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  • GRID-seq reveals the global RNA–chromatin interactome
    Nat. Biotechnol. (IF 41.667) Pub Date : 
    Xiao Li, Bing Zhou, Liang Chen, Lan-Tao Gou, Hairi Li, Xiang-Dong Fu

    Higher eukaryotic genomes are bound by a large number of coding and non-coding RNAs, but approaches to comprehensively map the identity and binding sites of these RNAs are lacking. Here we report a method to capture in situ global RNA interactions with DNA by deep sequencing (GRID-seq), which enables the comprehensive identification of the entire repertoire of chromatin-interacting RNAs and their respective binding sites. In human, mouse, and Drosophila cells, we detected a large set of tissue-specific coding and non-coding RNAs that are bound to active promoters and enhancers, especially super-enhancers. Assuming that most mRNA–chromatin interactions indicate the physical proximity of a promoter and an enhancer, we constructed a three-dimensional global connectivity map of promoters and enhancers, revealing transcription-activity-linked genomic interactions in the nucleus.

    更新日期:2017-09-19
  • Pearl millet genome sequence provides a resource to improve agronomic traits in arid environments
    Nat. Biotechnol. (IF 41.667) Pub Date : 
    Rajeev K Varshney, Chengcheng Shi, Mahendar Thudi, Cedric Mariac, Jason Wallace, Peng Qi, He Zhang, Yusheng Zhao, Xiyin Wang, Abhishek Rathore, Rakesh K Srivastava, Annapurna Chitikineni, Guangyi Fan, Prasad Bajaj, Somashekhar Punnuri, S K Gupta, Hao Wang, Yong Jiang, Marie Couderc, Mohan A V S K Katta, Dev R Paudel, K D Mungra, Wenbin Chen, Karen R Harris-Shultz, Vanika Garg, Neetin Desai, Dadakhalandar Doddamani, Ndjido Ardo Kane, Joann A Conner, Arindam Ghatak, Palak Chaturvedi, Sabarinath Subramaniam, Om Parkash Yadav, Cécile Berthouly-Salazar, Falalou Hamidou, Jianping Wang, Xinming Liang, Jérémy Clotault, Hari D Upadhyaya, Philippe Cubry, Bénédicte Rhoné, Mame Codou Gueye, Ramanjulu Sunkar, Christian Dupuy, Francesca Sparvoli, Shifeng Cheng, R S Mahala, Bharat Singh, Rattan S Yadav, Eric Lyons, Swapan K Datta, C Tom Hash, Katrien M Devos, Edward Buckler, Jeffrey L Bennetzen, Andrew H Paterson, Peggy Ozias-Akins, Stefania Grando, Jun Wang, Trilochan Mohapatra, Wolfram We..

    Pearl millet [Cenchrus americanus (L.) Morrone] is a staple food for more than 90 million farmers in arid and semi-arid regions of sub-Saharan Africa, India and South Asia. We report the ~1.79 Gb draft whole genome sequence of reference genotype Tift 23D2B1-P1-P5, which contains an estimated 38,579 genes. We highlight the substantial enrichment for wax biosynthesis genes, which may contribute to heat and drought tolerance in this crop. We resequenced and analyzed 994 pearl millet lines, enabling insights into population structure, genetic diversity and domestication. We use these resequencing data to establish marker trait associations for genomic selection, to define heterotic pools, and to predict hybrid performance. We believe that these resources should empower researchers and breeders to improve this important staple crop.

    更新日期:2017-09-19
  • Shotgun metagenomics, from sampling to analysis
    Nat. Biotechnol. (IF 41.667) Pub Date : 
    Christopher Quince, Alan W Walker, Jared T Simpson, Nicholas J Loman, Nicola Segata

    Diverse microbial communities of bacteria, archaea, viruses and single-celled eukaryotes have crucial roles in the environment and in human health. However, microbes are frequently difficult to culture in the laboratory, which can confound cataloging of members and understanding of how communities function. High-throughput sequencing technologies and a suite of computational pipelines have been combined into shotgun metagenomics methods that have transformed microbiology. Still, computational approaches to overcome the challenges that affect both assembly-based and mapping-based metagenomic profiling, particularly of high-complexity samples or environments containing organisms with limited similarity to sequenced genomes, are needed. Understanding the functions and characterizing specific strains of these communities offers biotechnological promise in therapeutic discovery and innovative ways to synthesize products using microbial factories and can pinpoint the contributions of microorganisms to planetary, animal and human health.

    更新日期:2017-09-14
  • Blood feud erupts over Roche's bispecific antibody for hemophilia
    Nat. Biotechnol. (IF 41.667) Pub Date : 
    Elie Dolgin

    Blood feud erupts over Roche's bispecific antibody for hemophilia Nature Biotechnology, Published online: 11 September 2017; doi:10.1038/nbt0917-803

    更新日期:2017-09-14
  • Single-cell deep phenotyping of IgG-secreting cells for high-resolution immune monitoring
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11
    Klaus Eyer, Raphaël C L Doineau, Carlos E Castrillon, Luis Briseño-Roa, Vera Menrath, Guillaume Mottet, Patrick England, Alexei Godina, Elodie Brient-Litzler, Clément Nizak, Allan Jensen, Andrew D Griffiths, Jérôme Bibette, Pierre Bruhns, Jean Baudry

    Single-cell deep phenotyping of IgG-secreting cells for high-resolution immune monitoring Nature Biotechnology, Published online: 11 September 2017; doi:10.1038/nbt.3964 An in-droplet immunoassay enables determination of the rate and affinity of secreted antigen-specific antibodies at the single-cell level.

