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Nuclear stability and transcriptional directionality separate functionally distinct RNA species
Despite our growing understanding of their complexity, different types of RNA are still classified using technical rather than functional criteria. Andersson et al.show that categorization of RNAs based on stability and direction of transcription is an effective means of functional classification.
- Robin Andersson
- , Peter Refsing Andersen
- & Albin Sandelin
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MS-GF+ makes progress towards a universal database search tool for proteomics
The development of software tools to analyse large mass spectrometry data sets lags behind the increase in diversity of the data. Here the authors develop MS-GF+, a database search tool that outperforms other popular tools in identifying peptides from a variety of data sets.
- Sangtae Kim
- & Pavel A. Pevzner
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| Open AccessOn the absence of intrahelical DNA dynamics on the μs to ms timescale
No experimental evidence exists for intra-helical motion of DNA at the μs timescale, which has been attributed to technical difficulties in observing motion in this time range. Here, the authors demonstrate, using extensive molecular dynamics simulations and experimental analysis, that such motion is effectively absent from a B-DNA duplex.
- Rodrigo Galindo-Murillo
- , Daniel R. Roe
- & Thomas E. Cheatham III
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Protein design with a comprehensive statistical energy function and boosted by experimental selection for foldability
Methods to design proteins de novo can give insights into how amino acids fold into particular structures and aid in protein engineering. Here, Xiong et al. compare a novel statistical energy function with established methods and use it to generate four de novoproteins.
- Peng Xiong
- , Meng Wang
- & Haiyan Liu
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| Open AccessConcomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut
Metastasizing tumour cells undergo epithelial-to-mesenchymal transition. Using both bioinformatic and in vivo approaches, Chanrion et al.identify combined Notch activation and p53 inactivation as a potent inducer of this transition, and apply this to create a highly metastatic tumour model in mice.
- Maia Chanrion
- , Inna Kuperstein
- & Sylvie Robine
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| Open AccessAn exact arithmetic toolbox for a consistent and reproducible structural analysis of metabolic network models
Current tools to analyse constraint-based models of metabolic networks have limited accuracy due to their use of floating-point arithmetic. Here the authors present MONGOOSE, a new computational tool that analyses such models in exact arithmetic, providing improved accuracy and reproducibility.
- Leonid Chindelevitch
- , Jason Trigg
- & Bonnie Berger
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Assessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures
Differential gene expression experiments yield quantitative insight into biological activity and may be important in disease classification and treatment. Here, the authors analyse external spike-in RNA controls to provide a standard method to assess and compare experiment performance.
- Sarah A. Munro
- , Steven P. Lund
- & Marc Salit
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| Open AccessWarped linear mixed models for the genetic analysis of transformed phenotypes
Linear mixed models (LMMs) provide a powerful method for studying genotype–phenotype associations. Here the authors present a LMM application that estimates an optimal transformation from observed data and increases the accuracy of heritability estimation and phenotype prediction.
- Nicolo Fusi
- , Christoph Lippert
- & Oliver Stegle
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Improved nucleosome-positioning algorithm iNPS for accurate nucleosome positioning from sequencing data
Changes in nucleosome positioning often underlie the reprogramming of gene expression during differentiation. Here Chen et al. describe a novel algorithm - iNPS - that outperforms current methods in accurately determine nucleosome position genome-wide.
- Weizhong Chen
- , Yi Liu
- & Jing-Dong Jackie Han
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Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans
The functional consequences of naturally occurring variation in ribosomal DNA (rDNA) copy number are poorly understood. Here the authors estimate rDNA copy number and mitochondrial DNA abundance in humans using whole-genome short-read DNA sequencing and characterize global regulatory mechanisms for cellular homeostasis and adaptation.
- John G. Gibbons
- , Alan T. Branco
- & Bernardo Lemos
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| Open AccessGenome dynamics of the human embryonic kidney 293 lineage in response to cell biology manipulations
The human embryonic kidney 293 (HEK293) cell lineage is widely used in cell biology and biotechnology. Here, the authors apply whole genome resequencing methods to characterise genomic variation in six HEK293 cell lines and suggest that this variation could affect experiments using these cell lines.
