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| Open AccessTargeted calcium influx boosts cytotoxic T lymphocyte function in the tumour microenvironment
Regulatory T cells (Tregs) promote immune suppression in the tumour. Here, the authors show that Tregs suppress cytotoxic T lymphocyte (CTL) activity by impairing Ca2+ signalling and that adoptive transfer of CTLs engineered with an optogenetic control of Ca2+overcome the immune suppression at the tumour site.
- Kyun-Do Kim
- , Seyeon Bae
- & Minsoo Kim
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Article
| Open AccessActomyosin meshwork mechanosensing enables tissue shape to orient cell force
Large-scale tissue reorganization requires the generation of directional tension, which requires orientation of the cytoskeleton. Here Chanetet al. alter tissue shape and tension in the Drosophilaembryo to show that geometric and mechanical constraints act as cues to orient the cytoskeleton and tension.
- Soline Chanet
- , Callie J. Miller
- & Adam C. Martin
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Article
| Open AccessSirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins
The deacetylase Sirt1, known to regulate many cellular functions, can be activated by energy deprivation, however the mechanism is unclear. Here, the authors show that ATP inhibits Sirt1 by binding to the C-terminal domain, and energy deprivation derepresses Sirt1 activity by lowering the ATP level.
- Hyeog Kang
- , Shinichi Oka
- & Jay H. Chung
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Article
| Open AccessImage-guided genomics of phenotypically heterogeneous populations reveals vascular signalling during symbiotic collective cancer invasion
The mechanisms linking phenotypic heterogeneity to collective cancer invasion are unclear. Here the authors develop an image-guided genomic technique to select and amplify leader and follower cells fromin vitroinvading cell packs and find a cooperative symbiotic relationship between these two cell populations.
- J. Konen
- , E. Summerbell
- & A. I. Marcus
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Article
| Open AccessL-selectin mechanochemistry restricts neutrophil priming in vivo
Neutrophil adhesion is tightly regulated to enforce protective immunity, but it is unclear how mechanochemical processes such as catch bonds and slip bonds modulate neutrophilsin vivo. Here the authors show that a point mutation in the adhesion molecule L-selectin alters mechanochemical regulation to affect neutrophil functions in mice.
- Zhenghui Liu
- , Tadayuki Yago
- & Rodger P. McEver
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Article
| Open AccessA simple optogenetic MAPK inhibitor design reveals resonance between transcription-regulating circuitry and temporally-encoded inputs
Light-sensitive regulators of protein kinases could offer valuable insights into intracellular signalling. Here the authors design an optogenetic inhibitor of c-Jun N-terminal kinase (JNK) and show evidence for resonance in JNK signalling circuits in neurons, and use the same design principle to develop an inhibitor for p38MAPK.
- Raquel M. Melero-Fernandez de Mera
- , Li-Li Li
- & Michael J. Courtney
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Article
| Open AccessC. elegans chromosomes connect to centrosomes by anchoring into the spindle network
A connection between centrosomes and chromosomes is a key feature of mitotic spindles. Here the authors generate 3D reconstructions of whole mitotic spindles in earlyC. elegansembryos and show that chromosomes are anchored by the entire spindle network and that connections through kinetochore microtubules are few and likely very transient.
- Stefanie Redemann
- , Johannes Baumgart
- & Thomas Müller-Reichert
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Article
| Open AccessTargeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity
How NALP7 inflammasome formation is regulated is unclear. Here the authors show that STAMBP prevents lysosomal degradation of NALP7 and present BC-1471 as a potential therapeutic STAMBP inhibitor, showing it can reduce TLR-induced IL-1β production.
- Joseph S. Bednash
- , Nathaniel Weathington
- & Rama K. Mallampalli
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Article
| Open AccessHistone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression
Senescence of mammalian cells is characterized by proliferative arrest and expression of an inflammatory phenotype. Here the authors show the H2A variant H2A.J, found only in mammals, accumulates following persistent DNA damage or natural aging.