    更新日期:2017-09-14
  • Challenges in the gene therapy commercial ecosystem
    Nat. Biotechnol. (IF 41.667) Pub Date : 
    Rahul Kapoor, Thomas Klueter, James M Wilson

    Challenges in the gene therapy commercial ecosystem Nature Biotechnology, Published online: 11 September 2017; doi:10.1038/nbt.3931

    更新日期:2017-09-14
  • Adenosine checkpoint agent blazes a trail, joins immunotherapy roster
    Nat. Biotechnol. (IF 41.667) Pub Date : 
    Ken Garber

    Adenosine checkpoint agent blazes a trail, joins immunotherapy roster Nature Biotechnology, Published online: 11 September 2017; doi:10.1038/nbt0917-805

    更新日期:2017-09-14
  • Analysis of somatic microsatellite indels identifies driver events in human tumors
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11
    Yosef E Maruvka, Kent W Mouw, Rosa Karlic, Prasanna Parasuraman, Atanas Kamburov, Paz Polak, Nicholas J Haradhvala, Julian M Hess, Esther Rheinbay, Yehuda Brody, Amnon Koren, Lior Z Braunstein, Alan D'Andrea, Michael S Lawrence, Adam Bass, Andre Bernards, Franziska Michor, Gad Getz

    Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).

    更新日期:2017-09-14
  • Recent patents related to clinical applications of sequencing
    Nat. Biotechnol. (IF 41.667) Pub Date : 

    Recent patents related to clinical applications of sequencing Nature Biotechnology, Published online: 11 September 2017; doi:10.1038/nbt.3970

    更新日期:2017-09-14
  • Vertex CF data wow Wall Street
    Nat. Biotechnol. (IF 41.667) Pub Date : 

    Vertex CF data wow Wall Street Nature Biotechnology, Published online: 11 September 2017; doi:10.1038/nbt0917-807

    更新日期:2017-09-14
  • Buying time for transplants
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11

    Funders need to pay more attention to research aimed at increasing the shelf life of human organs. Doing so could pay dividends for both transplantation and basic research.

    更新日期:2017-09-12
  • After Myriad, what makes a gene patent claim 'markedly different' from nature?
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11
    Mateo Aboy, Johnathon Liddicoat, Kathleen Liddell, Matthew Jordan, Cristina Crespo

    Examining the types of claim amendments that have transformed isolated gene claims from patent-ineligible into eligible subject matter provides clarity into the threshold of eligibility for gene-related patents.

    更新日期:2017-09-12
  • Tagging activated neurons with light
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11
    Dheeraj S Roy, Teruhiro Okuyama, Susumu Tonegawa

    Two new protein tools translate neuronal activity into gene expression during a light-defined time window.

    更新日期:2017-09-12
  • Interpreting the T-cell receptor repertoire
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11
    Robert A Holt

    T cell receptor sequence motifs can predict T cell antigen specificity.

    更新日期:2017-09-12
  • Shotgun metagenomics, from sampling to analysis
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-12
    Christopher Quince, Alan W Walker, Jared T Simpson, Nicholas J Loman, Nicola Segata

    Diverse microbial communities of bacteria, archaea, viruses and single-celled eukaryotes have crucial roles in the environment and in human health. However, microbes are frequently difficult to culture in the laboratory, which can confound cataloging of members and understanding of how communities function. High-throughput sequencing technologies and a suite of computational pipelines have been combined into shotgun metagenomics methods that have transformed microbiology. Still, computational approaches to overcome the challenges that affect both assembly-based and mapping-based metagenomic profiling, particularly of high-complexity samples or environments containing organisms with limited similarity to sequenced genomes, are needed. Understanding the functions and characterizing specific strains of these communities offers biotechnological promise in therapeutic discovery and innovative ways to synthesize products using microbial factories and can pinpoint the contributions of microorganisms to planetary, animal and human health.

    更新日期:2017-09-12
  • Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-21
    Naoki Iwamoto, David C D Butler, Nenad Svrzikapa, Susovan Mohapatra, Ivan Zlatev, Dinah W Y Sah, Meena, Stephany M Standley, Genliang Lu, Luciano H Apponi, Maria Frank-Kamenetsky, Jason Jingxin Zhang, Chandra Vargeese, Gregory L Verdine

    Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeric mixtures containing as many as a half million components persist in antisense oligonucleotide (ASO) therapeutics because it has been feasible neither to separate the individual stereoisomers, nor to synthesize stereochemically pure ASOs. Here we report the development of a scalable synthetic process that yields therapeutic ASOs having high stereochemical and chemical purity. Using this method, we synthesized rationally designed stereopure components of mipomersen, a drug comprising 524,288 stereoisomers. We demonstrate that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. We report that Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug. Further, we elucidated a triplet stereochemical code in the stereopure ASOs, 3′-SpSpRp, that promotes target RNA cleavage by RNase H1 in vitro and provides a more durable response in mice than stereorandom ASOs.

    更新日期:2017-09-12
  • Haplotype phasing of whole human genomes using bead-based barcode partitioning in a single tube
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-06-26
    Fan Zhang, Lena Christiansen, Jerushah Thomas, Dmitry Pokholok, Ros Jackson, Natalie Morrell, Yannan Zhao, Melissa Wiley, Emily Welch, Erich Jaeger, Ana Granat, Steven J Norberg, Aaron Halpern, Maria C Rogert, Mostafa Ronaghi, Jay Shendure, Niall Gormley, Kevin L Gunderson, Frank J Steemers

    Haplotype information for whole genomes is rapidly generated with a single-tube method.

