Nature Methods Contents: April 2014 Volume 11 pp 351 - 462

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Advertisement New from Exiqon Services: microRNA and small RNA NGS  - A complete sample-to-answer solution - Comprehensive analysis including biological interpretation - Experiments set up in close cooperation with our microRNA and NGS experts Learn more TABLE OF CONTENTS April 2014 Volume 11, Issue 4 In This Issue Editorial This Month Correspondence Research Highlights Technology Feature News and Views Analysis Brief Communications Articles Advertisement   Accurate, fast cell cycle studies made easy Free software templates and ready-to-go reagent kits are available for the BD Accuri™ C6 personal flow cytometer to speed setup time, give you more insight, and ease workflow. Download free templates today and take advantage of special offers on cell cycle-specific reagent kits. bdbiosciences.com/go/templates Subscribe   Facebook   RSS   Recommend to library   Twitter   Advertisement BD Horizon Brilliant™ Ultraviolet Expand your research capabilities by adding ultraviolet excitable dyes to your multicolor panel design. Special offers available for a whole new spectrum of choice and productivity, along with tools and information to help you get the most from your studies. bdbiosciences.com/go/ultra   Advertisement In a complicated world, the future is about to get simpler. See how the automated droplet generator will simplify your Droplet Digital™ PCR workflow. Learn more>   Advertisement Expedite your western blotting workflow. See how Bio-Rad's Trans-Blot® Turbo™ transfer system provides a complete solution for fast and high-efficiency transfer of even high molecular weight proteins. Learn more>    In This Issue Top InThisIssue    Editorial Top The editorial scope tightrope   p351 doi:10.1038/nmeth.2920 Nature Methods is dedicated to publishing methodological developments for basic biological research. Yet many papers that we receive, and some that we publish, also have later-stage applications. Where do we draw the line of editorial scope? This Month Top The author file: Hana El-Samad   p353 Vivien Marx doi:10.1038/nmeth.2901 Traversing biology at multiple scales, a system automates flow cytometry. And a constitution changes lab culture. Points of significance: Comparing samples—part II   pp355 - 356 Martin Krzywinski and Naomi Altman doi:10.1038/nmeth.2900 When a large number of tests are performed, P values must be interpreted differently. Correspondence Top A fair comparison   p359 Paul I Costea, Georg Zeller, Shinichi Sunagawa and Peer Bork doi:10.1038/nmeth.2897 See also: Correspondence by Paulson et al. Reply to: "A fair comparison"   pp359 - 360 Joseph N Paulson, Héctor Corrada Bravo and Mihai Pop doi:10.1038/nmeth.2898 See also: Correspondence by Costea et al. Single-cell in situ RNA profiling by sequential hybridization   pp360 - 361 Eric Lubeck, Ahmet F Coskun, Timur Zhiyentayev, Mubhij Ahmad and Long Cai doi:10.1038/nmeth.2892 MutationTaster2: mutation prediction for the deep-sequencing age   pp361 - 362 Jana Marie Schwarz, David N Cooper, Markus Schuelke and Dominik Seelow doi:10.1038/nmeth.2890 Research Highlights Top CRISPR snapshots of a gene-editing tool From single-molecule functional studies to atomic-resolution structures, a windfall of data sheds light on the Cas9 mechanism of targeted DNA scission. Making protein crystals fly A new device for injecting membrane-protein microcrystals into the path of an X-ray free-electron laser beam improves the efficiency of serial femtosecond crystallography. FISHing for faster findings Quick-hybridizing probes help scientists image the high-speed events leading up to gene transcription. Scoring all human mutations Combining 63 annotations provides a unified score for the potential deleteriousness of every possible human mutation. Single cells make the tissue By pushing throughput, single-cell transcript profiling can replace marker-based sorting and bulk RNA sequencing to redefine tissues from the bottom up. Interspecies systems biology (a.k.a. interspecies genetics) The power of genetics in the worm, and in the bacteria that worms eat, is