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| Open AccessCell-selective labelling of proteomes in Drosophila melanogaster
Mutated tRNA synthetases can incorporate non-canonical amino acids into proteins. Erdmann et al. exploit this property to metabolically label newly synthesized proteins in selected cell types in Drosophila, and demonstrate their detection using proteomics (BONCAT) and fluorescence imaging (FUNCAT).
- Ines Erdmann
- , Kathrin Marter
- & Daniela C. Dieterich
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Article
| Open AccessImpaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases
Charcot–Marie–Tooth (CMT) neuropathy is associated with dominant mutations in five tRNA synthetase genes. Niehues et al. use BONCAT and FUNCAT to monitor proteome dynamics in a DrosophilaCMT model, and reveal that these mutations result in translational slowdown.
- Sven Niehues
- , Julia Bussmann
- & Erik Storkebaum
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Article
| Open AccessSystem-wide identification of wild-type SUMO-2 conjugation sites
Tryptic digestion of SUMOylated proteins generates large peptides, rendering proteomic characterisation of this post-translational modification particularly challenging unless mutant SUMO is used. Hendriks et al.present a method that allows the quantitative identification of wild-type SUMO sites.
- Ivo A. Hendriks
- , Rochelle C. D’Souza
- & Alfred C. O. Vertegaal
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Article
| Open AccessExtreme multifunctional proteins identified from a human protein interaction network
Proteins are sometimes implicated in separate and seemingly unrelated processes, so called moonlighting functions. Here the authors use bioinformatics tools to identify extreme multifunctional proteins and define a signature of extreme multifunctionality.
- Charles E. Chapple
- , Benoit Robisson
- & Christine Brun
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Article
| Open AccessCombinatorial code governing cellular responses to complex stimuli
Cells constantly integrate information from multiple stimuli. By considering every possible means by which two stimuli can interact, Cappuccio et al. define 10 interaction modes and demonstrate their preferential use by dendritic cells responding to different combinations of microbial and host inflammatory cues.
- Antonio Cappuccio
- , Raphaël Zollinger
- & Vassili Soumelis
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| Open AccessLarge-scale determination of absolute phosphorylation stoichiometries in human cells by motif-targeting quantitative proteomics
Measuring phosphorylation stoichiometry on a proteomic scale remains a challenge. Tsai et al. develop a technique to measure the basal level of phosphorylation stoichiometry in a single human phosphoproteome and identify molecular changes associated with gefitinib resistance in lung cancer cells.
- Chia-Feng Tsai
- , Yi-Ting Wang
- & Yu-Ju Chen
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Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions
Toll-like receptors detect conserved microbial features to initiate host defence and are tightly regulated. Here the authors show that the orphan receptor interleukin-17 receptor D negatively regulates signalling downstream of Toll-like receptors to prevent excessive inflammation.
- Mark Mellett
- , Paola Atzei
- & Paul N. Moynagh
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Article
| Open AccessThe autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment
Autism genes converge in midfetal cortical co-expression networks, and chromatin regulators such as CHD8 are increasingly associated with autism spectrum disorder (ASD). Here the authors map CHD8 targets in developing brain, and find that CHD8 directly regulates other ASD risk genes during human neurodevelopment.
- Justin Cotney
- , Rebecca A. Muhle
- & James P. Noonan
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Article
| Open AccessDefining the phospho-adhesome through the phosphoproteomic analysis of integrin signalling
Protein phosphorylation is known to play an important role in cell adhesion signalling. Robertson et al. present a proteomic resource mapping the phosphorylation states of proteins isolated from adhesion complexes and, taking advantage of this data set, show that the cell cycle kinase CDK1 may influence cell adhesion.
- Joseph Robertson
- , Guillaume Jacquemet
- & Martin J. Humphries
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Article
| Open AccessInteractome analysis identifies a new paralogue of XRCC4 in non-homologous end joining DNA repair pathway
DNA double-strand breaks (DSBs), a highly deleterious form of DNA damage, are associated with multiple types of broken ends. Here, the authors identify a XRCC4-like factor that functions in the non-homologous end-joining DNA repair pathway to repair DSBs with complex broken ends.
- Mengtan Xing
- , Mingrui Yang
- & Dongyi Xu
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Article
| Open AccessA proteomic approach reveals integrin activation state-dependent control of microtubule cortical targeting
Integrins are activated by many extracellular cues and respond by assembling diverse signalling complexes. Byron et al.use activation state-specific antibodies to proteomically characterize these complexes, and provide insight into integrin-dependent microtubule stabilization.
- Adam Byron
- , Janet A. Askari
- & Martin J. Humphries
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Article
| Open AccessCommunity-integrated omics links dominance of a microbial generalist to fine-tuned resource usage
Within microbial communities, microorganisms adopt different lifestyle strategies to use the available resources. Here, the authors use an integrated ‘multi-omic’ approach to study niche breadth (generalist versus specialist lifestyles) in oleaginous microbial assemblages from an anoxic wastewater treatment tank.
