Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all branches of science and how science impacts upon all aspects of society and life.
  • Endosymbiotic origin and differential loss of eukaryotic genes
    [Aug 2015]

    Endosymbiotic origin and differential loss of eukaryotic genes

    Nature 524, 7566 (2015). doi:10.1038/nature14963

    Authors: Chuan Ku, Shijulal Nelson-Sathi, Mayo Roettger, Filipa L. Sousa, Peter J. Lockhart, David Bryant, Einat Hazkani-Covo, James O. McInerney, Giddy Landan & William F. Martin

    Chloroplasts arose from cyanobacteria, mitochondria arose from proteobacteria. Both organelles have conserved their prokaryotic biochemistry, but their genomes are reduced, and most organelle proteins are encoded in the nucleus. Endosymbiotic theory posits that bacterial genes in eukaryotic genomes entered the eukaryotic lineage via organelle ancestors.

    Categories: Journal Articles
  • Sidekick 2 directs formation of a retinal circuit that detects differential motion
    [Aug 2015]

    Sidekick 2 directs formation of a retinal circuit that detects differential motion

    Nature 524, 7566 (2015). doi:10.1038/nature14682

    Authors: Arjun Krishnaswamy, Masahito Yamagata, Xin Duan, Y. Kate Hong & Joshua R. Sanes

    In the mammalian retina, processes of approximately 70 types of interneurons form specific synapses on roughly 30 types of retinal ganglion cells (RGCs) in a neuropil called the inner plexiform layer. Each RGC type extracts salient features from visual input, which are sent deeper into the brain for further processing. The specificity and stereotypy of synapses formed in the inner plexiform layer account for the feature-detecting ability of RGCs. Here we analyse the development and function of synapses on one mouse RGC type, called the W3B-RGC. These cells have the remarkable property of responding when the timing of the movement of a small object differs from that of the background, but not when they coincide. Such cells, known as local edge detectors or object motion sensors, can distinguish moving objects from a visual scene that is also moving. We show that W3B-RGCs receive strong and selective input from an unusual excitatory amacrine cell type known as VG3-AC (vesicular glutamate transporter 3). Both W3B-RGCs and VG3-ACs express the immunoglobulin superfamily recognition molecule sidekick 2 (Sdk2), and both loss- and gain-of-function studies indicate that Sdk2-dependent homophilic interactions are necessary for the selectivity of the connection. The Sdk2-specified synapse is essential for visual responses of W3B-RGCs: whereas bipolar cells relay visual input directly to most RGCs, the W3B-RGCs receive much of their input indirectly, via the VG3-ACs. This non-canonical circuit introduces a delay into the pathway from photoreceptors in the centre of the receptive field to W3B-RGCs, which could improve their ability to judge the synchrony of local and global motion.

    Categories: Journal Articles
  • Cell mixing induced by myc is required for competitive tissue invasion and destruction
    [Aug 2015]

    Cell mixing induced by myc is required for competitive tissue invasion and destruction

    Nature 524, 7566 (2015). doi:10.1038/nature14684

    Authors: Romain Levayer, Barbara Hauert & Eduardo Moreno

    Cell–cell intercalation is used in several developmental processes to shape the normal body plan. There is no clear evidence that intercalation is involved in pathologies. Here we use the proto-oncogene myc to study a process analogous to early phase of tumour expansion: myc-induced cell competition. Cell competition is a conserved mechanism driving the elimination of slow-proliferating cells (so-called ‘losers’) by faster-proliferating neighbours (so-called ‘winners’) through apoptosis and is important in preventing developmental malformations and maintain tissue fitness. Here we show, using long-term live imaging of myc-driven competition in the Drosophila pupal notum and in the wing imaginal disc, that the probability of elimination of loser cells correlates with the surface of contact shared with winners. As such, modifying loser–winner interface morphology can modulate the strength of competition. We further show that elimination of loser clones requires winner–loser cell mixing through cell–cell intercalation. Cell mixing is driven by differential growth and the high tension at winner–winner interfaces relative to winner–loser and loser–loser interfaces, which leads to a preferential stabilization of winner–loser contacts and reduction of clone compactness over time. Differences in tension are generated by a relative difference in F-actin levels between loser and winner junctions, induced by differential levels of the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate. Our results establish the first link between cell–cell intercalation induced by a proto-oncogene and how it promotes invasiveness and destruction of healthy tissues.