- Kévin Contrepois
- , Clément Coudereau
- & Carl Mann
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Article
| Open AccessRegulation of cardiomyocyte behavior in zebrafish trabeculation by Neuregulin 2a signaling
Cardiac trabeculae (which are sponge-like muscular structures) form mostly as a result of cardiomyocyte (CM) delamination in zebrafish. Here, the authors identify Nrg2a in zebrafish as a key regulator of trabeculation, and atrial and non-contractile CMs also respond to Nrg2a despite not forming trabeculae.
- S. Javad Rasouli
- & Didier Y. R. Stainier
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Article
| Open AccessEGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration
In response to gut epithelial damage,Drosophilastem cells proliferate to produce large polyploid enterocytes (EC), which comprise the bulk of the epithelium. Here, the authors show that stress-dependent EGFR/MAP kinase signalling drives both endoreplication and cell growth in newborn ECs.
- Jinyi Xiang
- , Jennifer Bandura
- & Bruce A. Edgar
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Article
| Open AccessCharting organellar importomes by quantitative mass spectrometry
Knowing the specific protein content of individual organelles is necessary for an integrated understanding of cellular physiology. Here the authors describe a mass spectrometry-based approach to identify the substrates of distinct protein import pathways and define organellar proteomes.
- Christian D. Peikert
- , Jan Mani
- & Bettina Warscheid
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Article
| Open AccessSignalome-wide assessment of host cell response to hepatitis C virus
Development of antiviral strategies depends on an understanding of virus–host interactions. Here, using HCV, Haqshenaset al. show that antibody microarray combined with a targeted siRNA screen can be a powerful tool to identify cellular signalling pathways that are important for virus replication.
- Gholamreza Haqshenas
- , Jianmin Wu
- & Christian Doerig
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Article
| Open AccessStat3 regulates centrosome clustering in cancer cells via Stathmin/PLK1
Cancer cells have amplified centrosomes and deal with this abnormality by clustering them together so that they can be segregated in daughter cells. Here the authors perform a screening looking for inhibitors of this clustering process and find that STAT3 regulates this process independently of its transcriptional function.
- Edward J. Morris
- , Eiko Kawamura
- & Shoukat Dedhar
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Article
| Open AccessSubnanometre-resolution structure of the doublet microtubule reveals new classes of microtubule-associated proteins
Cilia are hair-like appendages involved in cell motility and sensory reception. Here, the authors report a high resolution cryo-EM structure of the microtubule doublet from motile cilia and identify microtubule inner proteins (MIPs) bound to the inner surface of the doublet that appear to stabilize its structure.
- Muneyoshi Ichikawa
- , Dinan Liu
- & Khanh Huy Bui
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Article
| Open AccessMechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate
The guanine nucleotide exchange factor SOS is a critical intermediary that transduces receptor tyrosine kinase stimulation into Ras activation. Here the authors develop a single molecule assay in which SOS is captured from raw lysates using Ras-functionalized membrane microarrays and uncover an autoinhibitory mechanism of SOS regulation.
- Young Kwang Lee
- , Shalini T. Low-Nam
- & Jay T. Groves
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Article
| Open AccessDistinct molecular cues ensure a robust microtubule-dependent nuclear positioning in the Drosophila oocyte
Asymmetric nuclear positioning in the fruit fly oocyte is essential for the correct localization of axis determinants. Here, the authors show that different microtubule-dependent mechanisms contribute to nuclear transport and ensure the robustness of nuclear positioning.
- Nicolas Tissot
- , Jean-Antoine Lepesant
- & Antoine Guichet
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Article
| Open AccessDNA replication licensing factor Cdc6 and Plk4 kinase antagonistically regulate centrosome duplication via Sas-6
Centrosome duplication is synchronized with cell cycle events but how this is regulated at a molecular level is unclear. Here, the authors show that the DNA replication licensing factor Cdc6 restrains centrosome duplication via binding and inhibiting Sas-6, and the inhibition of Cdc6 on Sas-6 is negatively regulated by Plk4 phosphorylation.
