Virus Imaging

Select by virus name
About Images
Art Gallery
Covers Gallery
ICTV 8th Color Plates
PS10 Screen Saver   

Virus Structure Tutorials

Triangulation Number
Topography Maps 3D


Virology Links

In the News

- News -
- Video -
- Blogs -
 * Virology Highlights
- Flu & H1N1 - (CDC|WHO)

Journal Contents

Science
Nature
Nature Structural & Molecular Biology

Structure & Assembly (J.Virol)
Journal of Virology
J. General Virology
Retrovirology
Virology
Virology Journal
Virus Genes
Viruses

Educational Resouces


Video Lectures  NEW 
TextBook  NEW 
Educational Links
Educational Kids

Legacy

Archived Web Papers

Jean-Yves Sgro
Inst. for Mol.Virology
731B Bock Labs
1525 Linden Drive Madison, WI 53706

Table of Contents for this page:

  • Current Issue
  • Advanced Online Publications Articles

  • Current Issue of Nature

    Nature - Issue - nature.com science feeds

  • The democracy carousel

  • European law has allowed citizens to force a debate on human embryonic stem cells less than a year after the previous one. This fruitless democratic exercise has left scientists spinning in uncertainty.

  • Cancer crossroads

  • Efforts to understand cancer genomes should take on a fresh focus.

  • Practical nonsense

  • Downgrading practical science will impede UK students in the global workplace

  • Beware of backroom deals in the name of 'science'

  • The term 'sound science' has become Orwellian double-speak for various forms of pro-business spin, says Colin Macilwain.

  • Ecology: Fallen trees form a sea-floor feast

  • Dead trees at the bottom of the ocean host a diverse range of bacteria, fungi and molluscs (pictured; a cent is included for scale).Craig McClain of the National Evolutionary Synthesis Center in Durham, North Carolina, and James Barry of the Monterey Bay Aquarium Research

  • Photonics: Light goes one way on a chip

  • A device that controls light so that it travels in just one direction could be used in high-speed computers that carry signals using light, rather than electric charges.A team led by Lan Yang andŞahin Kaya Özdemir at Washington University in St. Louis created

  • Evolution: Ancient lion DNA yields family tree

  • Five genetically distinct lion populations roam in Africa and Asia— a finding that hints at greater diversity in these animals than previously thought.A team led by Ross Barnett, now at the University of Copenhagen, analysed mitochondrial DNA (mtDNA) from the remains of 14

  • Conservation biology: Unique birds top conservation list

  • An analysis of evolutionary relationships between all of the world's known birds prioritizes some of them for conservation on the basis of their genetic uniqueness.Walter Jetz of Yale University in New Haven, Connecticut, Arne Mooers of Simon Fraser University in Burnaby, Canada, and their

  • Civil engineering: Seismic 'shield' stops quake shake

  • An array of deep holes in the ground seems to lessen shaking in certain locations during a simulated earthquake.Stéphane Brûlé of soil-engineering company Ménard in Nozay, France, and his colleagues drilled a grid of boreholes 5 metres deep into the soil near Grenoble. A

  • Neurobiology: Surprising effects of prion drug

  • A chemical that combats pathogenic prion proteins in infected mouse cells worsens the problem in cells from other species. The finding could explain why the drug, quinacrine, has been ineffective in many clinical trials.Prion infections turn healthy proteins into abnormally folded forms, which cause

  • Materials: Printer squirts out nanotubes

  • Inkjet printers can produce thin films of carbon nanotubes for use as electrodes in stretchy electronic circuits.Yongtaek Hong and his colleagues at Seoul National University printed layers of single-walled carbon nanotubes onto a stretchable silicon-based material. The authors found that the electrical properties of

  • Neuroscience: Turn on the light to make myelin

  • Brain circuits change throughout life, and researchers in California have discovered a mechanism for one such change: the thickening of the myelin sheath that surrounds nerve fibres and helps neurons to fire.Michelle Monje and her co-workers at Stanford University School of Medicine studied mice

  • Biomechanics: Fast moves of fleeing fruit flies

  • To dodge predators, flies in flight execute banked turns in just a few wingbeats— much faster than the steering motions that have been previously observed in flies.Michael Dickinson and his colleagues at the University of Washington in Seattle used three high-speed cameras operating

  • Lionfish prove a main draw on Twitter

  • What types of research papers move a scientist to turn from test tube or data-crunch to spread the word on social media? Here are some papers that saw Twitter activity from researchers in early April.Lionfish took a bite of Twitter attention at the start

  • Seven days: 11–17 April 2014

  • The week in science: Japan reapproves use of nuclear power, second sighting of an exotic tetraquark, and biotech stocks plunge.