    更新日期:2017-09-12
  • A calcium- and light-gated switch to induce gene expression in activated neurons
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-06-26
    Dongmin Lee, Jung Ho Hyun, Kanghoon Jung, Patrick Hannan, Hyung-Bae Kwon

    Gene expression is controlled in activated neurons in the mouse brain using a two-component optogenetic system.

    更新日期:2017-09-12
  • A light- and calcium-gated transcription factor for imaging and manipulating activated neurons
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-06-26
    Wenjing Wang, Craig P Wildes, Tanyaporn Pattarabanjird, Mateo I Sanchez, Gordon F Glober, Gillian A Matthews, Kay M Tye, Alice Y Ting

    Activity remodels neurons, altering their molecular, structural, and electrical characteristics. To enable the selective characterization and manipulation of these neurons, we present FLARE, an engineered transcription factor that drives expression of fluorescent proteins, opsins, and other genetically encoded tools only in the subset of neurons that experienced activity during a user-defined time window. FLARE senses the coincidence of elevated cytosolic calcium and externally applied blue light, which together produce translocation of a membrane-anchored transcription factor to the nucleus to drive expression of any transgene. In cultured rat neurons, FLARE gives a light-to-dark signal ratio of 120 and a high- to low-calcium signal ratio of 10 after 10 min of stimulation. Opsin expression permitted functional manipulation of FLARE-marked neurons. In adult mice, FLARE also gave light- and motor-activity-dependent transcription in the cortex. Due to its modular design, minute-scale temporal resolution, and minimal dark-state leak, FLARE should be useful for the study of activity-dependent processes in neurons and other cells that signal with calcium.

    更新日期:2017-09-12
  • An integrated expression atlas of miRNAs and their promoters in human and mouse
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-21
    Derek de Rie, Imad Abugessaisa, Tanvir Alam, Erik Arner, Peter Arner, Haitham Ashoor, Gaby Åström, Magda Babina, Nicolas Bertin, A Maxwell Burroughs, Ailsa J Carlisle, Carsten O Daub, Michael Detmar, Ruslan Deviatiiarov, Alexandre Fort, Claudia Gebhard, Daniel Goldowitz, Sven Guhl, Thomas J Ha, Jayson Harshbarger, Akira Hasegawa, Kosuke Hashimoto, Meenhard Herlyn, Peter Heutink, Kelly J Hitchens, Chung Chau Hon, Edward Huang, Yuri Ishizu, Chieko Kai, Takeya Kasukawa, Peter Klinken, Timo Lassmann, Charles-Henri Lecellier, Weonju Lee, Marina Lizio, Vsevolod Makeev, Anthony Mathelier, Yulia A Medvedeva, Niklas Mejhert, Christopher J Mungall, Shohei Noma, Mitsuhiro Ohshima, Mariko Okada-Hatakeyama, Helena Persson, Patrizia Rizzu, Filip Roudnicky, Pål Sætrom, Hiroki Sato, Jessica Severin, Jay W Shin, Rolf K Swoboda, Hiroshi Tarui, Hiroo Toyoda, Kristoffer Vitting-Seerup, Louise Winteringham, Yoko Yamaguchi, Kayoko Yasuzawa, Misako Yoneda, Noriko Yumoto, Susan Zabierowski, Peter G ..

    MicroRNAs (miRNAs) are short non-coding RNAs with key roles in cellular regulation. As part of the fifth edition of the Functional Annotation of Mammalian Genome (FANTOM5) project, we created an integrated expression atlas of miRNAs and their promoters by deep-sequencing 492 short RNA (sRNA) libraries, with matching Cap Analysis Gene Expression (CAGE) data, from 396 human and 47 mouse RNA samples. Promoters were identified for 1,357 human and 804 mouse miRNAs and showed strong sequence conservation between species. We also found that primary and mature miRNA expression levels were correlated, allowing us to use the primary miRNA measurements as a proxy for mature miRNA levels in a total of 1,829 human and 1,029 mouse CAGE libraries. We thus provide a broad atlas of miRNA expression and promoters in primary mammalian cells, establishing a foundation for detailed analysis of miRNA expression patterns and transcriptional control regions.

    更新日期:2017-09-12
  • An atlas of B-cell clonal distribution in the human body
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-21
    Wenzhao Meng, Bochao Zhang, Gregory W Schwartz, Aaron M Rosenfeld, Daqiu Ren, Joseph J C Thome, Dustin J Carpenter, Nobuhide Matsuoka, Harvey Lerner, Amy L Friedman, Tomer Granot, Donna L Farber, Mark J Shlomchik, Uri Hershberg, Eline T Luning Prak

    B-cell responses result in clonal expansion, and can occur in a variety of tissues. To define how B-cell clones are distributed in the body, we sequenced 933,427 B-cell clonal lineages and mapped them to eight different anatomic compartments in six human organ donors. We show that large B-cell clones partition into two broad networks—one spans the blood, bone marrow, spleen and lung, while the other is restricted to tissues within the gastrointestinal (GI) tract (jejunum, ileum and colon). Notably, GI tract clones display extensive sharing of sequence variants among different portions of the tract and have higher frequencies of somatic hypermutation, suggesting extensive and serial rounds of clonal expansion and selection. Our findings provide an anatomic atlas of B-cell clonal lineages, their properties and tissue connections. This resource serves as a foundation for studies of tissue-based immunity, including vaccine responses, infections, autoimmunity and cancer.