- Xiaowei Xu
- , Shijiao Huang
- & Chuanmao Zhang
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Article
| Open AccessCell-size dependent progression of the cell cycle creates homeostasis and flexibility of plant cell size
The mechanistic coupling of cell growth and cell cycle control with cell size regulation in tissues is not well understood. Here, the authors show that within the shoot apical meristem of Arabidopsis cell size depends on developmental stage, genotype and environmental signals; however cell growth and cell division are cell-autonomously coordinated.
- Angharad R. Jones
- , Manuel Forero-Vargas
- & James A. H. Murray
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Article
| Open AccessFAF1 phosphorylation by AKT accumulates TGF-β type II receptor and drives breast cancer metastasis
Aberrant activation of TGF-β signalling promotes cancer metastasis but the initial steps of this activation are unclear. Here Xieet al. show that FAF1 regulates the surface levels of TGF-β type II receptor thus influencing the persistence of the signalling and breast cancer metastasis.
- Feng Xie
- , Ke Jin
- & Long Zhang
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Article
| Open AccessDirect comparison of distinct naive pluripotent states in human embryonic stem cells
Human embryonic stem cells (hESCs) in culture display a state of primed pluripotency, but recent protocols have been developed that enable hESCs to adopt a naive-like pluripotent state. Here the authors perform a side-by-side comparison of methods used to culture naive hESCs and confirm the role of PI3K/AKT/mTORC signalling in facilitating the induction of naive pluripotency.
- S. Warrier
- , M. Van der Jeught
- & B. Heindryckx
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Article
| Open AccessThe glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility
The factors that limit the nutrient flexibility of cells remain largely unknown. Here, the authors identify the glutamate/cysteine antiporter xCT in a genetic screen for glucose dependency and show it determines the ability of cells to survive under conditions of low glucose by limiting the utilization of glutamine.
- Chun-Shik Shin
- , Prashant Mishra
- & David C. Chan
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Article
| Open AccessLamin B1 is required for mature neuron-specific gene expression during olfactory sensory neuron differentiation
Emerging evidence suggests that lamins regulate gene expression during cellular differentiation. Giganteet al. show that lamin B1 is necessary for the upregulation of mature neuron-specific genes during olfactory neuron differentiation, and its deficiency leads to attenuated olfactory neuron response to odour in mice.
- Crystal M. Gigante
- , Michele Dibattista
- & Haiqing Zhao
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Article
| Open AccessFRET biosensor uncovers cAMP nano-domains at β-adrenergic targets that dictate precise tuning of cardiac contractility
cAMP/PKA signalling plays important roles in physiology, but there are a lack of tools to spatially distinguish cAMP. Here the authors present a FRET-based cAMP biosensor they call CUTie that can directly compare cAMP signals at multiple subcellular sites and detect nanoscale heterogeneity in cAMP in cardiac myocytes.
- Nicoletta C. Surdo
- , Marco Berrera
- & Manuela Zaccolo
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Article
| Open AccessHierarchical assembly of centriole subdistal appendages via centrosome binding proteins CCDC120 and CCDC68
Centriole subdistal appendages (SDAs) anchor microtubules in interphase cells, but their composition and assembly mechanisms are unclear. Here the authors show that two new SDA components, CCDC120 and CCDC68, are required for hierarchical SDA assembly and centrosome microtubule anchoring.
- Ning Huang
- , Yuqing Xia
- & Jianguo Chen
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Article
| Open AccessLysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface
Lysyl oxidase is able to remodel the extracellular matrix and its expression correlates with poor prognosis. Here the authors show that this protein modulates trapping of the epidermal growth factor receptor at the cell surface, causing persistent signalling activation and tumour progression.
- HaoRan Tang
- , Leo Leung
- & Richard Marais
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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 AccessLocal inhibition of microtubule dynamics by dynein is required for neuronal cargo distribution
Microtubule dynamics are essential for axonal transport. InC. elegans, the authors show that dynein heavy chain regulates the spatial distribution of dendritic microtubules which ensures correct transport progression.