  • Hepatitis C drugs not reaching poor

  • Treatment guidelines for virus highlight challenge of paying for expensive drugs in low-income countries.

  • Sperm RNA carries marks of trauma

  • Stress alters the expression of small RNAs in male mice and leads to depressive behaviours in later generations.

  • Panel homes in on sites forγ-ray detector

  • Cherenkov Telescope Array will track high-energy photons to probe black holes, dark matter and relativity.

  • IPCC report under fire

  • Critics attack panel’s lack of specific guidance on how countries should lower emissions.

  • Biologist defiant over stem-cell method

  • Japanese author of controversial papers denies wrongdoing and stands by results as testing of her protocol begins.

  • Mini satellites prove their scientific power

  • Proliferation of‘CubeSats’ offers fresh and fast way to gather space data.

  • Power from the oceans: Blue energy

  • After years in the doldrums, the quest to harvest energy from the oceans is gathering speed.

  • Toxicology: The plastics puzzle

  • When toxicologists warned that the plastics ingredient BPA might be harmful, consumers clamoured for something new. But problems persist.

  • Policy: Bring sustainable energy to the developing world

  • Investment and policies must support cheap, clean energy technologies to cut both poverty and climate change, say Reid Detchon and Richenda Van Leeuwen.

  • Publishing: Credit where credit is due

  • Liz Allen, Amy Brand, Jo Scott, Micah Altman and Marjorie Hlava are trialling digital taxonomies to help researchers to identify their contributions to collaborative projects.

  • Astronomy: Art of the eclipse

  • As the next solar eclipse approaches, Jay M. Pasachoff and Roberta J. M. Olson ponder how artists from the early Renaissance onwards have interpreted the phenomenon.

  • Geology: Parsing eruptions

  • Ted Nield weighs up histories of two momentous volcanic events in Iceland and Indonesia.

  • Animal behaviour: Nomads of necessity

  • Joel Greenberg casts an ornithologist's eye on a wide-ranging reading of animal migration.

  • Books in brief

  • In this manifesto for a logical linguistics, one of John H. McWhorter's many intriguing examples hinges on the colour blue. To an English speaker, it is one subtly graded hue, from robin's-egg to deep navy. To a Russian, pale and dark blue are different colours.

  • Energy: China leads the way on renewables

  • The boom in renewable energy being led by China, India, Europe, the United States and Japan is key to the mitigation of carbon emissions (see Nature507, 300–302; 201410.1038/507300a). Last year marked an important turning point for China's renewable-energy

  • Rechargeables: Vanadium batteries will be cost-effective

  • Vanadium flow batteries are an attractive commercial proposition because they are safe and environmentally friendly, use recyclable electrolytes, have a long cycle life (around 13,000 cycles) and last for more than 15 years. Their cost is not as prohibitive as believed (Nature507,

  • Reproducibility: A trading scheme to reduce false results

  • Cap-and-trade systems have proved useful in cutting pollutants such as sulphur dioxide, nitrogen oxides and lead additives in petrol (see L. H.GoulderJ. Econ. Perspect.27, 87–102; 2013). We suggest that they could also be applied to reduce pollution

  • Animal models: Mouse already being charted gene by gene

  • Steve Perrin's call to make mouse studies work (Nature507, 423–425; 201410.1038/507423a) resonates with the goals and practices of the International Mouse Phenotyping Consortium (see www.impc.org).The consortium's ten-year goal is to generate a 'knockout' mutant for

  • Laboratory training: Experimentation is science's lifeblood

  • No one can become a genuine scientist without doing practical work, as John Baruch points out (see Nature507, 141; 201410.1038/507141a)— whether it is at the lab bench or desk. But it is not the successful experiments that count so

  • Tactical tenure manoeuvres

  • The tenure process is stressful, but there are ways to prepare for it. And one denial need not curtail a life in academia.

  • Turning point: Joel Elmquist

  • Making time for protégés is the key to great guidance, says award-winning mentor.

  • The vermilion market

  • Where thoughts crystallize.

  • Obesity

  • Society at large

  • The increasing prevalence of obesity is a worldwide phenomenon, affecting peoples from diverse cultural and economic backgrounds. By Tony Scully.