    更新日期:2017-09-12
  • What faculty hiring committees want
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11
    Charles B Wright, Nathan L Vanderford

    PhD trainees aspiring to become faculty need to know the credentials search committees value most in an applicant.

    更新日期:2017-09-12
  • Replacing reprogramming factors with antibodies selected from combinatorial antibody libraries
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11
    Joel W Blanchard, Jia Xie, Nadja El-Mecharrafie, Simon Gross, Sohyon Lee, Richard A Lerner, Kristin K Baldwin

    The reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) is usually achieved by exogenous induction of transcription by factors acting in the nucleus. In contrast, during development, signaling pathways initiated at the membrane induce differentiation. The central idea of this study is to identify antibodies that can catalyze cellular de-differentiation and nuclear reprogramming by acting at the cell surface. We screen a lentiviral library encoding ~100 million secreted and membrane-bound single-chain antibodies and identify antibodies that can replace either Sox2 and Myc (c-Myc) or Oct4 during reprogramming of mouse embryonic fibroblasts into iPSCs. We show that one Sox2-replacing antibody antagonizes the membrane-associated protein Basp1, thereby de-repressing nuclear factors WT1, Esrrb and Lin28a (Lin28) independent of Sox2. By manipulating this pathway, we identify three methods to generate iPSCs. Our results establish unbiased selection from autocrine combinatorial antibody libraries as a robust method to discover new biologics and uncover membrane-to-nucleus signaling pathways that regulate pluripotency and cell fate.

    更新日期:2017-09-11
  • Detection of dysregulated protein-association networks by high-throughput proteomics predicts cancer vulnerabilities
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11
    John D Lapek, Patricia Greninger, Robert Morris, Arnaud Amzallag, Iulian Pruteanu-Malinici, Cyril H Benes, Wilhelm Haas

    Multiplexed mass spectrometry analysis of breast cancer cell lines uncovers co-regulation of protein abundance that predicts the vulnerabilities of different cancers to drugs.

    更新日期:2017-09-11
  • Mapping the secrets of the antibody pool
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-09-11
    Jonathan R McDaniel, Gregory C Ippolito, George Georgiou

    The progression of antibody-mediated immunity can now be monitored at high-throughput on a single-cell level.

    更新日期:2017-09-11
  • A calcium- and light-gated switch to induce gene expression in activated neurons
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-06-26
    Dongmin Lee, Jung Ho Hyun, Kanghoon Jung, Patrick Hannan, Hyung-Bae Kwon

    Gene expression is controlled in activated neurons in the mouse brain using a two-component optogenetic system.

    更新日期:2017-09-04
  • A light- and calcium-gated transcription factor for imaging and manipulating activated neurons
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-06-26
    Wenjing Wang, Craig P Wildes, Tanyaporn Pattarabanjird, Mateo I Sanchez, Gordon F Glober, Gillian A Matthews, Kay M Tye, Alice Y Ting

    Activity remodels neurons, altering their molecular, structural, and electrical characteristics. To enable the selective characterization and manipulation of these neurons, we present FLARE, an engineered transcription factor that drives expression of fluorescent proteins, opsins, and other genetically encoded tools only in the subset of neurons that experienced activity during a user-defined time window. FLARE senses the coincidence of elevated cytosolic calcium and externally applied blue light, which together produce translocation of a membrane-anchored transcription factor to the nucleus to drive expression of any transgene. In cultured rat neurons, FLARE gives a light-to-dark signal ratio of 120 and a high- to low-calcium signal ratio of 10 after 10 min of stimulation. Opsin expression permitted functional manipulation of FLARE-marked neurons. In adult mice, FLARE also gave light- and motor-activity-dependent transcription in the cortex. Due to its modular design, minute-scale temporal resolution, and minimal dark-state leak, FLARE should be useful for the study of activity-dependent processes in neurons and other cells that signal with calcium.

    更新日期:2017-09-04
  • Haplotype phasing of whole human genomes using bead-based barcode partitioning in a single tube
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-06-26
    Fan Zhang, Lena Christiansen, Jerushah Thomas, Dmitry Pokholok, Ros Jackson, Natalie Morrell, Yannan Zhao, Melissa Wiley, Emily Welch, Erich Jaeger, Ana Granat, Steven J Norberg, Aaron Halpern, Maria C Rogert, Mostafa Ronaghi, Jay Shendure, Niall Gormley, Kevin L Gunderson, Frank J Steemers

    Haplotype information for whole genomes is rapidly generated with a single-tube method.

    更新日期:2017-09-04
  • Multiplexed quantification of proteins and transcripts in single cells
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-30
    Vanessa M Peterson, Kelvin Xi Zhang, Namit Kumar, Jerelyn Wong, Lixia Li, Douglas C Wilson, Renee Moore, Terrill K McClanahan, Svetlana Sadekova, Joel A Klappenbach

    We present a tool to measure gene and protein expression levels in single cells with DNA-labeled antibodies and droplet microfluidics. Using the RNA expression and protein sequencing assay (REAP-seq), we quantified proteins with 82 barcoded antibodies and >20,000 genes in a single workflow. We used REAP-seq to assess the costimulatory effects of a CD27 agonist on human CD8+ lymphocytes and to identify and characterize an unknown cell type.