harnessed for a systems view of the effect of diet on a host organism. Methods in Brief Variants in a bottle | Efficient reprogramming from a privileged cell state | Better estimates of diffusion | miRNA profiling depends on platform Tools in Brief Single-transcript dynamics in a live mouse | Avoiding artifacts in optogenetics studies | Microbial population structure served on the web | Sustainable magnetic nanoparticle synthesis Methods JOBS of the week Post-Doctoral Research Associate position northewestern university Bioinformatician Max Planck Institute for Plant Breeding Research Fully-funded PhD studentship in Ultrafast Imaging and Quantum Dynamics University of Edinburgh Bioinformaticist Postdoc Fellow - Subsurface Microbiology Lawrence Berkeley National Laboratory (LBNL) PhD research fellow: Computational Materials Science University of Oslo More Science jobs from Methods EVENT Methods in Computational Neuroscience 30th July 2014 Woods Hole, USA More science events from Technology Feature Top Cancer genomes: discerning drivers from passengers   pp375 - 379 Vivien Marx doi:10.1038/nmeth.2891 Tumors impart hints at what drives their progression. Parsing those signals takes old and new approaches. News and Views Top Next-gen immunohistochemistry   pp381 - 383 David L Rimm doi:10.1038/nmeth.2896 The combination of mass spectroscopy with immunohistochemistry allows highly multiplexed, directly quantitative imaging of tissue samples for both basic and clinical research. See also: Article by Giesen et al. Analysis Top Sleep-spindle detection: crowdsourcing and evaluating performance of experts, non-experts and automated methods   pp385 - 392 Simon C Warby, Sabrina L Wendt, Peter Welinder, Emil G S Munk, Oscar Carrillo et al. doi:10.1038/nmeth.2855 A comparative analysis of methods for scoring human sleep data, in particular sleep spindles, from encephalographic recordings is reported. The authors develop methods for crowdsourcing the identification of sleep spindles and compare the detection performance of experts, non-experts and automated algorithms. Brief Communications Top A synthetic luciferin improves bioluminescence imaging in live mice   pp393 - 395 Melanie S Evans, Joanna P Chaurette, Spencer T Adams Jr, Gadarla R Reddy, Miranda A Paley et al. doi:10.1038/nmeth.2839 The synthetic firefly luciferase substrate CycLuc1 offers brighter bioluminescence and improved imaging in mouse models at lower doses than the standard D-luciferin. PyClone: statistical inference of clonal population structure in cancer   pp396 - 398 Andrew Roth, Jaswinder Khattra, Damian Yap, Adrian Wan, Emma Laks et al. doi:10.1038/nmeth.2883 The hierarchical Bayesian model identifies and quantifies clonal populations in tumors from deep-sequenced somatic mutations. Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects   pp399 - 402 Bin Shen, Wensheng Zhang, Jun Zhang, Jiankui Zhou, Jianying Wang et al. doi:10.1038/nmeth.2857 This paper describes the use of paired Cas9 nickases to edit the mammalian genome with no detectable off-target effects. A mass spectrometry-based hybrid method for structural modeling of protein complexes   pp403 - 406 Argyris Politis, Florian Stengel, Zoe Hall, Helena Hernández, Alexander Leitner et al. doi:10.1038/nmeth.2841 Four types of mass spectrometry (MS) data—label-free quantitative bottom-up proteomics, native MS, ion mobility-MS and cross-linking MS—are used to derive restraints for structural modeling of large protein assemblies. Efficient multivariate linear mixed model algorithms for genome-wide association studies   pp407 - 409 Xiang Zhou and Matthew Stephens doi:10.1038/nmeth.2848 Multivariate linear mixed models implemented in the GEMMA software package add speed, power and the ability to test for genome-wide associations between genetic polymorphisms and multiple correlated phenotypes. Live-cell imaging of alkyne-tagged small biomolecules by stimulated Raman scattering   pp410 - 412 Lu Wei, Fanghao Hu, Yihui Shen, Zhixing Chen, Yong Yu et al. doi:10.1038/nmeth.2878 The combination of stimulated Raman scattering (SRS) microscopy with an alkyne group as a Raman-active tag allows high-contrast, live-cell