  • Cell physiology: The changing colour of fat

  • The different functions of white, brown and beige fat might yield new targets in the fight against obesity and metabolic disease.

  • Treatment: Marginal gains

  • Behavioural interventions work, but not for everyone, and weight regain is common. Are there better ways to treat obesity?

  • Perspective: Obesity is not a disease

  • The misguided urge to pathologize this condition reflects society's failure to come to terms with the need for prevention, says D. L. Katz.

  • Heritability: The family roots of obesity

  • Scores of genes are implicated in obesity, but they cannot account for a family's predisposition to obesity. Are there other ways parents can influence their children?

  • Microbiome: A complicated relationship status

  • Nothing is simple about the links between the bacteria living in our guts and obesity.

  • Neuroscience: Dissecting appetite

  • A slew of new technologies are helping to map the neural circuits that control when, and how much, we eat.

  • Perspective: Tricks of the trade

  • Processed foods that dilute protein content subvert our appetite control systems, say Stephen J. Simpson and David Raubenheimer.

  • Correction

  • The photo that accompanied the News story‘Ukraine’s science in turmoil’ (Nature508, 15–16; 2014) was not of the Crimean Astrophysical Observatory as stated but of a military radar station in the region. The correct image of the observatory can be seen

  • Evolutionary biology: Dating chimpanzees

  • Genetic research has tracked lineages of male chimpanzees thousands of years into the past, opening the door to the study of long-term behavioural evolution in our close primate relatives.

  • Genetics: Up and down in Down's syndrome

  • A comparison of identical human twins, only one of whom has Down's syndrome, reveals a genome-wide flattening of gene-expression levels in the affected individual. See Article p.345

  • Organic chemistry: Catalysis marches on

  • A fresh take on an established chemical reaction has solved a long-standing problem in organic synthesis: how to prepare single mirror-image isomers of groups known as isolated quaternary stereocentres. See Article p.340

  • Synthetic biology: Biocircuits in synchrony

  • Cellular biocircuit design has taken a major step forward. The circuit reuses the cell's own protein-degradation system to synchronize the expression of two synthetic modules throughout an entire bacterial population. See Letter p.387

  • Thermoelectricity: The ugly duckling

  • Single crystals of tin selenide have been shown to display, along one crystallographic direction of their high-temperature state, the highest thermoelectric efficiency of any bulk material. See Letter p.373

  • Cell biology: The stressful influence of microbes

  • An investigation into cellular stress responses reveals how cell compartments called mitochondria use information about the surrounding metabolites and microorganisms to protect themselves from damage. See Letter p.406

  • Correction

  • The News aamp; Views article 'Tuberculosis: Drug discovery goes au naturel' by Clifton E. Barry (Nature506, 436–437; 2014) incorrectly described the pharmaceutical company Lepetit as being French. It is an Italian firm.

  • The ensemble nature of allostery

  • Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems.

  • Enantioselective construction of remote quaternary stereocentres

  • Small molecules that contain all-carbon quaternary stereocentres—carbon atoms bonded to four distinct carbon substituents—are found in many secondary metabolites and some pharmaceutical agents. The construction of such compounds in an enantioselective fashion remains a long-standing challenge to synthetic organic chemists. In particular, methods for synthesizing

  • Domains of genome-wide gene expression dysregulation in Down’s syndrome

  • Trisomy 21 is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in trisomy 21, and to eliminate the noise of genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy

  • Brainstem nucleus MdV mediates skilled forelimb motor tasks

  • Translating the behavioural output of the nervous system into movement involves interaction between brain and spinal cord. The brainstem provides an essential bridge between the two structures, but circuit-level organization and function of this intermediary system remain poorly understood. Here we use intersectional virus tracing

  • Skilled reaching relies on a V2a propriospinal internal copy circuit

  • The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the

  • Isotopic links between atmospheric chemistry and the deep sulphur cycle on Mars