    更新日期:2017-09-04
  • An integrated expression atlas of miRNAs and their promoters in human and mouse
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-21
    Derek de Rie, Imad Abugessaisa, Tanvir Alam, Erik Arner, Peter Arner, Haitham Ashoor, Gaby Åström, Magda Babina, Nicolas Bertin, A Maxwell Burroughs, Ailsa J Carlisle, Carsten O Daub, Michael Detmar, Ruslan Deviatiiarov, Alexandre Fort, Claudia Gebhard, Daniel Goldowitz, Sven Guhl, Thomas J Ha, Jayson Harshbarger, Akira Hasegawa, Kosuke Hashimoto, Meenhard Herlyn, Peter Heutink, Kelly J Hitchens, Chung Chau Hon, Edward Huang, Yuri Ishizu, Chieko Kai, Takeya Kasukawa, Peter Klinken, Timo Lassmann, Charles-Henri Lecellier, Weonju Lee, Marina Lizio, Vsevolod Makeev, Anthony Mathelier, Yulia A Medvedeva, Niklas Mejhert, Christopher J Mungall, Shohei Noma, Mitsuhiro Ohshima, Mariko Okada-Hatakeyama, Helena Persson, Patrizia Rizzu, Filip Roudnicky, Pål Sætrom, Hiroki Sato, Jessica Severin, Jay W Shin, Rolf K Swoboda, Hiroshi Tarui, Hiroo Toyoda, Kristoffer Vitting-Seerup, Louise Winteringham, Yoko Yamaguchi, Kayoko Yasuzawa, Misako Yoneda, Noriko Yumoto, Susan Zabierowski, Peter G ..

    MicroRNAs (miRNAs) are short non-coding RNAs with key roles in cellular regulation. As part of the fifth edition of the Functional Annotation of Mammalian Genome (FANTOM5) project, we created an integrated expression atlas of miRNAs and their promoters by deep-sequencing 492 short RNA (sRNA) libraries, with matching Cap Analysis Gene Expression (CAGE) data, from 396 human and 47 mouse RNA samples. Promoters were identified for 1,357 human and 804 mouse miRNAs and showed strong sequence conservation between species. We also found that primary and mature miRNA expression levels were correlated, allowing us to use the primary miRNA measurements as a proxy for mature miRNA levels in a total of 1,829 human and 1,029 mouse CAGE libraries. We thus provide a broad atlas of miRNA expression and promoters in primary mammalian cells, establishing a foundation for detailed analysis of miRNA expression patterns and transcriptional control regions.

    更新日期:2017-09-04
  • An atlas of B-cell clonal distribution in the human body
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-21
    Wenzhao Meng, Bochao Zhang, Gregory W Schwartz, Aaron M Rosenfeld, Daqiu Ren, Joseph J C Thome, Dustin J Carpenter, Nobuhide Matsuoka, Harvey Lerner, Amy L Friedman, Tomer Granot, Donna L Farber, Mark J Shlomchik, Uri Hershberg, Eline T Luning Prak

    B-cell responses result in clonal expansion, and can occur in a variety of tissues. To define how B-cell clones are distributed in the body, we sequenced 933,427 B-cell clonal lineages and mapped them to eight different anatomic compartments in six human organ donors. We show that large B-cell clones partition into two broad networks—one spans the blood, bone marrow, spleen and lung, while the other is restricted to tissues within the gastrointestinal (GI) tract (jejunum, ileum and colon). Notably, GI tract clones display extensive sharing of sequence variants among different portions of the tract and have higher frequencies of somatic hypermutation, suggesting extensive and serial rounds of clonal expansion and selection. Our findings provide an anatomic atlas of B-cell clonal lineages, their properties and tissue connections. This resource serves as a foundation for studies of tissue-based immunity, including vaccine responses, infections, autoimmunity and cancer.

    更新日期:2017-09-04
  • Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-21
    Naoki Iwamoto, David C D Butler, Nenad Svrzikapa, Susovan Mohapatra, Ivan Zlatev, Dinah W Y Sah, Stephany M Standley, Genliang Lu, Luciano H Apponi, Maria Frank-Kamenetsky, Jason Jingxin Zhang, Chandra Vargeese, Gregory L Verdine

    Whereas stereochemical purity in drugs has become the standard for small molecules, stereoisomeric mixtures containing as many as a half million components persist in antisense oligonucleotide (ASO) therapeutics because it has been feasible neither to separate the individual stereoisomers, nor to synthesize stereochemically pure ASOs. Here we report the development of a scalable synthetic process that yields therapeutic ASOs having high stereochemical and chemical purity. Using this method, we synthesized rationally designed stereopure components of mipomersen, a drug comprising 524,288 stereoisomers. We demonstrate that phosphorothioate (PS) stereochemistry substantially affects the pharmacologic properties of ASOs. We report that Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug. Further, we elucidated a triplet stereochemical code in the stereopure ASOs, 3′-SpSpRp, that promotes target RNA cleavage by RNase H1 in vitro and provides a more durable response in mice than stereorandom ASOs.

