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| Open AccessSystematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data
There are no robust methods for systematically identifying mutation-specific synthetic lethal (SL) partners in cancer. Here, the authors develop a computational algorithm that uses pan-cancer data to detect mutation-andcancer-specific SL partners and they validate a novel SL interaction between mutant IDH and loss of ACACA in leukaemia.
- Subarna Sinha
- , Daniel Thomas
- & David L. Dill
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Article
| Open AccessCancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification
Tumour expression profiling is currently used for prognostic and predictive purposes without taking into account the intra patient heterogeneity. Here the authors show that cancer cell specific signatures overcome the tumour heterogeneity effect and result in better classification of colorectal cancer patients.
- Philip D. Dunne
- , Matthew Alderdice
- & Mark Lawler
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Article
| Open AccessRedesigning metabolism based on orthogonality principles
Growth-coupled designs for chemical production are limited by native metabolic networks’ optimality for growth. Here, the authors introduce pathway orthogonality as a measure of the independence of biomass and chemical production pathways, identify metabolic valves that allow substrate utilization to be switched between the two, and demonstrate advantages of orthogonal designs.
- Aditya Vikram Pandit
- , Shyam Srinivasan
- & Radhakrishnan Mahadevan
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Article
| Open AccessMiCASA is a new method for quantifying cellular organization
There are few methods available that can quantify relationships between cell types in tissue images. Here the authors present a quantitative method to evaluate cellular organization, validated in the mouse thymus and spinal cord, called Multitaper Circularly Averaged Spectral Analysis (MiCASA).
- Andrew Sornborger
- , Jie Li
- & Nancy R. Manley
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Article
| Open AccessA complete tool set for molecular QTL discovery and analysis
Analysis of molecular quantitative trait loci (molQTL) can help interpret genome-wide association studies and requires efficient approaches to correct for multiple testing. This study describes a bioinformatics toolkit called QTLtool that can handle large data sets and quickly perform multiple types of molQTL analyses.
- Olivier Delaneau
- , Halit Ongen
- & Emmanouil T. Dermitzakis
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Article
| Open AccessAn integrated model for detecting significant chromatin interactions from high-resolution Hi-C data
Genome-wide chromosome conformation capture has helped us identify features of genome topology influencing biology but requires careful statistical analysis. Here the authors present HiC-DC, a bioinformatics method that can detect statistically significant regulatory interactions.
- Mark Carty
- , Lee Zamparo
- & Christina S. Leslie
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Article
| Open AccessA hybrid cloud read aligner based on MinHash and kmer voting that preserves privacy
Outsourcing computation for genomic data processing offers the ability to allocate massive computing power and storage on demand. Here, Popic and Batzoglou develop a hybrid cloud aligner for sequence read mapping that preserves privacy with competitive accuracy and speed.
- Victoria Popic
- & Serafim Batzoglou
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Article
| Open AccessWhole genome analysis of a schistosomiasis-transmitting freshwater snail
Biomphalaria glabrata is a fresh water snail that acts as a host for trematode Schistosoma mansoni that causes intestinal infection in human. This work describes the genome and transcriptome analyses from 12 different tissues of B glabrata, and identify genes for snail behavior and evolution.
- Coen M. Adema
- , LaDeana W. Hillier
- & Richard K. Wilson
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Article
| Open AccessAnalysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection
Cell lines are central to cancer research, but knowing which cell lines are the best representative of actual tumours is a major challenge. Here the authors provide a resource assessment of 65 renal cell lines to assist researchers in selecting suitable lines for studying specific renal carcinoma subtypes.
- Rileen Sinha
- , Andrew G. Winer
- & A. Ari Hakimi
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Article
| Open AccessExchange pathways of plastoquinone and plastoquinol in the photosystem II complex
Plastoquinone (PLQ) shuttles electrons between photosystem II (PSII) and cytochrome b6f. Here the authors perform molecular dynamics simulations and propose that PLQ enters the exchange cavity of PSII by a promiscuous diffusion mechanism whereby three different channels each act as entry and exit points.