    Categories: Journal Articles
  • Multimetallic catalysed cross-coupling of aryl bromides with aryl triflates
    [Aug 2015]

    Multimetallic catalysed cross-coupling of aryl bromides with aryl triflates

    Nature 524, 7566 (2015). doi:10.1038/nature14676

    Authors: Laura K. G. Ackerman, Matthew M. Lovell & Daniel J. Weix

    The advent of transition-metal catalysed strategies for forming new carbon-carbon bonds has revolutionized the field of organic chemistry, enabling the efficient synthesis of ligands, materials, and biologically active molecules. In cases where a single metal fails to promote a selective or efficient transformation, the synergistic cooperation of two distinct catalysts—multimetallic catalysis—can be used instead. Many important reactions rely on multimetallic catalysis, such as the Wacker oxidation of olefins and the Sonogashira coupling of alkynes with aryl halides, but this approach has largely been limited to the use of metals with distinct reactivities, with only one metal catalyst undergoing oxidative addition. Here, we demonstrate that cooperativity between two group 10 metal catalysts—(bipyridine)nickel and (1,3-bis(diphenylphosphino)propane)palladium—enables a general cross-Ullmann reaction (the cross-coupling of two different aryl electrophiles). Our method couples aryl bromides with aryl triflates directly, eliminating the use of arylmetal reagents and avoiding the challenge of differentiating between multiple carbon–hydrogen bonds that is required for direct arylation methods. Selectivity can be achieved without an excess of either substrate and originates from the orthogonal reactivity of the two catalysts and the relative stability of the two arylmetal intermediates. While (1,3-bis(diphenylphosphino)propane)palladium reacts preferentially with aryl triflates to afford a persistent intermediate, (bipyridine)nickel reacts preferentially with aryl bromides to form a transient, reactive intermediate. Although each catalyst forms less than 5 per cent cross-coupled product in isolation, together they are able to achieve a yield of up to 94 per cent. Our results reveal a new method for the synthesis of biaryls, heteroaryls, and dienes, as well as a general mechanism for the selective transfer of ligands between two metal catalysts. We anticipate that this reaction will simplify the synthesis of pharmaceuticals, many of which are currently made with pre-formed organometallic reagents, and lead to the discovery of new multimetallic reactions.

    Categories: Journal Articles
  • Structural biology: Lipid gymnastics
    [Aug 2015]

    Structural biology: Lipid gymnastics

    Nature 524, 7566 (2015). doi:10.1038/nature15202

    Authors: Alice Verchère & Anant K. Menon

    Crystal structures of the bacterial protein PglK uncover structural features that suggest how the protein 'flips' lipid-bound oligosaccharide molecules from one side of the cell membrane to the other. See Article p.433

    Categories: Journal Articles
  • Structure and mechanism of an active lipid-linked oligosaccharide flippase
    [Aug 2015]

    Structure and mechanism of an active lipid-linked oligosaccharide flippase

    Nature 524, 7566 (2015). doi:10.1038/nature14953

    Authors: Camilo Perez, Sabina Gerber, Jérémy Boilevin, Monika Bucher, Tamis Darbre, Markus Aebi, Jean-Louis Reymond & Kaspar P. Locher

    The flipping of membrane-embedded lipids containing large, polar head groups is slow and energetically unfavourable, and is therefore catalysed by flippases, the mechanisms of which are unknown. A prominent example of a flipping reaction is the translocation of lipid-linked oligosaccharides that serve as donors in