- Yao-Cheng Lin
- , Morgane Boone
- & Nico Callewaert
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| Open AccessA genome-wide map of hyper-edited RNA reveals numerous new sites
Common methods to detect adenosine-to-inosine RNA editing sites rely on mapping short RNA reads to the genome while allowing only a limited number of mismatches. Here, Porath et al. present a novel RNA-seq based approach to identify hyper-edited reads that significantly expands the RNA editome.
- Hagit T. Porath
- , Shai Carmi
- & Erez Y. Levanon
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| Open AccessA highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes
Metagenomic studies of microbial communities often report DNA sequences from unidentified viruses. Here, Dutilh et al. analyse metagenomic data to reveal the complete genome of an abundant, ubiquitous virus from human faeces, and predict that the virus infects bacteria of the Bacteroides group.
- Bas E. Dutilh
- , Noriko Cassman
- & Robert A. Edwards
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| Open AccessVirtual finger boosts three-dimensional imaging and microsurgery as well as terabyte volume image visualization and analysis
Large three-dimensional images are commonly generated through biological experimentation. Here the authors report software tools for exploration of three-dimensional images along with applications to assist in imaging, microsurgery, visualization and annotation of large image data sets.
- Hanchuan Peng
- , Jianyong Tang
- & Fuhui Long
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| Open AccessTipping elements in the human intestinal ecosystem
Intestinal microbes can have important effects on our health. Here, the authors analyse the gut microbiota composition in 1,000 western adults and find that certain bacteria are either abundant or nearly absent, and that these alternative states are associated with ageing and overweight.
- Leo Lahti
- , Jarkko Salojärvi
- & Willem M. de Vos
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| Open AccessProtruding knob-like proteins violate local symmetries in an icosahedral marine virus
Some viruses are spherical particles in which protein components are organized with well-defined icosahedral and local symmetries. Here, Gipson et al. describe a unique arrangement of proteins, breaking all expected local symmetries, in particles of a marine bacterial virus.
- Preeti Gipson
- , Matthew L. Baker
- & Wah Chiu
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| Open AccessIdentification of promiscuous ene-reductase activity by mining structural databases using active site constellations
Enzymes are very efficient reaction catalysts, though taking advantage of this synthetically is hampered by their notorious specificity. Here, the authors identify important arrangements of active site residues and use structural bioinformatics to successfully predict enzyme activity.
- Georg Steinkellner
- , Christian C. Gruber
- & Karl Gruber
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| Open AccessAmerindian-specific regions under positive selection harbour new lipid variants in Latinos
Dyslipidemia and obesity have a high prevalence in populations with Amerindian backgrounds, such as Mexican–Americans. Here, the authors design an approach to identify Amerindian risk genes in Mexicans and identify five genomic loci, which include RORA and SIK3that may contribute to the risk of dyslipidemia and obesity in Amerindian populations.
- Arthur Ko
- , Rita M. Cantor
- & Päivi Pajukanta
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A pan-cancer proteomic perspective on The Cancer Genome Atlas
Analyses of genome and transcriptome data are unable to accurately predict protein levels and function in tumour samples. Here, the authors carry out a comprehensive protein analysis in 3,467 samples from the cancer genome atlas, providing a resource to study the prognostic and therapeutic potential of tumour proteins.
- Rehan Akbani
- , Patrick Kwok Shing Ng
- & Gordon B. Mills
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Design of synthetic yeast promoters via tuning of nucleosome architecture
Model-based part design is a key step in synthetic biology. Here, the authors report a method for tuning nucleosome architecture in order to strengthen native promoters and facilitate synthetic promoter design in yeast.