- Floris J. Van Eerden
- , Manuel N. Melo
- & Siewert J. Marrink
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Article
| Open AccessTradict enables accurate prediction of eukaryotic transcriptional states from 100 marker genes
Global patterns of gene transcription can be represented with reduced dimensionality. Here, the authors devise a method called Tradict that learns and uses 100 marker genes to predict transcriptome-wide pathway expression levels and patterns that reflect cell activity and state.
- Surojit Biswas
- , Konstantin Kerner
- & Philip A. Wigge
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Article
| Open AccessSubsampling scaling
We can often observe only a small fraction of a system, which leads to biases in the inference of its global properties. Here, the authors develop a framework that enables overcoming subsampling effects, apply it to recordings from developing neural networks, and find that neural networks become critical as they mature.
- A. Levina
- & V. Priesemann
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Article
| Open AccessSimilarity in viral and host promoters couples viral reactivation with host cell migration
The coevolution of viruses and host cells can be mapped with interactomics. Here the authors identify coupling of human and viral promoters, and show that HIV-reactivation from dormancy is coincident with migration of HIV-infected cells owing to coupling of human CXCR4 and HIV LTR promoters.
- Kathrin Bohn-Wippert
- , Erin N. Tevonian
- & Roy D. Dar
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Article
| Open AccessReconstructing 3D deformation dynamics for curved epithelial sheet morphogenesis from positional data of sparsely-labeled cells
Quantifying deformation patterns of curved epithelial sheets is challenging owing to imaging difficulties. Here the authors develop a method to obtain a quantitative description of 3D tissue deformation dynamics from a small set of cell positional data and applied it to chick forebrain morphogenesis.
- Yoshihiro Morishita
- , Ken-ichi Hironaka
- & Daisuke Ohtsuka
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Article
| Open AccessNoumeavirus replication relies on a transient remote control of the host nucleus
Large dsDNA viruses either replicate in or disrupt the nucleus to gain access to host RNA polymerases, or they rely on virus-encoded, packaged RNA polymerases. Here, the authors show that Noumeavirus replicates in the cytoplasm and relies on a transient recruitment of nuclear proteins to initiate replication.
- Elisabeth Fabre
- , Sandra Jeudy
- & Chantal Abergel
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Article
| Open AccessA computational systems approach identifies synergistic specification genes that facilitate lineage conversion to prostate tissue
The identification of master regulator genes that may be manipulatedin vitro to regulate reprogramming has been difficult. Here, the authors use a computational systems approach to identify three genes (FoxA1, Nkx3.1and the androgen receptor) that can reprogramme fibroblasts to prostate tissue.
- Flaminia Talos
- , Antonina Mitrofanova
- & Michael M. Shen
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Article
| Open AccessExercise contagion in a global social network
Some argue that health-related behaviours, such as obesity, are contagious, but empirical evidence of health contagion remains inconclusive. Here, using a large scale quasi-experiment in a global network of runners, Aral and Nicolaides show that this type of contagion exists in fitness behaviours.
- Sinan Aral
- & Christos Nicolaides
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Article
| Open AccessA new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling
Beta-arrestins play central roles in the mechanisms regulating GPCR signalling and trafficking. Here the authors identify a selective inhibitor of the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP-2, which they use to dissect the role of the β-arrestin/β2-adaptin interaction in GPCR signalling.
- Alexandre Beautrait
- , Justine S. Paradis
- & Michel Bouvier
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Article
| Open AccessGenome assembly with in vitro proximity ligation data and whole-genome triplication in lettuce
Genome assembly for many plant species can be challenging due to large size and high repeat content. Here, the authors usein vitroproximity ligation to assemble the genome of lettuce, revealing a family-specific triplication event and providing a comprehensive reference genome for a member of the Compositae.
- Sebastian Reyes-Chin-Wo
- , Zhiwen Wang
- & Richard W. Michelmore
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Article
| Open AccessComputational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in prostate cancer
Dysregulation of microRNAs is thought to be important for metastasis in castration-resistant prostate cancer (CRPC), but its drivers are unknown. Here, the authors use computational analysis to identify HOXC6 and NKX2-2 in addition to AR as alternative drivers of dysregulated miRNA expression in CRPC.