dynamic imaging of a variety of biomolecules including DNA, RNA, protein, lipids and small-molecule drugs. Structure determination of noncanonical RNA motifs guided by 1H NMR chemical shifts   pp413 - 416 Parin Sripakdeevong, Mirko Cevec, Andrew T Chang, Michèle C Erat, Melanie Ziegeler et al. doi:10.1038/nmeth.2876 CS-Rosetta-RNA is a web tool for determining high-resolution structures of noncoding RNA motifs using 1H NMR chemical shift data coupled with Rosetta-based modeling. Advertisement Unlimited BioImaging: Chemiluminescence, Fluorescence, Colorimetric, Multiplex and More. The BioSpectrum Imaging System with its advanced capabilities enables a wide range of imaging applications. Unlimited in its ability to grow with your lab's developing life science research needs today and into the future. Learn More @ http://www.uvp.com/biospectrum.   Articles Top Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry   pp417 - 422 Charlotte Giesen, Hao A O Wang, Denis Schapiro, Nevena Zivanovic, Andrea Jacobs et al. doi:10.1038/nmeth.2869 This paper reports the use of mass cytometry on adherent cells and tissue samples for highly multiplexed imaging at subcellular resolution. See also: News and Views by Rimm Cryo-scanning transmission electron tomography of vitrified cells   pp423 - 428 Sharon Grayer Wolf, Lothar Houben and Michael Elbaum doi:10.1038/nmeth.2842 Cryo-scanning transmission electron tomography (CSTET) of unstained, fully hydrated vitrified biological specimens is shown to have advantages over cryo-electron tomography (CET), notably at high sample tilts providing greater depth resolution for thick samples. Broad specificity profiling of TALENs results in engineered nucleases with improved DNA-cleavage specificity   pp429 - 435 John P Guilinger, Vikram Pattanayak, Deepak Reyon, Shengdar Q Tsai, Jeffry D Sander et al. doi:10.1038/nmeth.2845 High-throughput in vitro analysis of TALE nuclease (TALEN) cleavage specificity gives insight into the mechanism of TALE binding and allows the design of TALENs with lower off-target activity. Identification of small molecules that support human leukemia stem cell activity ex vivo   pp436 - 442 Caroline Pabst, Jana Krosl, Iman Farès, Genevieve Boucher, Réjean Ruel et al. doi:10.1038/nmeth.2847 This paper reports conditions for the in vitro culture of human leukemia stem cells, which should enable basic studies as well as chemical screens on these cells. Dynamic characterization of growth and gene expression using high-throughput automated flow cytometry   pp443 - 448 Ignacio A Zuleta, Andrés Aranda-Díaz, Hao Li and Hana El-Samad doi:10.1038/nmeth.2879 An automated flow cytometry setup is described for dynamic and quantitative measurements of yeast growth and molecular phenotypes at high throughput. Characterizing bacterial gene circuit dynamics with optically programmed gene expression signals   pp449 - 455 Evan J Olson, Lucas A Hartsough, Brian P Landry, Raghav Shroff and Jeffrey J Tabor doi:10.1038/nmeth.2884 This paper describes optical control of complex and dynamic bacterial gene expression patterns for the study of gene circuits. Gold rotor bead tracking for high-speed measurements of DNA twist, torque and extension   pp456 - 462 Paul Lebel, Aakash Basu, Florian C Oberstrass, Elsa M Tretter and Zev Bryant doi:10.1038/nmeth.2854 Single-molecule structural transitions involving DNA twisting can be measured with substantially greater spatiotemporal resolution than previously possible with a gold rotor bead tracking (AuRBT) method. This approach uses magnetic tweezers and evanescent darkfield microscopy to track a gold nanoparticle probe attached to a DNA molecule. Advertisement Introducing the S3(TM) Cell Sorter from Bio-Rad. This state-of-the-art benchtop solution features automated setup and costs up to 50% less than traditional systems. Watch the Video    Advertisement They're recruiting scientists just like you! The Naturejobs Career Expo is coming to Boston, Massachusetts on May 20, 2014. Take advantage of this free opportunity to meet employers, attend workshops and further develop your career. 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