  • The geochemistry of Martian meteorites provides a wealth of information about the solid planet and the surface and atmospheric processes that occurred on Mars. The degree to which Martian magmas may have assimilated crustal material, thus altering the geochemical signatures acquired from their mantle sources, is unclear. This issue features prominently in efforts to understand whether the source of light rare-earth elements in enriched shergottites lies in crustal material incorporated into melts or in mixing between enriched and depleted mantle reservoirs. Sulphur isotope systematics offer insight into some aspects of crustal assimilation. The presence of igneous sulphides in Martian meteorites with sulphur isotope signatures indicative of mass-independent fractionation suggests the assimilation of sulphur both during passage of magmas through the crust of Mars and at sites of emplacement. Here we report isotopic analyses of 40 Martian meteorites that represent more than half of the distinct known Martian meteorites, including 30 shergottites (28 plus 2 pairs, where pairs are separate fragments of a single meteorite), 8 nakhlites (5 plus 3 pairs), Allan Hills 84001 and Chassigny. Our data provide strong evidence that assimilation of sulphur into Martian magmas was a common occurrence throughout much of the planet’s history. The signature of mass-independent fractionation observed also indicates that the atmospheric imprint of photochemical processing preserved in Martian meteoritic sulphide and sulphate is distinct from that observed in terrestrial analogues, suggesting fundamental differences between the dominant sulphur chemistry in the atmosphere of Mars and that in the atmosphere of Earth.

  • Coherent suppression of electromagnetic dissipation due to superconducting quasiparticles

  • Owing to the low-loss propagation of electromagnetic signals in superconductors, Josephson junctions constitute ideal building blocks for quantum memories, amplifiers, detectors and high-speed processing units, operating over a wide band of microwave frequencies. Nevertheless, although transport in superconducting wires is perfectly lossless for direct current, transport of radio-frequency signals can be dissipative in the presence of quasiparticle excitations above the superconducting gap. Moreover, the exact mechanism of this dissipation in Josephson junctions has never been fully resolved experimentally. In particular, Josephson’s key theoretical prediction that quasiparticle dissipation should vanish in transport through a junction when the phase difference across the junction is π (ref. 2) has never been observed. This subtle effect can be understood as resulting from the destructive interference of two separate dissipative channels involving electron-like and hole-like quasiparticles. Here we report the experimental observation of this quantum coherent suppression of quasiparticle dissipation across a Josephson junction. As the average phase bias across the junction is swept through π, we measure an increase of more than one order of magnitude in the energy relaxation time of a superconducting artificial atom. This striking suppression of dissipation, despite the presence of lossy quasiparticle excitations above the superconducting gap, provides a powerful tool for minimizing decoherence in quantum electronic systems and could be directly exploited in quantum information experiments with superconducting quantum bits.

  • Ultralow thermal conductivity and high thermoelectric figure of merit in SnSe crystals

  • The thermoelectric effect enables direct and reversible conversion between thermal and electrical energy, and provides a viable route for power generation from waste heat. The efficiency of thermoelectric materials is dictated by the dimensionless figure of merit, ZT (where Z is the figure of merit and T is absolute temperature), which governs the Carnot efficiency for heat conversion. Enhancements above the generally high threshold value of 2.5 have important implications for commercial deployment, especially for compounds free of Pb and Te. Here we report an unprecedented ZT of 2.6 ± 0.3 at 923 K, realized in SnSe single crystals measured along the b axis of the room-temperature orthorhombic unit cell. This material also shows a high ZT of 2.3 ± 0.3 along the c axis but a significantly reduced ZT of 0.8 ± 0.2 along the a axis. We attribute the remarkably high ZT along the b axis to the intrinsically ultralow lattice thermal conductivity in SnSe. The layered structure of SnSe derives from a distorted rock-salt structure, and features anomalously high Grüneisen parameters, which reflect the anharmonic and anisotropic bonding. We attribute the exceptionally low lattice thermal conductivity (0.23 ± 0.03 W m−1 K−1 at 973 K) in SnSe to the anharmonicity. These findings highlight alternative strategies to nanostructuring for achieving high thermoelectric performance.

  • Mid-latitude interhemispheric hydrologic seesaw over the past 550,000 years

  • An interhemispheric hydrologic seesaw—in which latitudinal migrations of the Intertropical Convergence Zone (ITCZ) produce simultaneous wetting (increased precipitation) in one hemisphere and drying in the other—has been discovered in some tropical and subtropical regions. For instance, Chinese and Brazilian subtropical speleothem(cave formations such as stalactites and stalagmites) records show opposite trends in time series of oxygen isotopes (a proxy for precipitation variability) at millennial to orbital timescales, suggesting that hydrologic cycles were antiphased in the northerly versus southerly subtropics. This tropical to subtropical hydrologic phenomenon is likely to be an initial and important climatic response to orbital forcing. The impacts of such an interhemispheric hydrologic seesaw on higher-latitude regions and the global climate system, however, are unknown. Here we show that the antiphasing seen inthe tropical records is also present in both hemispheres of the mid-latitude western Pacific Ocean. Our results are based on a new 550,000-year record of the growth frequency of speleothems from the Korean peninsula, which we compare to Southern Hemisphere equivalents. The Korean data are discontinuous and derived from 24 separate speleothems, but still allow the identification of periods of peak speleothem growth and, thus, precipitation. The clear hemispheric antiphasing indicates that the sphere of influence of the interhemispheric hydrologic seesaw over the past 550,000 years extended at least to the mid-latitudes, such as northeast Asia, and that orbital-timescale ITCZ shifts can have serious effects on temperate climate systems. Furthermore, our result implies that insolation-driven ITCZ dynamics may provoke water vapour and vegetation feedbacks in northern mid-latitude regions and could have regulated global climate conditions throughout the late Quaternary ice age cycles.