    Categories: Journal Articles
  • SEC14L2 enables pan-genotype HCV replication in cell culture
    [Aug 2015]

    SEC14L2 enables pan-genotype HCV replication in cell culture

    Nature 524, 7566 (2015). doi:10.1038/nature14899

    Authors: Mohsan Saeed, Ursula Andreo, Hyo-Young Chung, Christine Espiritu, Andrea D. Branch, Jose M. Silva & Charles M. Rice

    Since its discovery in 1989, efforts to grow clinical isolates of the hepatitis C virus (HCV) in cell culture have met with limited success. Only the JFH-1 isolate has the capacity to replicate efficiently in cultured hepatoma cells without cell culture-adaptive mutations. We hypothesized that cultured cells lack one or more factors required for the replication of clinical isolates. To identify the missing factors, we transduced Huh-7.5 human hepatoma cells with a pooled lentivirus-based human complementary DNA (cDNA) library, transfected the cells with HCV subgenomic replicons lacking adaptive mutations, and selected for stable replicon colonies. This led to the identification of a single cDNA, SEC14L2, that enabled RNA replication of diverse HCV genotypes in several hepatoma cell lines. This effect was dose-dependent, and required the continuous presence of SEC14L2. Full-length HCV genomes also replicated and produced low levels of infectious virus. Remarkably, SEC14L2-expressing Huh-7.5 cells also supported HCV replication following inoculation with patient sera. Mechanistic studies suggest that SEC14L2 promotes HCV infection by enhancing vitamin E-mediated protection against lipid peroxidation. This provides a foundation for development of in vitro replication systems for all HCV isolates, creating a useful platform to dissect the mechanisms by which cell culture-adaptive mutations act.

    Categories: Journal Articles
  • The pre-vertebrate origins of neurogenic placodes
    [Aug 2015]

    The pre-vertebrate origins of neurogenic placodes

    Nature 524, 7566 (2015). doi:10.1038/nature14657

    Authors: Philip Barron Abitua, T. Blair Gainous, Angela N. Kaczmarczyk, Christopher J. Winchell, Clare Hudson, Kaori Kamata, Masashi Nakagawa, Motoyuki Tsuda, Takehiro G. Kusakabe & Michael Levine

    The sudden appearance of the neural crest and neurogenic placodes in early branching vertebrates has puzzled biologists for over a century. These embryonic tissues contribute to the development of the cranium and associated sensory organs, which were crucial for the evolution of the vertebrate “new head”. A previous study suggests that rudimentary neural crest cells existed in ancestral chordates. However, the evolutionary origins of neurogenic placodes have remained obscure owing to a paucity of embryonic data from tunicates, the closest living relatives to those early vertebrates. Here we show that the tunicate Ciona intestinalis exhibits a proto-placodal ectoderm (PPE) that requires inhibition of bone morphogenetic protein (BMP) and expresses the key regulatory determinant Six1/2 and its co-factor Eya, a developmental process conserved across vertebrates. The Ciona PPE is shown to produce ciliated neurons that express genes for gonadotropin-releasing hormone (GnRH), a G-protein-coupled receptor for relaxin-3 (RXFP3) and a functional cyclic nucleotide-gated channel (CNGA), which suggests dual chemosensory and neurosecretory activities. These observations provide evidence that Ciona has a neurogenic proto-placode, which forms neurons that appear to be related to those derived from the olfactory placode and hypothalamic neurons of vertebrates. We discuss the possibility that the PPE-derived GnRH neurons of Ciona resemble an ancestral cell type, a progenitor to the complex neuronal circuit that integrates sensory information and neuroendocrine functions in vertebrates.