- Kathleen A. Curran
- , Nathan C. Crook
- & Hal S. Alper
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Emergent properties of the interferon-signalling network may underlie the success of hepatitis C treatment
The standard treatment for hepatitis C virus (HCV) infection, combining interferon (IFN) α and ribavirin, fails in a number of patients. Here, the authors use a mathematical model of the IFN signalling network in the presence of HCV to explain the success or failure of hepatitis C treatment.
- Pranesh Padmanabhan
- , Urtzi Garaigorta
- & Narendra M. Dixit
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Sample sequencing of vascular plants demonstrates widespread conservation and divergence of microRNAs
Small RNAs and microRNAs are important regulators of gene expression. In this study, Chávez Montes et al.examine these molecules in 34 plant species, and explore the correlations between abundance, conservation and variability of microRNA sequences across all of the species studied.
- Ricardo A. Chávez Montes
- , de Fátima Flor Rosas-Cárdenas
- & Stefan de Folter
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| Open AccessProtein accumulation in the endoplasmic reticulum as a non-equilibrium phase transition
Misfolded protein accumulation is a hallmark of many neurodegenerative diseases. Here Budrikis et al. model protein aggregation in the endoplasmic reticulum and show that it is the result of a non-equilibrium phase transition caused by tipping the balance from the rates of protein production to degradation.
- Zoe Budrikis
- , Giulio Costantini
- & Stefano Zapperi
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| Open AccessMolecular architecture and the structural basis for anion interaction in prestin and SLC26 transporters
Prestin is an anion transporter-like protein in the mammalian inner ear that amplifies sound-induced vibration by voltage-driven structural rearrangements. Here, Gorbunov et al. show that this electromechanical activity is controlled by the binding of anions to a central cavity within the protein core.
- Dmitry Gorbunov
- , Mattia Sturlese
- & Dominik Oliver
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A highly efficient cocaine-detoxifying enzyme obtained by computational design
The enzyme butyrylcholinesterase (BChE) can metabolize cocaine, albeit at relatively low speeds. Here the authors use computational methods to define mutations that increase BChE-mediated cocaine hydrolysis, achieving a catalytic activity comparable to that of one of the fastest naturally occurring enzyme.
- Fang Zheng
- , Liu Xue
- & Chang-Guo Zhan
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A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods
Allosteric sites are an increasingly used target for drug design. Here, the authors computationally predict an allosteric site in cathepsin K and subsequently identify a small-molecule allosteric modifier.
- Marko Novinec
- , Matevž Korenč
- & Antonio Baici
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| Open AccessA rat RNA-Seq transcriptomic BodyMap across 11 organs and 4 developmental stages
Gene expression is highly variable between tissues, and changes during development and with age. Here, the authors provide a comprehensive RNA-Seq analysis of the rat transcriptome, spanning eleven organs, four developmental stages and both sexes.
- Ying Yu
- , James C. Fuscoe
- & Charles Wang
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| Open AccessAnalogue encoding of physicochemical properties of proteins in their cognate messenger RNAs
mRNA transport contributes to the proper localization of its cognate proteins. Here the authors report a correlation between the physicochemical properties of mRNAs and their cognate proteins, suggesting that these properties of mRNAs can predict the subcellular localization of their cognate proteins.
- Anton A. Polyansky
- , Mario Hlevnjak
- & Bojan Zagrovic
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From protein sequence to dynamics and disorder with DynaMine
Predicting the dynamics and disorder of a protein is a computationally complex task that, until now, has depended on prior knowledge of protein structure. Cilia et al.develop a tool to rapidly predict protein backbone dynamics based on sequence alone.
- Elisa Cilia
- , Rita Pancsa
- & Wim F. Vranken
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| Open AccessIdentification of a pan-cancer oncogenic microRNA superfamily anchored by a central core seed motif
AGO-CLIP permits the identification of miRNA target genes. Here, Hamilton et al. compile publicly available AGO-CLIP data and combine this information with miRNA analysis from The Cancer Genome Atlas, permitting the identification of an oncogenic miRNA superfamily that targets tumour suppressor genes.