  • A new fossil species supports an early origin for toothed whale echolocation

  • Odontocetes (toothed whales, dolphins and porpoises) hunt and navigate through dark and turbid aquatic environments using echolocation; a key adaptation that relies on the same principles as sonar. Among echolocating vertebrates, odontocetes are unique in producing high-frequency vocalizations at the phonic lips, a constriction in the nasal passages just beneath the blowhole, and then using air sinuses and the melon to modulate their transmission. All extant odontocetes seem to echolocate; however, exactly when and how this complex behaviour—and its underlying anatomy—evolved is largely unknown. Here we report an odontocete fossil, Oligocene in age (approximately 28 Myr ago), from South Carolina (Cotylocara macei, gen. et sp. nov.) that has several features suggestive of echolocation: a dense, thick and downturned rostrum; air sac fossae; cranial asymmetry; and exceptionally broad maxillae. Our phylogenetic analysis places Cotylocara in a basal clade of odontocetes, leading us to infer that a rudimentary form of echolocation evolved in the early Oligocene, shortly after odontocetes diverged from the ancestors of filter-feeding whales (mysticetes). This was followed by enlargement of the facial muscles that modulate echolocation calls, which in turn led to marked, convergent changes in skull shape in the ancestors of Cotylocara, and in the lineage leading to extant odontocetes.

  • Rapid and tunable post-translational coupling of genetic circuits

  • One promise of synthetic biology is the creation of genetic circuitry that enables the execution of logical programming in living cells. Such‘wet programming’ is positioned to transform a wide and diverse swathe of biotechnology ranging from therapeutics and diagnostics to water treatment strategies. Although progress in the development of a library of genetic modules continues apace, a major challenge for their integration into larger circuits is the generation of sufficiently fast and precise communication between modules. An attractive approach is to integrate engineered circuits with host processes that facilitate robust cellular signalling. In this context, recent studies have demonstrated that bacterial protein degradation can trigger a precise response to stress by overloading a limited supply of intracellular proteases. Here we use protease competition to engineer rapid and tunable coupling of genetic circuits across multiple spatial and temporal scales. We characterize coupling delay times that are more than an order of magnitude faster than standard transcription-factor-based coupling methods (less than 1 min compared with ∼20–40 min) and demonstrate tunability through manipulation of the linker between the protein and its degradation tag. We use this mechanism as a platform to couple genetic clocks at the intracellular and colony level, then synchronize the multi-colony dynamics to reduce variability in both clocks. We show how the coupled clock network can be used to encode independent environmental inputs into a single time series output, thus enabling frequency multiplexing (information transmitted on a common channel by distinct frequencies) in a genetic circuit context. Our results establish a general framework for the rapid and tunable coupling of genetic circuits through the use of native ‘queueing’ processes such as competitive protein degradation.

  • Apical constriction drives tissue-scale hydrodynamic flow to mediate cell elongation

  • Epithelial folding mediated by apical constriction converts flat epithelial sheets into multilayered, complex tissue structures and is used throughout development in most animals. Little is known, however, about how forces produced near the apical surface of the tissue are transmitted within individual cells to generate the global changes in cell shape that characterize tissue deformation. Here we apply particle tracking velocimetry in gastrulating Drosophila embryos to measure the movement of cytoplasm and plasma membrane during ventral furrow formation. We find that cytoplasmic redistribution during the lengthening phase of ventral furrow formation can be precisely described by viscous flows that quantitatively match the predictions of hydrodynamics. Cell membranes move with the ambient cytoplasm, with little resistance to, or driving force on, the flow. Strikingly, apical constriction produces similar flow patterns in mutant embryos that fail to form cells before gastrulation (‘acellular’ embryos), such that the global redistribution of cytoplasm mirrors the summed redistribution occurring in individual cells of wild-type embryos. Our results indicate that during the lengthening phase of ventral furrow formation, hydrodynamic behaviour of the cytoplasm provides the predominant mechanism transmitting apically generated forces deep into the tissue and that cell individualization is dispensable.