- Mengzhu Xue
- , Haiyue Liu
- & Peng Wang
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Article
| Open AccessMulti-scale chromatin state annotation using a hierarchical hidden Markov model
The impact of chromatin structure on gene expression makes it integral to our understanding of developmental and disease processes. Here, the authors introduce a hierarchical hidden Markov model to systematically annotate chromatin states at multiple length scales, and demonstrate its utility for the elucidation of the role of chromatin structure in gene expression.
- Eugenio Marco
- , Wouter Meuleman
- & Guo-Cheng Yuan
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Article
| Open AccessAn analytic approximation of the feasible space of metabolic networks
Large-scale metabolic models of organisms from microbes to mammals can provide great insight into cellular function, but their analysis remains challenging. Here, the authors provide an approximate analytic method to estimate the feasible solution space for the flux vectors of metabolic networks, enabling more accurate analysis under a wide range of conditions of interest.
- Alfredo Braunstein
- , Anna Paola Muntoni
- & Andrea Pagnani
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Article
| Open AccessSensitive detection of rare disease-associated cell subsets via representation learning
While rare cell subpopulations frequently make the difference between health and disease, their detection remains a challenge. Here, the authors devise CellCnn, a representation learning approach to detecting such rare cell populations from high-dimensional single cell data, and, among other examples, demonstrate its capacity for detecting rare leukaemic blasts in minimal residual disease.
- Eirini Arvaniti
- & Manfred Claassen
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Article
| Open AccessProteogenomic integration reveals therapeutic targets in breast cancer xenografts
Patient-derived xenografts recapitulate major genomic signatures and transcriptome profiles of their original tumours. Here, the authors, performing proteomic and phosphoproteomic analyses of 24 breast cancer PDX models, demonstrate that druggable candidates can be identified based on a comprehensive proteogenomic profiling.
- Kuan-lin Huang
- , Shunqiang Li
- & Li Ding
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Article
| Open AccessFunctional cis-regulatory modules encoded by mouse-specific endogenous retrovirus
The gene-battery model posits transposable elements (TEs) may becis-regulatory elements to control gene expression. Here, mouse-specific TEs are shown as binding sites for multiple collaborating transcription factors in embryonic stem cells, and act as cis-regulatory modules in synergistic fashion.
- Vasavi Sundaram
- , Mayank N. K. Choudhary
- & Ting Wang
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Article
| Open AccessMicroRNA filters Hox temporal transcription noise to confer boundary formation in the spinal cord
In the spinal cord, someHox genes are transcribed in progenitors while their proteins are only detected in differentiating postmitotic motor neurons. Here, the authors show that miRNAs (specifically mir-27) regulate post-transcriptional Hoxa5 expression in motor neurons.
- Chung-Jung Li
- , Tian Hong
- & Jun-An Chen
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Article
| Open AccessA genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells
Individual human epidermal cells differ in their self-renewal ability. Here the authors perform genome-wide pooled RNAi screens to uncover the molecular basis for this heterogeneity, and identify genes conferring a clonal growth advantage on normal and neoplastic human epidermal cells.
- Gernot Walko
- , Samuel Woodhouse
- & Fiona M. Watt
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Article
| Open AccessDNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression
Cell cycle arrest after DNA damage is achieved by the expression of the CDK inhibitor p21. Here the authors show that spontaneous DNA damage incurred in unperturbed cell cycles, leads to cell populations exhibiting a bistable state, with p53 and p21 regulating the proliferation-quiescence decision.
- Alexis R. Barr
- , Samuel Cooper
- & Chris Bakal
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Article
| Open AccessDefined chromosome structure in the genome-reduced bacterium Mycoplasma pneumoniae
The three-dimensional architecture of genome-reduced bacteria is poorly understood. Here the authors combine Hi-C with super-resolution microscopy inMycoplasma pneumoniaeand provide evidence of how supercoiling and local organization influences gene regulation.
- Marie Trussart
- , Eva Yus
- & LuĂs Serrano
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Article
| Open AccessCorrelation of fitness landscapes from three orthologous TIM barrels originates from sequence and structure constraints
The TIM barrel fold is an evolutionarily conserved motif found in proteins with a variety of enzymatic functions. Here the authors explore the fitness landscape of the TIM barrel protein IGPS and uncover evolutionary constraints on both sequence and structure, accompanied by long range allosteric interactions.