    更新日期:2017-09-04
  • People
    Nat. Biotechnol. (IF 41.667) Pub Date : 

    People Nature Biotechnology, Published online: 8 August 2017; doi:10.1038/nbt.3945

    更新日期:2017-09-04
  • Plant breeders test drive first open-source seed bank
    Nat. Biotechnol. (IF 41.667) Pub Date : 
    Lucas Laursen

    Plant breeders test drive first open-source seed bank Nature Biotechnology, Published online: 8 August 2017; doi:10.1038/nbt0817-700

    更新日期:2017-09-04
  • Retraction: DNA-guided genome editing using the Natronobacterium gregoryi Argonaute
    Nat. Biotechnol. (IF 41.667) Pub Date : 
    Feng Gao, Xiao Z Shen, Feng Jiang, Yongqiang Wu, Chunyu Han

    Retraction: DNA-guided genome editing using the Natronobacterium gregoryi Argonaute Nature Biotechnology, Published online: 8 August 2017; doi:10.1038/nbt0817-797a

    更新日期:2017-09-04
  • First multi-gene NGS diagnostic kit approved
    Nat. Biotechnol. (IF 41.667) Pub Date : 
    Mark Ratner

    First multi-gene NGS diagnostic kit approved Nature Biotechnology, Published online: 8 August 2017; doi:10.1038/nbt0817-699

    更新日期:2017-09-04
  • Time for the data to speak
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-02

    Retraction of a study claiming gene editing via an Argonaute enzyme illustrates the importance of post-publication peer review in the age of 24/7 media.

    更新日期:2017-08-09
  • Engineering the animal out of animal products
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-08
    Amber Dance

    Amber Dance reports on a new wave of domestication—turning cells, rather than animals, into food.

    更新日期:2017-08-09
  • Big data opens a window onto wellness
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-08
    Atul J Butte

    Longitudinal multi-omics data, clinical tests and biomarker analyses across a large cohort lay the groundwork for understanding the transition from wellness to disease.

    更新日期:2017-08-09
  • Pluripotent stem cells that evade the immune radar
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-08
    Steven C Kim, Andrew B Adams

    Human pluripotent stem cells are cloaked to evade immune rejection.

    更新日期:2017-08-09
  • Minimum information about a single amplified genome (MISAG) and a metagenome-assembled genome (MIMAG) of bacteria and archaea
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-08
    Robert M Bowers, Nikos C Kyrpides, Ramunas Stepanauskas, Miranda Harmon-Smith, Devin Doud, T B K Reddy, Frederik Schulz, Jessica Jarett, Adam R Rivers, Emiley A Eloe-Fadrosh, Susannah G Tringe, Natalia N Ivanova, Alex Copeland, Alicia Clum, Eric D Becraft, Rex R Malmstrom, Bruce Birren, Mircea Podar, Peer Bork, George M Weinstock, George M Garrity, Jeremy A Dodsworth, Shibu Yooseph, Granger Sutton, Frank O Glöckner, Jack A Gilbert, William C Nelson, Steven J Hallam, Sean P Jungbluth, Thijs J G Ettema, Scott Tighe, Konstantinos T Konstantinidis, Wen-Tso Liu, Brett J Baker, Thomas Rattei, Jonathan A Eisen, Brian Hedlund, Katherine D McMahon, Noah Fierer, Rob Knight, Rob Finn, Guy Cochrane, Ilene Karsch-Mizrachi, Gene W Tyson, Christian Rinke, The Genome Standards Consortium, Alla Lapidus, Folker Meyer, Pelin Yilmaz, Donovan H Parks, A M Eren, Lynn Schriml, Jillian F Banfield, Philip Hugenholtz, Tanja Woyke

    We present two standards developed by the Genomic Standards Consortium (GSC) for reporting bacterial and archaeal genome sequences. Both are extensions of the Minimum Information about Any (x) Sequence (MIxS). The standards are the Minimum Information about a Single Amplified Genome (MISAG) and the Minimum Information about a Metagenome-Assembled Genome (MIMAG), including, but not limited to, assembly quality, and estimates of genome completeness and contamination. These standards can be used in combination with other GSC checklists, including the Minimum Information about a Genome Sequence (MIGS), Minimum Information about a Metagenomic Sequence (MIMS), and Minimum Information about a Marker Gene Sequence (MIMARKS). Community-wide adoption of MISAG and MIMAG will facilitate more robust comparative genomic analyses of bacterial and archaeal diversity.

    更新日期:2017-08-09
  • Characterization of noncoding regulatory DNA in the human genome
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-08
    Ran Elkon, Reuven Agami

    Genetic variants associated with common diseases are usually located in noncoding parts of the human genome. Delineation of the full repertoire of functional noncoding elements, together with efficient methods for probing their biological roles, is therefore of crucial importance. Over the past decade, DNA accessibility and various epigenetic modifications have been associated with regulatory functions. Mapping these features across the genome has enabled researchers to begin to document the full complement of putative regulatory elements. High-throughput reporter assays to probe the functions of regulatory regions have also been developed but these methods separate putative regulatory elements from the chromosome so that any effects of chromatin context and long-range regulatory interactions are lost. Definitive assignment of function(s) to putative cis-regulatory elements requires perturbation of these elements. Genome-editing technologies are now transforming our ability to perturb regulatory elements across entire genomes. Interpretation of high-throughput genetic screens that incorporate genome editors might enable the construction of an unbiased map of functional noncoding elements in the human genome.

    更新日期:2017-08-09
  • A wellness study of 108 individuals using personal, dense, dynamic data clouds
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-17
    Nathan D Price, Andrew T Magis, John C Earls, Gustavo Glusman, Roie Levy, Christopher Lausted, Daniel T McDonald, Ulrike Kusebauch, Christopher L Moss, Yong Zhou, Shizhen Qin, Robert L Moritz, Kristin Brogaard, Gilbert S Omenn, Jennifer C Lovejoy, Leroy Hood

    Personal data for 108 individuals were collected during a 9-month period, including whole genome sequences; clinical tests, metabolomes, proteomes, and microbiomes at three time points; and daily activity tracking. Using all of these data, we generated a correlation network that revealed communities of related analytes associated with physiology and disease. Connectivity within analyte communities enabled the identification of known and candidate biomarkers (e.g., gamma-glutamyltyrosine was densely interconnected with clinical analytes for cardiometabolic disease). We calculated polygenic scores from genome-wide association studies (GWAS) for 127 traits and diseases, and used these to discover molecular correlates of polygenic risk (e.g., genetic risk for inflammatory bowel disease was negatively correlated with plasma cystine). Finally, behavioral coaching informed by personal data helped participants to improve clinical biomarkers. Our results show that measurement of personal data clouds over time can improve our understanding of health and disease, including early transitions to disease states.