    Categories: Journal Articles
  • Conformational dynamics of a class C G-protein-coupled receptor
    [Aug 2015]

    Conformational dynamics of a class C G-protein-coupled receptor

    Nature 524, 7566 (2015). doi:10.1038/nature14679

    Authors: Reza Vafabakhsh, Joshua Levitz & Ehud Y. Isacoff

    G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors in eukaryotes. Crystal structures have provided insight into GPCR interactions with ligands and G proteins, but our understanding of the conformational dynamics of activation is incomplete. Metabotropic glutamate receptors (mGluRs) are dimeric class C GPCRs that modulate neuronal excitability, synaptic plasticity, and serve as drug targets for neurological disorders. A ‘clamshell’ ligand-binding domain (LBD), which contains the ligand-binding site, is coupled to the transmembrane domain via a cysteine-rich domain, and LBD closure seems to be the first step in activation. Crystal structures of isolated mGluR LBD dimers led to the suggestion that activation also involves a reorientation of the dimer interface from a ‘relaxed’ to an ‘active’ state, but the relationship between ligand binding, LBD closure and dimer interface rearrangement in activation remains unclear. Here we use single-molecule fluorescence resonance energy transfer to probe the activation mechanism of full-length mammalian group II mGluRs. We show that the LBDs interconvert between three conformations: resting, activated and a short-lived intermediate state. Orthosteric agonists induce transitions between these conformational states, with efficacy determined by occupancy of the active conformation. Unlike mGluR2, mGluR3 displays basal dynamics, which are Ca2+-dependent and lead to basal protein activation. Our results support a general mechanism for the activation of mGluRs in which agonist binding induces closure of the LBDs, followed by dimer interface reorientation. Our experimental strategy should be widely applicable to study conformational dynamics in GPCRs and other membrane proteins.

    Categories: Journal Articles
  • Cell biology: Surviving import failure
    [Aug 2015]

    Cell biology: Surviving import failure

    Nature 524, 7566 (2015). doi:10.1038/nature14644

    Authors: Cole M. Haynes

    Two studies reveal that dysfunction in organelles called mitochondria causes the toxic accumulation of mitochondrial proteins in the cell's cytosolic fluid, and identify ways in which damage is mitigated. See Letters p.481 & p.485

    Categories: Journal Articles
  • Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol
    [Aug 2015]

    Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol

    Nature 524, 7566 (2015). doi:10.1038/nature14951

    Authors: Lidia Wrobel, Ulrike Topf, Piotr Bragoszewski, Sebastian Wiese, Malgorzata E. Sztolsztener, Silke Oeljeklaus, Aksana Varabyova, Maciej Lirski, Piotr Chroscicki, Seweryn Mroczek, Elzbieta Januszewicz, Andrzej Dziembowski, Marta Koblowska, Bettina Warscheid & Agnieszka Chacinska

    Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction.

    Categories: Journal Articles
  • Structural basis for stop codon recognition in eukaryotes
    [Aug 2015]

    Structural basis for stop codon recognition in eukaryotes

    Nature 524, 7566 (2015). doi:10.1038/nature14896

    Authors: Alan Brown, Sichen Shao, Jason Murray, Ramanujan S. Hegde & V. Ramakrishnan

    Termination of protein synthesis occurs when a translating ribosome encounters one of three universally conserved stop codons: UAA, UAG or UGA. Release factors recognize stop codons in the ribosomal A-site to mediate release of the nascent chain and recycling of the ribosome. Bacteria decode stop codons using two separate release factors with differing specificities for the second and third bases. By contrast, eukaryotes rely on an evolutionarily unrelated omnipotent release factor (eRF1) to recognize all three stop codons. The molecular basis of eRF1 discrimination for stop codons over sense codons is not known. Here we present cryo-electron microscopy (cryo-EM) structures at 3.5–3.8 Å resolution of mammalian ribosomal complexes containing eRF1 interacting with each of the three stop codons in the A-site. Binding of eRF1 flips nucleotide A1825 of 18S ribosomal RNA so that it stacks on the second and third stop codon bases. This configuration pulls the fourth position base into the A-site, where it is stabilized by stacking against G626 of 18S rRNA. Thus, eRF1 exploits two rRNA nucleotides also used during transfer RNA selection to drive messenger RNA compaction. In this compacted mRNA conformation, stop codons are favoured by a hydrogen-bonding network formed between rRNA and essential eRF1 residues that constrains the identity of the bases. These results provide a molecular framework for eukaryotic stop codon recognition and have implications for future studies on the mechanisms of canonical and premature translation termination.