- Yvonne H. Chan
- , Sergey V. Venev
- & C. Robert Matthews
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Article
| Open AccessScaffolding and completing genome assemblies in real-time with nanopore sequencing
Assembling genomes using currently available computational methods can be time consuming. Here, Coin and colleagues describe a bioinformatics tool named npScarf that can scaffold and complete an existing short read assembly in real-time using nanopore sequencing.
- Minh Duc Cao
- , Son Hoang Nguyen
- & Lachlan J. M. Coin
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Article
| Open AccessRecurrently deregulated lncRNAs in hepatocellular carcinoma
Long noncoding-RNAs have been linked to hepatocellular carcinoma (HCC) and some can be used as prognostic markers. Here the authors, by analysing RNA-seq in 60 clinical samples from 20 patients, provide a resource of functional lncRNAs and biomarkers associated with HCC tumorigenesis and metastasis.
- Yang Yang
- , Lei Chen
- & Zhi John Lu
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Article
| Open AccessSmall genomic insertions form enhancers that misregulate oncogenes
Sequencing initiatives have detected multiple types of mutations in cancer. Here the authors, analysing enhancer-targeting sequence data, show that small insertions in transcriptional enhancers are frequently found near oncogenes, and demonstrate how one mutation deregulates expression of LMO2 in leukemia cells.
- Brian J. Abraham
- , Denes Hnisz
- & Richard A. Young
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Article
| Open AccessDpath software reveals hierarchical haemato-endothelial lineages of Etv2 progenitors based on single-cell transcriptome analysis
Single-cell RNA sequencing has enabled great advances in understanding developmental biology but reconstructing cellular lineages from this data remains challenging. Here the authors develop an algorithm,dpath, which models the lineage relationships of underlying single cells based on single cell RNA seq data and apply it to study lineage progression of Etv2 expressing progenitors.
- Wuming Gong
- , Tara L. Rasmussen
- & Daniel J. Garry
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Article
| Open AccessReconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions
The rat is a widely-used model for human biology, but we must be aware of metabolic differences. Here, the authors reconstruct the genome-scale metabolic network of the rat, and after reconciling it with an improved human metabolic model, demonstrate the power of the models to integrate toxicogenomics data, providing species-specific biomarker predictions in response to a panel of drugs.
- Edik M. Blais
- , Kristopher D. Rawls
- & Jason A. Papin
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Article
| Open AccessRecurring RNA structural motifs underlie the mechanics of L1 stalk movement
Translocation of the tRNA on the ribosome is associated with large-scale molecular movements of the ribosomal L1 stalk. Here the authors identify the key determinants that allow these dramatic movements, and suggest they represent general strategies used to enable large-scale motions in functional RNAs.
- Srividya Mohan
- & Harry F Noller
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Article
| Open AccessClustering of 770,000 genomes reveals post-colonial population structure of North America
Genetic data has led to great advances in our understanding of human evolution and dispersal, but information on more recent events is limited. Here, the authors analyse genotypes from 770,000 US individuals to map the fine-scale population structure of North America after European settlement.
- Eunjung Han
- , Peter Carbonetto
- & Catherine A. Ball
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Article
| Open AccessPancancer modelling predicts the context-specific impact of somatic mutations on transcriptional programs
Cancer genomic data sets contain a wealth of data that can be used to predict prognosis and further understand disease. Here, the authors integrate multiple genomics data types to identify transcriptional dysregulation in response to somatic mutations.
- Hatice U. Osmanbeyoglu
- , Eneda Toska
- & Christina S. Leslie
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Article
| Open AccessReconstructing metastatic seeding patterns of human cancers
Tumours frequently metastasize to multiple anatomical sites and understanding how these different metastases evolve may be important for therapy. Here, the authors develop a method—Treeomics—that can construct phylogenies from multiple metastases from next-generation sequencing data.