- Mark P. Hamilton
- , Kimal Rajapakshe
- & Sean E. McGuire
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Model-based identification of drug targets that revert disrupted metabolism and its application to ageing
Systems biology is considered a promising tool for the identification of new drug targets. Here Yizhak and colleagues present an algorithm to analyse gene expression data and identify potential drug targets that would shift cellular metabolism from a given disease state to that of a healthier state.
- Keren Yizhak
- , Orshay Gabay
- & Eytan Ruppin
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Reconstructing targetable pathways in lung cancer by integrating diverse omics data
Non-small cell lung cancers (NSCLC) that harbour mutations in KRas can be separated into KRas-dependent and -independent subsets. By analysing transcriptome, proteome and phosphoproteome data from NSCLC cell lines, Balbin et al. show that KRas-dependent cell lines activate the Lck pathway.
- O. Alejandro Balbin
- , John R. Prensner
- & Arul M. Chinnaiyan
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Article
| Open AccessMaster regulators of FGFR2 signalling and breast cancer risk
FGFR2 gene variation is associated with breast cancer risk but the molecular mechanism is unknown. Fletcher et al. provide a link between FGFR2 signalling and breast cancer susceptibility by demonstrating that FGFR2 signalling activates the ERa transcriptional network, which drives transcription of risk genes.
- Michael N. C. Fletcher
- , Mauro A. A. Castro
- & Kerstin B. Meyer
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Expansion of the mutually exclusive spliced exome in Drosophila
Mutually exclusive splicing of genes is a mechanism for generating proteome diversity. Here Kollmar et al. determine the mutually exclusive spliced exome of Drosophila melanogaster and reveal insights into its evolutionary history within the Drosophilagroup.
- Klas Hatje
- & Martin Kollmar
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Article
| Open AccessIMGT/HighV QUEST paradigm for T cell receptor IMGT clonotype diversity and next generation repertoire immunoprofiling
Dynamic changes in T cell repertoire underlie immune responses during infection, allergy, autoimmunity and cancer. Here, Li et al. present a workflow for high throughput sequencing and analysis of T cell receptor sequences, and use it to monitor the T cell response to influenza vaccination in a human patient.
- Shuo Li
- , Marie-Paule Lefranc
- & Eric J. Gowans
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PhyloPhlAn is a new method for improved phylogenetic and taxonomic placement of microbes
Sequencing whole microbial genomes has become standard practice and methods to examine their phylogenetic relationships need to match the increasing demand. Segata et al. present a new computational pipeline that allows fast and accurate taxonomic assignment of microbial species.
- Nicola Segata
- , Daniela Börnigen
- & Curtis Huttenhower
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| Open AccessCounting motifs in the human interactome
Biological network data are often incomplete, which makes it difficult to determine interaction motifs within such data sets. Here Tran et al. present a new method to count motif numbers in large networks from noisy and incomplete biological data.
- Ngoc Hieu Tran
- , Kwok Pui Choi
- & Louxin Zhang
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| Open AccessHigh-speed panoramic light-sheet microscopy reveals global endodermal cell dynamics
Systematic large-scale analysis of embryonic development requires the processing of large amounts of microscopy data. Here Schmid et al.solve this problem by developing a high-speed imaging system that projects zebrafish embryos onto a ‘world map’ in real time, revealing characteristic migration patterns in the early endoderm.
- Benjamin Schmid
- , Gopi Shah
- & Jan Huisken
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Article
| Open AccessGenome evolution predicts genetic interactions in protein complexes and reveals cancer drug targets
Genetic interactions can reveal insights into cellular functions. Here, Lu et al.show that negative genetic interactions in protein complexes can be predicted by systematically exploring the evolutionary history of genes, which may be useful for the identification of novel targets for anti-cancer drugs.