    Categories: Journal Articles
  • Corrigendum: Eocene primates of South America and the African origins of New World monkeys
    [Jul 2015]

    Corrigendum: Eocene primates of South America and the African origins of New World monkeys

    Nature 525, 7570 (2015). doi:10.1038/nature14955

    Authors: Mariano Bond, Marcelo F. Tejedor, Kenneth E. Campbell, Laura Chornogubsky, Nelson Novo & Francisco Goin

    Nature520, 538–541 (2015); doi:10.1038/nature14120In Extended Data Fig. 1 of this Letter, the northern border of Peru was incorrectly placed, giving a much larger territorial extent to Ecuador than was appropriate. This has now been corrected in

    Categories: Journal Articles
  • Structure of the TRPA1 ion channel suggests regulatory mechanisms
    [Jul 2015]

    Structure of the TRPA1 ion channel suggests regulatory mechanisms

    Nature 525, 7570 (2015). doi:10.1038/nature14871

    Authors: Candice E. Paulsen, Jean-Paul Armache, Yuan Gao, Yifan Cheng & David Julius

    Nature520, 511–517 (2015); doi:10.1038/nature14367In this Article, the raw micrographs shown in Extended Data Figs 4a and 5a were inadvertently identical images. The panel originally shown in Extended Data Fig. 4a is the correct one, and Extended

    Categories: Journal Articles
  • Timeless advice
    [Jul 2015]

    Timeless advice

    Nature 523, 7561 (2015). doi:10.1038/523381b

    The best guidance on how to get ahead in science stands the test of time.

    Categories: Journal Articles
  • It’s good to talk
    [Jul 2015]

    It’s good to talk

    Nature 523, 7561 (2015). doi:10.1038/523382a

    Help for those struggling to reproduce results could be just a phone call away.

    Categories: Journal Articles
  • Russia's crackdowns are jeopardizing its science
    [Jul 2015]

    Russia's crackdowns are jeopardizing its science

    Nature 523, 7561 (2015).

    Author: Fyodor Kondrashov

    The escalating encroachment on democratic freedoms undermines the nation's claim of support for science, says Fyodor Kondrashov.

    Categories: Journal Articles
  • Energy: Sun's heat could cut fossil-fuel use
    [Jul 2015]

    Energy: Sun's heat could cut fossil-fuel use

    Nature 523, 7561 (2015). doi:10.1038/523384a

    Integrating solar technologies into coal-fired power plants could ease the transition from fossil fuels to renewable energy sources.Vishwanath Haily Dalvi of the Institute of Chemical Technology in Mumbai, India, and his colleagues looked at solar thermal technology, which collects the Sun's energy as heat.

    Categories: Journal Articles
  • Anthropology: Earliest signs of chicken husbandry
    [Jul 2015]

    Anthropology: Earliest signs of chicken husbandry

    Nature 523, 7561 (2015). doi:10.1038/523384b

    Humans first used chickens for economic gain roughly 2,300 years ago in the Middle East, before Europeans began exploiting the bird.The chicken (Gallus gallus domesticus) was first domesticated in southeast Asia, but its dispersal from that region has been unclear. Lee Perry-Gal

    Categories: Journal Articles
  • Stem cells: Heart cells come of age
    [Jul 2015]

    Stem cells: Heart cells come of age

    Nature 523, 7561 (2015). doi:10.1038/523384c

    Human stem cells have been coaxed into forming heart progenitor cells that then develop into more-specialized heart cells.Researchers have struggled to turn stem cells into large pools of cardiac cells that would further divide. Christine Mummery at Leiden University Medical Center in the Netherlands

    Categories: Journal Articles