- Johannes G. Reiter
- , Alvin P. Makohon-Moore
- & Martin A. Nowak
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Article
| Open AccessTransient structural variations have strong effects on quantitative traits and reproductive isolation in fission yeast
Fission yeastSchizosaccharomyces pombe has diverse traits. Jeffares et al. characterize large copy number variations (CNVs) and rearrangements in S. pombe, and show that CNVs are transient with effects on quantitative traits and gene expression, whereas rearrangements influence intrinsic reproductive isolation.
- Daniel C. Jeffares
- , Clemency Jolly
- & Fritz J. Sedlazeck
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Article
| Open AccessA cell-based computational model of early embryogenesis coupling mechanical behaviour and gene regulation
Embryonic development is a complex process where genetic and biochemical information direct morphogenesis. Here the authors describe MecaGen, an agent-based model and simulation platform of multicellular development designed to allow a quantitative comparison between simulations and real biological data.
- Julien Delile
- , Matthieu Herrmann
- & René Doursat
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Article
| Open AccessMetaSort untangles metagenome assembly by reducing microbial community complexity
Currently available metagenomic data analysis relies on reference genomes. Here, the authors describe a newde novometagenomic assembly method, metaSort, that constructs bacterial genomes from metagenomic samples to reduce microbial community complexity while increasing genome recovery and assembly.
- Peifeng Ji
- , Yanming Zhang
- & Fangqing Zhao
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Article
| Open AccessRapid tuning shifts in human auditory cortex enhance speech intelligibility
Experience constantly shapes perception, but the neural mechanisms of this rapid plasticity are unclear. Here, Holdgraf et al. record neural activity in the human auditory cortex and show that listening to normal speech elicits rapid plasticity that increases the neural gain for features of sound that are key for speech intelligibility.
- Christopher R. Holdgraf
- , Wendy de Heer
- & Frédéric E. Theunissen
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Article
| Open AccessIntegrative modelling of tumour DNA methylation quantifies the contribution of metabolism
Altered DNA methylation is a feature of cancer and between-patient variability is prevalent. Here, the authors integrate data on thousands of human tumours, and find that expression levels of methionine metabolism genes are predictive of methylation features, and that the breakdown of this relationship is a negative prognostic marker.
- Mahya Mehrmohamadi
- , Lucas K. Mentch
- & Jason W. Locasale
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Article
| Open AccessDefining functional interactions during biogenesis of epithelial junctions
Formation and reinforcement of E-cadherin-mediated adhesion depends on intracellular trafficking and interactions with the actin cytoskeleton, but how these are coordinated is not known. Here the authors conduct a focused phenotypic screen to identify new pathways regulating cell–cell junction homeostasis.
- J. C. Erasmus
- , S. Bruche
- & V. M. M. Braga
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Article
| Open AccessAn ethnically relevant consensus Korean reference genome is a step towards personal reference genomes
The utility of a universal reference sequence for human genome comparisons is dependent on the ethnic origins of the individuals being sequenced. Here the authors report a Korean reference genome and consensus variome, and show that an ethnically-relevant reference can improve variant detection.
- Yun Sung Cho
- , Hyunho Kim
- & Jong Bhak
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Article
| Open AccessA principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.
- Janina S. Ried
- , Janina Jeff M.
- & Ruth J. F. Loos
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Article
| Open AccessDeep phenotyping unveils hidden traits and genetic relations in subtle mutants
Experimenter scoring of cellular imaging data can be biased. This study describes an automated and unbiased multidimensional phenotyping method that relies on machine learning and complex feature computation of imaging data, and identifies weak alleles affecting synapse morphology in live C. elegans.
- Adriana San-Miguel
- , Peri T. Kurshan
- & Hang Lu
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Article
| Open AccessA systems study reveals concurrent activation of AMPK and mTOR by amino acids
mTORC1 is known to mediate the signalling activity of amino acids. Here, the authors combine modelling with experiments and find that amino acids acutely stimulate mTORC2, IRS/PI3K and AMPK, independently of mTORC1. AMPK activation through CaMKKβ sustains autophagy under non-starvation conditions.
- Piero Dalle Pezze
- , Stefanie Ruf
- & Kathrin Thedieck
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