Zheng, Yongyong Shi & Yao Zhao
doi:10.1038/ng.3322
Yao Zhao, Yongyong Shi and colleagues performed a genome-wide association study on sporadic pituitary adenoma in the Han Chinese population. They identify three new susceptibility loci.
| | | | Construction of a population-specific HLA imputation reference panel and its application to Graves' disease risk in Japanese pp798 - 802
Yukinori Okada, Yukihide Momozawa, Kyota Ashikawa, Masahiro Kanai, Koichi Matsuda, Yoichiro Kamatani, Atsushi Takahashi & Michiaki Kubo
doi:10.1038/ng.3310
Yukinori Okada, Michiaki Kubo and colleagues report the construction of a new HLA imputation reference panel for the Japanese population. They apply this resource to analyze the association of the HLA region with Graves' disease and find that variants in multiple class I and class II HLA genes contribute independently to disease risk.
| | | | Transcriptional regulator PRDM12 is essential for human pain perception pp803 - 808
Ya-Chun Chen, Michaela Auer-Grumbach, Shinya Matsukawa, Manuela Zitzelsberger, Andreas C Themistocleous, Tim M Strom, Chrysanthi Samara, Adrian W Moore, Lily Ting-Yin Cho, Gareth T Young, Caecilia Weiss, Maria Schabhüttl, Rolf Stucka, Annina B Schmid, Yesim Parman, Luitgard Graul-Neumann, Wolfram Heinritz, Eberhard Passarge, Rosemarie M Watson, Jens Michael Hertz, Ute Moog, Manuela Baumgartner, Enza Maria Valente, Diego Pereira, Carlos M Restrepo, Istvan Katona, Marina Dusl, Claudia Stendel, Thomas Wieland, Fay Stafford, Frank Reimann, Katja von Au, Christian Finke, Patrick J Willems, Michael S Nahorski, Samiha S Shaikh, Ofélia P Carvalho, Adeline K Nicholas, Gulshan Karbani, Maeve A McAleer, Maria Roberta Cilio, John C McHugh, Sinead M Murphy, Alan D Irvine, Uffe Birk Jensen, Reinhard Windhager, Joachim Weis, Carsten Bergmann, Bernd Rautenstrauss, Jonathan Baets, Peter De Jonghe, Mary M Reilly, Regina Kropatsch, Ingo Kurth, Roman Chrast, Tatsuo Michiue, David L H Bennett, C Geoffrey Woods & Jan Senderek
doi:10.1038/ng.3308
Geoffrey Woods, Jan Senderek and colleagues show that biallelic mutations in PRDM12 cause congenital insensitivity to pain. They further show that PRDM12 is expressed in nociceptors and their progenitors and participates in sensory neuron development in Xenopus.
| | | | Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome pp809 - 813
Alicia Guemez-Gamboa, Long N Nguyen, Hongbo Yang, Maha S Zaki, Majdi Kara, Tawfeg Ben-Omran, Naiara Akizu, Rasim Ozgur Rosti, Basak Rosti, Eric Scott, Jana Schroth, Brett Copeland, Keith K Vaux, Amaury Cazenave-Gassiot, Debra Q Y Quek, Bernice H Wong, Bryan C Tan, Markus R Wenk, Murat Gunel, Stacey Gabriel, Neil C Chi, David L Silver & Joseph G Gleeson
doi:10.1038/ng.3311
Joseph Gleeson, David Silver and colleagues show that inactivating mutations in MFSD2A, which encodes an essential transporter of long-chain fatty acids in brain, cause a lethal microcephaly syndrome. These results establish a link between the activity of this transporter and human brain growth.
See also: News and Views by Betsholtz | | | | A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome pp814 - 817
Vafa Alakbarzade, Abdul Hameed, Debra Q Y Quek, Barry A Chioza, Emma L Baple, Amaury Cazenave-Gassiot, Long N Nguyen, Markus R Wenk, Arshia Q Ahmad, Ajith Sreekantan-Nair, Michael N Weedon, Phil Rich, Michael A Patton, Thomas T Warner, David L Silver & Andrew H Crosby
doi:10.1038/ng.3313
Andrew Crosby, David Silver and colleagues show that a partially inactivating mutation in MFSD2A causes a non-lethal microcephaly syndrome with symptoms that include intellectual disability, spasticity and absent speech. Their findings indicate an essential role for lysophosphatidylcholine uptake in human brain development and function.