    更新日期:2017-08-09
  • Nanoscale imaging of clinical specimens using pathology-optimized expansion microscopy
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-17
    Yongxin Zhao, Octavian Bucur, Humayun Irshad, Fei Chen, Astrid Weins, Andreea L Stancu, Eun-Young Oh, Marcello DiStasio, Vanda Torous, Benjamin Glass, Isaac E Stillman, Stuart J Schnitt, Andrew H Beck, Edward S Boyden

    Expansion microscopy (ExM), a method for improving the resolution of light microscopy by physically expanding a specimen, has not been applied to clinical tissue samples. Here we report a clinically optimized form of ExM that supports nanoscale imaging of human tissue specimens that have been fixed with formalin, embedded in paraffin, stained with hematoxylin and eosin, and/or fresh frozen. The method, which we call expansion pathology (ExPath), converts clinical samples into an ExM-compatible state, then applies an ExM protocol with protein anchoring and mechanical homogenization steps optimized for clinical samples. ExPath enables ~70-nm-resolution imaging of diverse biomolecules in intact tissues using conventional diffraction-limited microscopes and standard antibody and fluorescent DNA in situ hybridization reagents. We use ExPath for optical diagnosis of kidney minimal-change disease, a process that previously required electron microscopy, and we demonstrate high-fidelity computational discrimination between early breast neoplastic lesions for which pathologists often disagree in classification. ExPath may enable the routine use of nanoscale imaging in pathology and clinical research.

    更新日期:2017-08-09
  • HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-05-15
    Germán G Gornalusse, Roli K Hirata, Sarah E Funk, Laura Riolobos, Vanda S Lopes, Gabriel Manske, Donna Prunkard, Aric G Colunga, Laïla-Aïcha Hanafi, Dennis O Clegg, Cameron Turtle, David W Russell

    Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this 'missing-self' response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8+ T cells, do not bind anti-HLA antibodies and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression.

    更新日期:2017-08-09
  • Long time-lapse nanoscopy with spontaneously blinking membrane probes
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-03
    Hideo Takakura, Yongdeng Zhang, Roman S Erdmann, Alexander D Thompson, Yu Lin, Brian McNellis, Felix Rivera-Molina, Shin-nosuke Uno, Mako Kamiya, Yasuteru Urano, James E Rothman, Joerg Bewersdorf, Alanna Schepartz, Derek Toomre

    Imaging cellular structures and organelles in living cells by long time-lapse super-resolution microscopy is challenging, as it requires dense labeling, bright and highly photostable dyes, and non-toxic conditions. We introduce a set of high-density, environment-sensitive (HIDE) membrane probes, based on the membrane-permeable silicon-rhodamine dye HMSiR, that assemble in situ and enable long time-lapse, live-cell nanoscopy of discrete cellular structures and organelles with high spatiotemporal resolution. HIDE-enabled nanoscopy movies span tens of minutes, whereas movies obtained with labeled proteins span tens of seconds. Our data reveal 2D dynamics of the mitochondria, plasma membrane and filopodia, and the 2D and 3D dynamics of the endoplasmic reticulum, in living cells. HIDE probes also facilitate acquisition of live-cell, two-color, super-resolution images, expanding the utility of nanoscopy to visualize dynamic processes and structures in living cells.

    更新日期:2017-08-09
  • Inference and quantification of peptidoforms in large sample cohorts by SWATH-MS
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-06-12
    George Rosenberger, Yansheng Liu, Hannes L Röst, Christina Ludwig, Alfonso Buil, Ariel Bensimon, Martin Soste, Tim D Spector, Emmanouil T Dermitzakis, Ben C Collins, Lars Malmström, Ruedi Aebersold

    Consistent detection and quantification of protein post-translational modifications (PTMs) across sample cohorts is a prerequisite for functional analysis of biological processes. Data-independent acquisition (DIA) is a bottom-up mass spectrometry approach that provides complete information on precursor and fragment ions. However, owing to the convoluted structure of DIA data sets, confident, systematic identification and quantification of peptidoforms has remained challenging. Here, we present inference of peptidoforms (IPF), a fully automated algorithm that uses spectral libraries to query, validate and quantify peptidoforms in DIA data sets. The method was developed on data acquired by the DIA method SWATH-MS and benchmarked using a synthetic phosphopeptide reference data set and phosphopeptide-enriched samples. IPF reduced false site-localization by more than sevenfold compared with previous approaches, while recovering 85.4% of the true signals. Using IPF, we quantified peptidoforms in DIA data acquired from >200 samples of blood plasma of a human twin cohort and assessed the contribution of heritable, environmental and longitudinal effects on their PTMs.

    更新日期:2017-08-09
  • Engineered Cpf1 variants with altered PAM specificities
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-06-05
    Linyi Gao, David B T Cox, Winston X Yan, John C Manteiga, Martin W Schneider, Takashi Yamano, Hiroshi Nishimasu, Osamu Nureki, Nicola Crosetto, Feng Zhang

    The targeting range of the CRISPR endonuclease Cpf1 is increased three-fold by molecular engineering.