- Emilie E. L. Muller
- , Nicolás Pinel
- & Paul Wilmes
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Global 3′ UTR shortening has a limited effect on protein abundance in proliferating T cells
The use of alternative polyadenylation sites can potentially result in mRNA being more or less susceptible to interaction with modulators of translation or stability. Here Gruber et al. find that the shortening of 3′UTRs observed in proliferating T cells does not significantly impact protein abundance.
- Andreas R. Gruber
- , Georges Martin
- & Mihaela Zavolan
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Changing the peptide specificity of a human T-cell receptor by directed evolution
Whether the specificity of a TCR can be changed in vitroto recognize an entirely different peptide has not been shown. Here, the authors use directed evolution to change the specificity of a human TCR from recognition of a viral peptide to that of a melanoma antigen.
- Sheena N. Smith
- , Yuhang Wang
- & David M. Kranz
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Evolutionarily conserved coupling of adaptive and excitable networks mediates eukaryotic chemotaxis
An excitable signalling network has been proposed to act as a pacemaker that drives cell motility. Tang et al. show that control of this network by an adaptive module is sufficient to explain how cells sense and adapt to changes in chemoattractant concentration as they migrate through a gradient.
- Ming Tang
- , Mingjie Wang
- & Chuan-Hsiang Huang
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Highly modular bow-tie gene circuits with programmable dynamic behaviour
Engineering gene expression systems that can be programmed to respond to specific environmental conditions is challenging. Here, the authors develop a synthetic bow-tie circuit that is able to sense signals from microRNA molecules and affect a change in protein dynamics in mammalian cells.
- Laura Prochazka
- , Bartolomeo Angelici
- & Yaakov Benenson
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Article
| 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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Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2
Patients with the Long QT Syndrome type 2 have abnormal cardiac electrical activity, which is diagnosed by an electrocardiogram (ECG) that shows a prolonged QT interval and a notched T wave. Here the authors uncover the origins of this signature ECG phenotype by using a multi-scale cardiac modelling.
- Arash Sadrieh
- , Luke Domanski
- & Adam P Hill
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Article
| Open AccessA unified design space of synthetic stripe-forming networks
Constructing gene circuits with predefined behaviours is typically done on a case-by-case basis. Schaerli et al.instead computationally explore the design space for 3-node networks that generate a stripe in response to a morphogen gradient, and build networks based on their simplest possible forms.
- Yolanda Schaerli
- , Andreea Munteanu
- & Mark Isalan
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Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli
The ferric uptake regulator, Fur, is involved in the transcriptional regulation of iron metabolism. Here the authors show that Fur exhibits genome-wide regulatory effects in Escherichia colithat control many fundamental cellular processes linked to iron metabolism.
- Sang Woo Seo
- , Donghyuk Kim
- & Bernhard O. Palsson
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Article
| Open AccessDivision of labour between Myc and G1 cyclins in cell cycle commitment and pace control
The transcription factor E2F is critical for determining cell proliferation. By monitoring E2F activity in single cells throughout the cell cycle, Dong et al.provide evidence that Myc and G1 cyclin/CDKs regulate different aspects of E2F temporal dynamics, resulting in distinct phenotypic outputs.
- Peng Dong
- , Manoj V. Maddali
- & Lingchong You
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Contribution of RNA polymerase concentration variation to protein expression noise
The quantitative relationship between the fluctuation of specific extrinsic and intrinsic factors, and stochastic fluctuations in gene expression - or noise - has not been clearly established. Here, Yang et al.demonstrate that intrinsic noise is independent of - while extrinsic noise scales linearly with - variation in RNA polymerase abundance.
- Sora Yang
- , Seunghyeon Kim
- & Nam Ki Lee
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Article
| Open AccessIdentification of a human neonatal immune-metabolic network associated with bacterial infection
Infection remains a leading cause of morbidity and mortality in neonates worldwide. Here the authors report disproportionate immune stimulatory, co-inhibitory and metabolic pathway responses that specifically mark bacterial infection and can be used to predict sepsis in neonatal patients at the first clinical signs of infection.
- Claire L. Smith
- , Paul Dickinson
- & Peter Ghazal
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Modulating the frequency and bias of stochastic switching to control phenotypic variation
Mechanisms that control gene expression variation in cells can affect factors such as population growth and adaptability. Here, the authors present a strategy that allows both the level and amount of variation in gene expression to be tuned in E. coli populations using the fimswitch.
- Michelle Hung
- , Emily Chang
- & Han N. Lim
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Article
| Open AccessCreation of a gated antibody as a conditionally functional synthetic protein
The ability to control antibody binding could have important medical implications. Here, the authors present a method to engineer phosphatase-controllable antibodies that bind to a specific recognition site in the presence of two biomarker inputs.