See also: News and Views by Betsholtz | | | | CTCF/cohesin-binding sites are frequently mutated in cancer pp818 - 821
Riku Katainen, Kashyap Dave, Esa Pitkänen, Kimmo Palin, Teemu Kivioja, Niko Välimäki, Alexandra E Gylfe, Heikki Ristolainen, Ulrika A Hänninen, Tatiana Cajuso, Johanna Kondelin, Tomas Tanskanen, Jukka-Pekka Mecklin, Heikki Järvinen, Laura Renkonen-Sinisalo, Anna Lepistö, Eevi Kaasinen, Outi Kilpivaara, Sari Tuupanen, Martin Enge, Jussi Taipale & Lauri A Aaltonen
doi:10.1038/ng.3335
Lauri Aaltonen, Jussi Taipale and colleagues report frequent mutation of CTCF- and cohesin-binding sites (CBSs) in multiple cancer types. They find that the frequency of CBS mutations in microsatellite-stable colorectal cancer is 1.5 times higher than that of other known cancer mutational targets.
| | | | Genome-wide patterns and properties of de novo mutations in humans pp822 - 826
Laurent C Francioli, Paz P Polak, Amnon Koren, Androniki Menelaou, Sung Chun, Ivo Renkens, Genome of the Netherlands Consortium, Cornelia M van Duijn, Morris Swertz, Cisca Wijmenga, Gertjan van Ommen, P Eline Slagboom, Dorret I Boomsma, Kai Ye, Victor Guryev, Peter F Arndt, Wigard P Kloosterman, Paul I W de Bakker & Shamil R Sunyaev
doi:10.1038/ng.3292
Shamil Sunyaev, Paul de Bakker and colleagues report an analysis of 11,020 de novo mutations from the whole-genome sequences of Dutch families sequenced as part of the Genome of the Netherlands project. They identify correlations related to paternal age and genic content and develop an empirical human mutation rate map.
| | | | Natural alleles of a proteasome α subunit gene contribute to thermotolerance and adaptation of African rice pp827 - 833
Xin-Min Li, Dai-Yin Chao, Yuan Wu, Xuehui Huang, Ke Chen, Long-Gang Cui, Lei Su, Wang-Wei Ye, Hao Chen, Hua-Chang Chen, Nai-Qian Dong, Tao Guo, Min Shi, Qi Feng, Peng Zhang, Bin Han, Jun-Xiang Shan, Ji-Ping Gao & Hong-Xuan Lin
doi:10.1038/ng.3305
Hong-Xuan Lin, Ji-Ping Gao, Jun-Xiang Shan and colleagues show that natural variation in a proteasome α subunit gene contributes to thermotolerance in African rice. Their follow-up studies suggest that the variant allele protects cells from heat stress by enhancing the elimination of cytotoxic denatured proteins and maintaining heat-response processes.
| | | | Variation in NRT1.1B contributes to nitrate-use divergence between rice subspecies pp834 - 838
Bin Hu, Wei Wang, Shujun Ou, Jiuyou Tang, Hua Li, Ronghui Che, Zhihua Zhang, Xuyang Chai, Hongru Wang, Yiqin Wang, Chengzhen Liang, Linchuan Liu, Zhongze Piao, Qiyun Deng, Kun Deng, Chi Xu, Yan Liang, Lianhe Zhang, Legong Li & Chengcai Chu
doi:10.1038/ng.3337
Chengcai Chu and colleagues show that genetic variation in NRT1.1B/OsNPF6.5 contributes to nitrate-use divergence between two main subspecies of Asian cultivated rice. Their findings may help to improve nitrogen-use efficiency in plant production.
| | Technical Report | Top | | | | Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls pp839 - 846
Mary D Fortune, Hui Guo, Oliver Burren, Ellen Schofield, Neil M Walker, Maria Ban, Stephen J Sawcer, John Bowes, Jane Worthington, Anne Barton, Steve Eyre, John A Todd & Chris Wallace
doi:10.1038/ng.3330
Mary Fortune, Chris Wallace and colleagues report a new method that allows statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls. They apply their method to type 1 diabetes, rheumatoid arthritis, celiac disease and multiple sclerosis and highlight the complexity in genetic variation underlying these distinct autoimmune diseases.
| | Corrigendum | Top | | | | Corrigendum: Induction, suppression and requirement of RNA silencing pathways in virulent Agrobacterium tumefaciens infections p847
Patrice Dunoyer, Christophe Himber & Olivier Voinnet
doi:10.1038/ng0715-847
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