- Shaul Yogev
- , Celine I. Maeder
- & Kang Shen
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Article
| Open AccessCell-matrix adhesion and cell-cell adhesion differentially control basal myosin oscillation and Drosophila egg chamber elongation
Pulsatile actomyosin contractility during tissue morphogenesis has been mainly studied in apical domains but less is known about the contribution of the basal domain. Here the authors show differential influence of cell-matrix and cell-cell adhesions in regulating oscillations and tissue elongation.
- Xiang Qin
- , Byung Ouk Park
- & Xiaobo Wang
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Article
| Open AccessAnisotropic forces from spatially constrained focal adhesions mediate contact guidance directed cell migration
Contact guidance on aligned substrates leads to directed cell migration through a poorly defined mechanism. Here the authors show that alignment of adhesion structures and F-actin generates anisotropic traction stress to drive directional migration, and cell-cell contact reduces force orientation and directional response.
- Arja Ray
- , Oscar Lee
- & Paolo P. Provenzano
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Article
| Open AccessStructural and functional analysis of the human POT1-TPP1 telomeric complex
POT1 and TTP1 are part of the shelterin complex that caps and stabilizes the ends of telomeres. Here the authors present a structural analysis of the human POT1-TTP1 complex, shedding light on how it assembles and how cancer-associated mutations impact its assembly and function.
- Cory Rice
- , Prashanth Krishna Shastrula
- & Emmanuel Skordalakes
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Article
| Open AccessStructural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer
Human telomeres are protected by a specialized shelterin complex composed of six proteins. Here the authors structurally characterize the interaction between the POT1-TPP1 shelterin component and identify mutations associated with genome instability and cancer that disrupt the POT1-TPP1 interaction.
- Cong Chen
- , Peili Gu
- & Ming Lei
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Article
| Open AccessExosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis
EGFR signalling has been linked to cancer development but whether it has any role in pre-metastatic niche formation is not known. Here the authors show that gastric cancer cells send EGFR through exosomes to the liver where it causes the establishment of a favourable microenvironment thus promoting metastasis.
- Haiyang Zhang
- , Ting Deng
- & Yi Ba
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Article
| Open AccessEndothelial LRP1 regulates metabolic responses by acting as a co-activator of PPARγ
LDL receptor-related protein 1 (LRP1) is an endocytic receptor involved in cell signalling and energy homeostasis. Here Maoet al. demonstrate that endothelial Lrp1 modulates lipid and glucose metabolism by binding the nuclear receptor Pparγ and promoting its transcriptional activity.
- Hua Mao
- , Pamela Lockyer
- & Xinchun Pi
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Article
| Open AccessCrystal structure of Zen4 in the apo state reveals a missing conformation of kinesin
Kinesins are molecular motors that travel along microtubules through a nucleotide-dependent stepping mechanism. Here the authors present the crystal structure of Zen4 (kinesin-6) in an apo state that sheds light on a key stepping intermediate of kinesin.
- Ruifang Guan
- , Lei Zhang
- & Zhucheng Chen
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Article
| Open AccessDefective Gpsm2/Gαi3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome
Mutations inGPSM2cause a rare disease characterized by deafness and brain abnormalities. Here the authors show that Gpsm2 forms a molecular complex with a heterotrimeric G-protein subunit, whirlin and a myosin motor to regulate actin dynamics in neurons and auditory hair cell stereocilia.
- Stephanie A. Mauriac
- , Yeri E. Hien
- & Mireille Montcouquiol
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Article
| Open AccessRetrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration
The endocytic adaptor protein complex AP-2 is mostly known for its role in endocytosis and in synaptic vesicle reformation. Here the authors show that AP-2 also mediates retrograde transport of TrkB-containing autophagosomes in neurons; this process promotes neuronal complexity and prevents the degeneration of cortical and thalamic neurons.
- Natalia L. Kononenko
- , Gala A. Claßen
- & Volker Haucke
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Article
| Open AccessHighly selective inhibition of histone demethylases by de novo macrocyclic peptides
JmjC histone demethylases (KDMs) are cancer targets due to their links to cell proliferation, but selective inhibition remains a challenge. Here the authors identify potent inhibitors of KDM4A-C—viain vitroselection from a vast library of cyclic peptides—that show selectivity over other KDMs.