  • A committed precursor to innate lymphoid cells

  • Innate lymphoid cells (ILCs) specialize in the rapid secretion of polarized sets of cytokines and chemokines to combat infection and promote tissue repair at mucosal barriers. Their diversity and similarities with previously characterized natural killer (NK) cells and lymphoid tissue inducers (LTi) have prompted a provisional classification of all innate lymphocytes into groups 1, 2 and 3 solely on the basis of cytokine properties, but their developmental pathways and lineage relationships remain elusive. Here we identify and characterize a novel subset of lymphoid precursors in mouse fetal liver and adult bone marrow that transiently express high amounts of PLZF, a transcription factor previously associated with NK T cell development, by using lineage tracing and transfer studies. PLZFhigh cells were committed ILC progenitors with multiple ILC1, ILC2 and ILC3 potential at the clonal level. They excluded classical LTi and NK cells, but included a peculiar subset of NK1.1+DX5− ‘NK-like’ cells residing in the liver. Deletion of PLZF markedly altered the development of several ILC subsets, but not LTi or NK cells. PLZFhigh precursors also expressed high amounts of ID2 and GATA3, as well as TOX, a known regulator of PLZF-independent NK and LTi lineages. These findings establish novel lineage relationships between ILC, NK and LTi cells, and identify the common precursor to ILCs, termed ILCP. They also reveal the broad, defining role of PLZF in the differentiation of innate lymphocytes.

  • Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430

  • Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.

  • Caenorhabditis elegans pathways that surveil and defend mitochondria

  • Mitochondrial function is challenged by toxic by-products of metabolism as well as by pathogen attack. Caenorhabditis elegans normally responds to mitochondrial dysfunction with activation of mitochondrial-repair, drug-detoxification and pathogen-response pathways. Here, from a genome-wide RNA interference (RNAi) screen, we identified 45 C. elegans genes that are required to upregulate detoxification, pathogen-response and mitochondrial-repair pathways after inhibition of mitochondrial function by drug-induced or genetic disruption. Animals defective in ceramide biosynthesis are deficient in mitochondrial surveillance, and addition of particular ceramides can rescue the surveillance defects. Ceramide can also rescue the mitochondrial surveillance defects of other gene inactivations, mapping these gene activities upstream of ceramide. Inhibition of the mevalonate pathway, either by RNAi or statin drugs, also disrupts mitochondrial surveillance. Growth of C. elegans with a significant fraction of bacterial species from their natural habitat causes mitochondrial dysfunction. Other bacterial species inhibit C. elegans defence responses to a mitochondrial toxin, revealing bacterial countermeasures to animal defence.

  • miRNAs trigger widespread epigenetically activated siRNAs from transposons in Arabidopsis

  • In plants, post-transcriptional gene silencing (PTGS) is mediated by DICER-LIKE 1 (DCL1)-dependent microRNAs (miRNAs), which also trigger 21-nucleotide secondary short interfering RNAs (siRNAs) via RNA-DEPENDENT RNA POLYMERASE 6 (RDR6), DCL4 and ARGONAUTE 1 (AGO1), whereas transcriptional gene silencing (TGS) of transposons is mediated by 24-nucleotide heterochromatic (het)siRNAs, RDR2, DCL3 and AGO4 (ref. 4). Transposons can also give rise to abundant 21-nucleotide‘epigenetically activated’ small interfering RNAs (easiRNAs) in DECREASED DNA METHYLATION 1 (ddm1) and DNA METHYLTRANSFERASE 1 (met1) mutants, as well as in the vegetative nucleus of pollen grains and in dedifferentiated plant cell cultures. Here we show that easiRNAs in Arabidopsis thaliana resemble secondary siRNAs, in that thousands of transposon transcripts are specifically targeted by more than 50 miRNAs for cleavage and processing by RDR6. Loss of RDR6, DCL4 or DCL1 in a ddm1 background results in loss of 21-nucleotide easiRNAs and severe infertility, but 24-nucleotide hetsiRNAs arepartially restored, supporting an antagonistic relationship between PTGS and TGS. Thus miRNA-directed easiRNA biogenesis is a latent mechanism that specifically targets transposon transcripts, but only when they are epigenetically reactivated during reprogramming of the germ line. This ancient recognition mechanism may have been retained both by transposons to evade long-term heterochromatic silencing and by their hosts for genome defence.