- Xiaowen Lu
- , Philip R. Kensche
- & Richard A. Notebaart
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| Open AccessProtein analysis by time-resolved measurements with an electro-switchable DNA chip
The comprehensive bioanalysis of proteins usually requires multi-step surface and mobile phase measurements. Here, the authors use chips functionalized with dynamically actuated nanolevers—DNA strands that can be switched in an electric field—to obtain motional dynamic measurements of proteins on a chip.
- Andreas Langer
- , Paul A. Hampel
- & Ulrich Rant
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| Open AccessEvaluating cell lines as tumour models by comparison of genomic profiles
Cell lines are widely used in cancer research to study tumour biology. Here Domcke et al.compare genomic data from ovarian cancer cell lines with those from clinical ovarian tumour samples and identify cell lines that most closely resemble the genomic features of high-grade serous ovarian cancer.
- Silvia Domcke
- , Rileen Sinha
- & Nikolaus Schultz
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Pattern classification by memristive crossbar circuits using ex situ and in situ training
Experimental demonstration of memristor circuits in artificial neural networks is challenging. Here, pattern classification by a single-layer perceptron network is realised with a memristive crossbar circuit, and both in situ and ex situtraining are applied.
- Fabien Alibart
- , Elham Zamanidoost
- & Dmitri B. Strukov
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Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer
As cervical tumours become more invasive, levels of episomal human papillomavirus paradoxically tend to decrease. Here the authors identify a network of antiviral and cell cycle genes that is amplified by chromosomal aberrations and promotes cervical tumour progression.
- Karina L. Mine
- , Natalia Shulzhenko
- & Andrey Morgun
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Identifying sources of tick blood meals using unidentified tandem mass spectral libraries
The identification of hosts of blood-sucking insects is important for studying ecological factors that affect pathogen distribution. Önder et al. report a proteomics-based methodology for the analysis of blood remnants in ticks that identifies the host species from which the tick has fed up to 6 months earlier.
- Özlem Önder
- , Wenguang Shao
- & Dustin Brisson
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Characterizing the interplay between multiple levels of organization within bacterial sigma factor regulatory networks
Sigma factors are proteins controlling gene expression that allow bacteria to adapt to changing environmental conditions. Qiu and colleagues investigate sigma factor regulatory networks in Geobacter sulfurreducens, providing insights into how sigma factors regulate bacterial growth and energy metabolism.
- Yu Qiu
- , Harish Nagarajan
- & Karsten Zengler
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DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes
Human cancer genomes often contain large amounts of single-nucleotide substitutions (SNS). Liu et al. catalogued SNS signatures across various cancer and normal genomes, demonstrating coordinative effects between replication timing and nuclear architecture on SNS patterns in cancer genomes.
- Lin Liu
- , Subhajyoti De
- & Franziska Michor
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Article
| Open AccessThe evolution and pathogenic mechanisms of the rice sheath blight pathogen
The rice sheath blight pathogen, Rhizoctonia solani, is an important fungal pathogen that can devastate rice and maize crops. Zheng and colleagues sequence and assemble the R. solani AG1 IA genome—the first to be sequenced from the Rhizoctoniagenus—using Illumina sequencing technology.
- Aiping Zheng
- , Runmao Lin
- & Ping Li
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Article
| Open AccessComputational identification of a transiently open L1/S3 pocket for reactivation of mutant p53
About 40% of human cancers carry missense mutations in the tumour suppressor protein p53. Here the authors identify a transiently open pocket in the protein, and by targeting a small molecule to it, partially restore mutant p53 tumour suppressor activity.
- Christopher D. Wassman
- , Roberta Baronio
- & Rommie E. Amaro
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Article
| Open AccessIn silico method for modelling metabolism and gene product expression at genome scale
To describe the biochemical composition of an organism multiple data sets must be combined and this information can then be used forin silico analysis. By combining metabolism and transcription data, Lerman et al. discovered new regulons and improved the gene annotation for the simple organism Thermotoga maritima.
- Joshua A. Lerman
- , Daniel R. Hyduke
- & Bernhard O. Palsson
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