- Smita B. Gunnoo
- , Helene M. Finney
- & Benjamin G. Davis
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Article
| Open AccessRewiring neural circuits by the insertion of ectopic electrical synapses in transgenic C. elegans
Neural circuits are functional ensembles of neurons that are selectively interconnected by chemical or electrical synapses. Here the authors describe an approach to the study of neural circuits in C. eleganswhereby electrical synapses are introduced between previously unconnected neurons to reprogram behaviour.
- Ithai Rabinowitch
- , Marios Chatzigeorgiou
- & William R. Schafer
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A synthetic biochemistry molecular purge valve module that maintains redox balance
In vitro biochemical pathways could provide the high yields required for economical commodity chemical production, but require circuitry development to regulate high-energy cofactors. Here, the authors design and test a simple purge valve system to maintain NADP+/NADPH balance in E. coli.
- Paul H. Opgenorth
- , Tyler P. Korman
- & James U. Bowie
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Article |
Sensitive detection of proteasomal activation using the Deg-On mammalian synthetic gene circuit
Proteasome activity can be monitored using a fluorescent substrate; however, screening for proteasome activators using this technique is challenging as signal loss is intrinsically more difficult to detect. Zhao et al.design a genetic inverter circuit that reports increased proteasome activity as signal gain.
- Wenting Zhao
- , Matthew Bonem
- & Laura Segatori
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Article
| Open AccessmicroRNA input into a neural ultradian oscillator controls emergence and timing of alternative cell states
Hes1 is an important regulator of progenitor maintenance and timed differentiation, which shows oscillatory expression. Here, the authors combine experimental data and mathematical modelling to show that the interaction between miRNA-9 and Hes1 can predict progenitor transition from one cell state to another, as well as the timing of this transition.
- Marc Goodfellow
- , Nicholas E. Phillips
- & Nancy Papalopulu
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Article
| Open AccessSILAC-based proteomic quantification of chemoattractant-induced cytoskeleton dynamics on a second to minute timescale
Actin-dependent motility is driven by the rapid changes in the recruitment of many different structural and regulatory proteins at the cell’s cortex. Sobczyk et al. characterize these changes in the cytoskeletal proteome on a second to minute timescale during chemotactic response in Dictyosteliumusing SILAC-based proteomics.
- Grzegorz J. Sobczyk
- , Jun Wang
- & Cornelis J. Weijer
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A high-energy-density sugar biobattery based on a synthetic enzymatic pathway
Incomplete oxidation of fuels is a common problem in enzymatic fuel cells and it leads to low energy densities. Zhu et al. report the complete oxidation of sugar in an enzymatic fuel cell through a synthetic enzymatic pathway, which exhibits higher energy densities than lithium-ion batteries.
- Zhiguang Zhu
- , Tsz Kin Tam
- & Y. -H. Percival Zhang
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Programming a Pavlovian-like conditioning circuit in Escherichia coli
Synthetic gene circuits can be programmed in living cells to perform diverse cellular functions. Here, the authors program a genetic circuit that performs a Pavlovian-like learning and recall function in E. coli, and demonstrate the dynamic nature of this conditioning process at a population level.
- Haoqian Zhang
- , Min Lin
- & Qi Ouyang
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Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease
Alterations in hepatocyte metabolism can lead to disorders such as non-alcoholic steatohepatitis (NASH). Here the authors create a comprehensive model of hepatocyte metabolism and use it to identify metabolic pathways altered in disease, revealing that serine levels are reduced in patients with NASH.
- Adil Mardinoglu
- , Rasmus Agren
- & Jens Nielsen
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Predicting network functions with nested patterns
Identifying functionally important features of complex biological networks is computationally challenging. Ganter et al.develop a probabilistic framework that uses recurrent metabolite patterns to predict the properties and existence of reactions within a genome-scale metabolic network.
- Mathias Ganter
- , Hans-Michael Kaltenbach
- & Jörg Stelling
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Characterization and modelling of interspecies electron transfer mechanisms and microbial community dynamics of a syntrophic association
Microbial community function depends on metabolic interdependencies between individual species, some of which include electron transfer. Nagarajan et al. use genomic, transcriptomic and modelling approaches to describe the mechanisms supporting the syntrophic relationship between Geobacter metallireducens and Geobacter sulfurreducens.
- Harish Nagarajan
- , Mallory Embree
- & Karsten Zengler
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Article
| Open AccessQuality versus quantity of social ties in experimental cooperative networks
The effect of the rate of forming and breaking social ties on cooperative behaviour is not clear. Here the authors experimentally test the effect of rewiring the connections between individuals, and find that optimal levels of cooperation are achieved at intermediate levels of change in ties.