  • Structural basis for translocation by AddAB helicase–nuclease and its arrest at χ sites

  • In bacterial cells, processing of double-stranded DNA breaks for repair by homologous recombination is dependent upon the recombination hotspot sequenceχ (Chi) and is catalysed by either an AddAB- or RecBCD-type helicase–nuclease (reviewed in refs 3, 4). These enzyme complexes unwind and digest the DNA duplex from the broken end until they encounter a χ sequence, whereupon they produce a 3′ single-stranded DNA tail onto which they initiate loading of the RecA protein. Consequently, regulation of the AddAB/RecBCD complex by χ is a key control point in DNA repair and other processes involving genetic recombination. Here we report crystal structures of Bacillus subtilis AddAB in complex with different χ-containing DNA substrates either with or without a non-hydrolysable ATP analogue. Comparison of these structures suggests a mechanism for DNA translocation and unwinding, suggests how the enzyme binds specifically to χ sequences, and explains how χ recognition leads to the arrest of AddAB (and RecBCD) translocation that is observed in single-molecule experiments.

  • Corrigendum: Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling

  • Nature499, 491–495 (2013); doi:10.1038/nature12396After publication of this Letter, we became aware that we had not reported the details of construction and validation of our floxed conditional deletion Ptpn11 allele. These details are presented in the Supplementary

  • Corrigendum: Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia

  • Nature506, 328–333 (2014); doi:10.1038/nature13038Author Fouad Yousif (of the Ontario Institute for Cancer Research, Toronto, Canada) should have been included in the author list after Andrew M. K. Brown with affiliation number 7 and listed in the Author

  • Corrigendum: Regulatory evolution through divergence of a phosphoswitch in the transcription factor CEBPB

  • Nature480, 383–386 (2011); doi:10.1038/nature10595We inadvertently included a duplicate gel image in the lower right panel of Fig. 3c of this Letter. The gel image should show the loading control (‘Input’) for the image directly above it (lanes

    Return To Top of the Page


    Nature -Advance Online Publications

    Return To Top of the Page

    Nature - AOP - nature.com science feeds

  • Climate science: Sea levels from ancient seashells

  • The isotopic composition of oxygen in sea water correlates with changes in global mean sea level. Microfossils carrying oxygen-isotope signals have been used to extend sea-level records as far back as 5 million years ago.

  • Reproductive biology: Sperm protein finds its mate

  • Knowledge of the sperm-specific protein that is required for the attachment of sperm to eggs during fertilization in mammals has led to the identification of the protein's receptor on the egg's plasma membrane.

  • Juno is the egg Izumo receptor and is essential for mammalian fertilization

  • The egg receptor for Izumo, a sperm cell-surface protein required for male fertility, is identified here and renamed Juno; these findings show that the Izumo–Juno interaction is conserved within mammals, and open new opportunities for the development of fertility treatments and contraceptives.

  • Sea-level and deep-sea-temperature variability over the past 5.3 million years

  • A novel approach to the estimation of sea level and deep-sea temperature has been used to determine these quantities over the past 5.3 million years; this approach, based on oxygen isotope records from the eastern Mediterranean, shows that temperature and sea-level histories are broadly correlated but also show intriguing temporal offsets.

  • Dynamics and associations of microbial community types across the human body

  • A primary goal of the Human Microbiome Project (HMP) was to provide a reference collection of 16S ribosomal RNA gene sequences collected from sites across the human body that would allow microbiologists to better associate changes in the microbiome with changes in health. The HMP Consortium has reported the structure and function of the human microbiome in 300 healthy adults at 18 body sites from a single time point. Using additional data collected over the course of 12–18 months, we used Dirichlet multinomial mixture models to partition the data into community types for each body site and made three important observations. First, there were strong associations between whether individuals had been breastfed as an infant, their gender, and their level of education with their community types at several body sites. Second, although the specific taxonomic compositions of the oral and gut microbiomes were different, the community types observed at these sites were predictive of each other. Finally, over the course of the sampling period, the community types from sites within the oral cavity were the least stable, whereas those in the vagina and gut were the most stable. Our results demonstrate that even with the considerable intra- and interpersonal variation in the human microbiome, this variation can be partitioned into community types that are predictive of each other and are probably the result of life-history characteristics. Understanding the diversity of community types and the mechanisms that result in an individual having a particular type or changing types, will allow us to use their community types to assess disease risk and to personalize therapies.