- Akane Kawamura
- , Martin Münzel
- & Christopher J. Schofield
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Article
| Open AccessQuantitative 3D analysis of complex single border cell behaviors in coordinated collective cell migration
Quantifying cell behavioursin vivo is essential to understanding the mechanisms of collective cell migration. Here the authors present an image analysis toolkit, CCMToolKit, to describe and characterize various modes of coordinated cell movements accompanying collective cell migration in Drosophilaborder cells.
- Adam Cliffe
- , David P. Doupé
- & Weimiao Yu
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Article
| Open AccessLoss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease
ARPC1B is a component of the actin-related protein 2/3 complex (Arp2/3), which is required for actin filament branching. Kahret al. show that ARPC1B deficiency in humans is associated with severe multisystem disease that includes platelet abnormalities, eosinophilia, eczema and other indicators of immune disease.
- Walter H. A. Kahr
- , Fred G. Pluthero
- & Aleixo M Muise
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Article
| Open AccessRole for formin-like 1-dependent acto-myosin assembly in lipid droplet dynamics and lipid storage
Lipid droplets (LDs) are cellular organelles dedicated to triacylglycerol storage that can undergo fusion and dissociation events. Here the authors show that formin-like 1-dependent acto-myosin assembly on LDs facilitates their dissociation and, as a consequence, affects hydrolysis and storage of triacylglycerols.
- Simon G. Pfisterer
- , Gergana Gateva
- & Elina Ikonen
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Article
| Open AccessThe Par3 polarity protein is an exocyst receptor essential for mammary cell survival
The exocyst delivers basolateral proteins from the secretory pathway to the plasma membrane of epithelial cells close to tight junctions. Here the authors show that Par3 acts as a docking site for the exocyst to regulate polarized delivery of basolateral proteins and this is essential to prevent apoptosis and promote mammary cell survival.
- Syed Mukhtar Ahmed
- & Ian G. Macara
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Article
| Open AccessDomain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression
Despite being structurally similar, the insulin receptor (IR) and insulin growth factor I receptor (IGF1R) elicit distinct signalling pathways. Here the authors use receptor chimeras to unveil that IR and IGF1R signalling is related primarily to differences in their intracellular juxtamembrane region.
- Weikang Cai
- , Masaji Sakaguchi
- & C. Ronald Kahn
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Article
| Open AccessLight-sensing via hydrogen peroxide and a peroxiredoxin
While yeasts lack dedicated photoreceptors, they nonetheless possess metabolic rhythms responsive to light. Here the authors find that light signalling in budding yeast involves the production of H2O2, which in turn regulates protein kinase A through a peroxiredoxin-thioredoxin redox relay.
- Kristofer Bodvard
- , Ken Peeters
- & Mikael Molin
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Article
| Open AccessA chemical chaperone improves muscle function in mice with a RyR1 mutation
Mutations in the RyR1 channel cause core myopathies. Here the authors show that ER stress and the unfolded protein response underlie the pathology caused by a common RyR1 channel mutation, and show that treatment with a chemical chaperone restores muscle function in mice.
- Chang Seok Lee
- , Amy D. Hanna
- & Susan L. Hamilton
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Correspondence
| Open AccessCorrespondence: Reply to ‘Oncogenic MYC persistently upregulates the molecular clock component REV-ERBα’
- Anton Shostak
- , Bianca Ruppert
- & Michael Brunner
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Correspondence
| Open AccessCorrespondence: Oncogenic MYC persistently upregulates the molecular clock component REV-ERBα
- Brian J. Altman
- , Annie L. Hsieh
- & Chi V. Dang
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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 AccessCell-free reconstitution reveals centriole cartwheel assembly mechanisms
The centriole is an organelle composed of rings of SAS-6 proteins that form a cartwheel structure. Here the authors develop a cell-free system to examine core cartwheel assembly ofC. reinhardtiiproteins and discover that CrSAS-6 has autonomous properties that facilitates self-organized stacking of pairs of rings.
- P. Guichard
- , V. Hamel
- & P. Gönczy
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