- Hirokazu Shirado
- , Feng Fu
- & Nicholas A. Christakis
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Tuning the range and stability of multiple phenotypic states with coupled positive–negative feedback loops
Interlocking positive and negative feedback loops are common in biological networks. By engineering separate external controls for both loops within the yeast galactose uptake system, Avendaño et al.show that this motif confers dual regulation of range and switching frequency between phenotypes.
- Maier S. Avendaño
- , Chad Leidy
- & Juan M. Pedraza
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miRNAs confer phenotypic robustness to gene networks by suppressing biological noise
MicroRNAs are thought to confer robustness to biological processes, but clear experimental evidence is still needed. Here, Siciliano et al. construct a toggle-switch in mammalian cells to show that microRNAs buffer fluctuations in protein levels, thereby providing phenotypic robustness to gene regulatory networks.
- Velia Siciliano
- , Immacolata Garzilli
- & Diego di Bernardo
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Implementation of stable and complex biological systems through recombinase-assisted genome engineering
Genetic engineering of bacteria is an important tool in biotechnology and synthetic biology. Here, the authors describe a method for genomic integration of complex, multi-gene sequences into bacteria and use it to create a strain of E. colithat generates ethanol from brown macroalgae.
- Christine Nicole S. Santos
- , Drew D. Regitsky
- & Yasuo Yoshikuni
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Article
| Open AccessA versatile cis-acting inverter module for synthetic translational switches
Artificial genetic circuits have been designed to enable precise control of cellular behaviour and phenotypes. Saito and colleagues present a new RNA module that can invert the function of a translational OFF to an ON switch and demonstrate its utility in mammalian cells.
- Kei Endo
- , Karin Hayashi
- & Hirohide Saito
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Dynamic optimization identifies optimal programmes for pathway regulation in prokaryotes
The ability to induce metabolic pathways in response to a changing environment is an important component of bacterial fitness. Bartl et al. identify optimal programmes for metabolic pathway activation depending on protein synthesis capacity constraints, and demonstrate their impact on operonic organization.
- Martin Bartl
- , Martin Kötzing
- & Christoph Kaleta
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Genome-scale proteome quantification by DEEP SEQ mass spectrometry
The complexity and dynamic range of mammalian proteomes has stymied comprehensive protein quantification for the past twenty years. Zhou et al. develop DEEP SEQ mass spectrometry and use it to quantify a murine stem cell proteome to a depth equivalent to RNA-seq-based ribosome profiling.
- Feng Zhou
- , Yu Lu
- & Jarrod A. Marto
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Article |
Realistic control of network dynamics
Nonlinearity is a hallmark of complex networks, but has generally been regarded as an obstacle to controlling their behaviour. Here Cornelius et al.show how nonlinear dynamics can be harnessed to control a network and drive it to desired states.
- Sean P. Cornelius
- , William L. Kath
- & Adilson E. Motter
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Model-based rational design of an oncolytic virus with improved therapeutic potential
Oncolytic viruses can serve as self-replicating anticancer agents. Le Bœuf et al. combine synthetic modelling and molecular biology approaches to create a virus with enhanced oncolytic activity in vitro and in vivodue to its expression of an interferon antagonist.
- Fabrice Le Bœuf
- , Cory Batenchuk
- & John C. Bell
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Transcription factor binding kinetics constrain noise suppression via negative feedback
Live cell imaging have recently revealed that transcription factors spend up to 4 min to find and bind their chromosomal binding site. Grönlund et al. show that this slow search process leads to tradeoffs between strength and speed of negative autoregulation for effective noise suppression.
- Andreas Grönlund
- , Per Lötstedt
- & Johan Elf
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Article
| Open AccessOptimization of stress response through the nuclear receptor-mediated cortisol signalling network
Stress causes cortisol release and this is associated with the development of pathophysiology. Plant and colleagues use a computational model to reproduce the interaction of cortisol with its two nuclear receptors, and reveal how feed-forward and feed-back loops coordinate adaptation to repeated stress.
- Alexey Kolodkin
- , Nilgun Sahin
- & Nick Plant
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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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Different types of synchrony in chaotic and cyclic communities
Natural populations are complex systems where interactions can lead to chaotic dynamics. This study tests how cyclic and chaotic microbial predator–prey communities synchronize, showing different phase-locking responses for cyclic and chaotic systems.
- Lutz Becks
- & Hartmut Arndt
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Sensitivity control through attenuation of signal transfer efficiency by negative regulation of cellular signalling
How the sensitivity of biological and pharmacological signalling responses is controlled is poorly understood. Here, computational analyses and cellular experiments show that the sensitivity of a simple biochemical reaction to activators and inhibitors is controlled by negative regulation of cellular signalling.
- Yu Toyoshima
- , Hiroaki Kakuda
- & Shinya Kuroda
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