    更新日期:2017-08-09
  • Rapid cloning of genes in hexaploid wheat using cultivar-specific long-range chromosome assembly
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-05-15
    Anupriya Kaur Thind, Thomas Wicker, Hana Šimková, Dario Fossati, Odile Moullet, Cécile Brabant, Jan Vrána, Jaroslav Doležel, Simon G Krattinger

    Rapid cloning of genes from any crop plant species (or cultivar) whose chromosomes can be flow sorted is enabled by a combination of short-read sequencing and proximity ligation.

    更新日期:2017-08-09
  • Time for the data to speak
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-08-02

    Retraction of a study claiming gene editing via an Argonaute enzyme illustrates the importance of post-publication peer review in the age of 24/7 media.

    更新日期:2017-08-03
  • A wellness study of 108 individuals using personal, dense, dynamic data clouds
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-17

    Longitudinal clinical and multi-omics data from 108 healthy individuals are analyzed to identify putative biomarkers and diagnostics of early disease states.

    更新日期:2017-07-18
  • Nanoscale imaging of clinical specimens using pathology-optimized expansion microscopy
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-17

    Expansion microscopy, a technique for super-resolution imaging, is extended to clinical human tissue samples that are formalin fixed, paraffin embedded, stained and/or fresh frozen.

    更新日期:2017-07-18
  • Wanted: biotech for an aging population
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-12

    Digital medicine's extraordinary ability to communicate with patients, especially in under-served communities, could help reorient the biotech industry to better address aging and its associated diseases.

    更新日期:2017-07-13
  • An emerging model for life sciences commercialization
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-12
    Ashley J Stevens

    There are challenges in transplanting the US–European technology transfer model to emerging economies.

    更新日期:2017-07-13
  • Public biotech in 2016—the numbers
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-12
    Chris Morrison, Riku Lähteenmäki

    The anticipated decline in the biotech industry's ability to raise capital from public investors and an accompanying slump in biotech markets materialized in 2016, but all is not gloom and doom.

    更新日期:2017-07-13
  • CRISPR–Cas9 claim sets and the potential to stifle innovation
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-12
    Benjamin N Gray, W Murray Spruill

    Extremely broad claims surrounding Cas9 nucleases have the potential to stifle innovation in the field of genome editing.

    更新日期:2017-07-13
  • Single-cell genomics for the masses
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-12
    Susannah G Tringe

    Microbial communities are rapidly sequenced at the single-cell level using droplet microfluidics.

    更新日期:2017-07-13
  • Algal oil productivity gets a fat bonus
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-07-12
    Matthew C Posewitz

    Partitioning of carbon to lipids is engineered to improve oil accumulation in an industrial alga.

    更新日期:2017-07-13
  • Single-cell genome sequencing at ultra-high-throughput with microfluidic droplet barcoding
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-05-29
    Freeman Lan, Benjamin Demaree, Noorsher Ahmed, Adam R Abate

    The application of single-cell genome sequencing to large cell populations has been hindered by technical challenges in isolating single cells during genome preparation. Here we present single-cell genomic sequencing (SiC-seq), which uses droplet microfluidics to isolate, fragment, and barcode the genomes of single cells, followed by Illumina sequencing of pooled DNA. We demonstrate ultra-high-throughput sequencing of >50,000 cells per run in a synthetic community of Gram-negative and Gram-positive bacteria and fungi. The sequenced genomes can be sorted in silico based on characteristic sequences. We use this approach to analyze the distributions of antibiotic-resistance genes, virulence factors, and phage sequences in microbial communities from an environmental sample. The ability to routinely sequence large populations of single cells will enable the de-convolution of genetic heterogeneity in diverse cell populations.

    更新日期:2017-07-13
  • Lipid production in Nannochloropsis gaditana is doubled by decreasing expression of a single transcriptional regulator
    Nat. Biotechnol. (IF 41.667) Pub Date : 2017-06-19
    Imad Ajjawi, John Verruto, Moena Aqui, Leah B Soriaga, Jennifer Coppersmith, Kathleen Kwok, Luke Peach, Elizabeth Orchard, Ryan Kalb, Weidong Xu, Tom J Carlson, Kristie Francis, Katie Konigsfeld, Judit Bartalis, Andrew Schultz, William Lambert, Ariel S Schwartz, Robert Brown, Eric R Moellering

    Lipid production in the industrial microalga Nannochloropsis gaditana exceeds that of model algal species and can be maximized by nutrient starvation in batch culture. However, starvation halts growth, thereby decreasing productivity. Efforts to engineer N. gaditana strains that can accumulate biomass and overproduce lipids have previously met with little success. We identified 20 transcription factors as putative negative regulators of lipid production by using RNA-seq analysis of N. gaditana during nitrogen deprivation. Application of a CRISPR–Cas9 reverse-genetics pipeline enabled insertional mutagenesis of 18 of these 20 transcription factors. Knocking out a homolog of fungal Zn(II)2Cys6-encoding genes improved partitioning of total carbon to lipids from 20% (wild type) to 40–55% (mutant) in nutrient-replete conditions. Knockout mutants grew poorly, but attenuation of Zn(II)2Cys6 expression yielded strains producing twice as much lipid (~5.0 g m−2 d−1) as that in the wild type (~2.5 g m−2 d−1) under semicontinuous growth conditions and had little effect on growth.

    更新日期:2017-07-13
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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