  • Coordination of entorhinal–hippocampal ensemble activity during associative learning

  • Accumulating evidence points to cortical oscillations as a mechanism for mediating interactions among functionally specialized neurons in distributed brain circuits. A brain function that may use such interactions is declarative memory—that is, memory that can be consciously recalled, such as episodes and facts. Declarative memory is enabled by circuits in the entorhinal cortex that interface the hippocampus with the neocortex. During encoding and retrieval of declarative memories, entorhinal and hippocampal circuits are thought to interact via theta and gamma oscillations, which in awake rodents predominate frequency spectra in both regions. In favour of this idea, theta–gamma coupling has been observed between entorhinal cortex and hippocampus under steady-state conditions in well-trained rats; however, the relationship between interregional coupling and memory formation remains poorly understood. Here we show, by multisite recording at successive stages of associative learning, that the coherence of firing patterns in directly connected entorhinal–hippocampus circuits evolves as rats learn to use an odour cue to guide navigational behaviour, and that such coherence is invariably linked to the development of ensemble representations for unique trial outcomes in each area. Entorhinal–hippocampal coupling was observed specifically in the 20–40-hertz frequency band and specifically between the distal part of hippocampal area CA1 and the lateral part of entorhinal cortex, the subfields that receive the predominant olfactory input to the hippocampal region. Collectively, the results identify 20–40-hertz oscillations as a mechanism for synchronizing evolving representations in dispersed neural circuits during encoding and retrieval of olfactory–spatial associative memory.

  • Structural basis of Sec-independent membrane protein insertion by YidC

  • Newly synthesized membrane proteins must be accurately inserted into the membrane, folded and assembled for proper functioning. The protein YidC inserts its substrates into the membrane, thereby facilitating membrane protein assembly in bacteria; the homologous proteins Oxa1 and Alb3 have the same function in mitochondria and chloroplasts, respectively. In the bacterial cytoplasmic membrane, YidC functions as an independent insertase and a membrane chaperone in cooperation with the translocon SecYEG. Here we present the crystal structure of YidC from Bacillus halodurans, at 2.4Å resolution. The structure reveals a novel fold, in which five conserved transmembrane helices form a positively charged hydrophilic groove that is open towards both the lipid bilayer and the cytoplasm but closed on the extracellular side. Structure-based in vivo analyses reveal that a conserved arginine residue in the groove is important for the insertion of membrane proteins by YidC. We propose an insertion mechanism for single-spanning membrane proteins, in which the hydrophilic environment generated by the groove recruits the extracellular regions of substrates into the low-dielectric environment of the membrane.

  • Scalable control of mounting and attack by Esr1+ neurons in the ventromedial hypothalamus

  • Social behaviours, such as aggression or mating, proceed through a series of appetitive and consummatory phases that are associated with increasing levels of arousal. How such escalation is encoded in the brain, and linked to behavioural action selection, remains an unsolved problem in neuroscience. The ventrolateral subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons whose activity increases during male–male and male–female social encounters. Non-cell-type-specific optogenetic activation of this region elicited attack behaviour, but not mounting. We have identified a subset of VMHvl neurons marked by the oestrogen receptor 1 (Esr1), and investigated their role in male social behaviour. Optogenetic manipulations indicated that Esr1+ (but not Esr1−) neurons are sufficient to initiate attack, and that their activity is continuously required during ongoing agonistic behaviour. Surprisingly, weaker optogenetic activation of these neurons promoted mounting behaviour, rather than attack, towards both males and females, as well as sniffing and close investigation. Increasing photostimulation intensity could promote a transition from close investigation and mounting to attack, within a single social encounter. Importantly, time-resolved optogenetic inhibition experiments revealed requirements for Esr1+ neurons in both the appetitive (investigative) and the consummatory phases of social interactions. Combined optogenetic activation and calcium imaging experiments in vitro, as well as c-Fos analysis in vivo, indicated that increasing photostimulation intensity increases both the number of active neurons and the average level of activity per neuron. These data suggest that Esr1+ neurons in VMHvl control the progression of a social encounter from its appetitive through its consummatory phases, in a scalable manner that reflects the number or type of active neurons in the population.

  • Predicting biodiversity change and averting collapse in agricultural landscapes

  • The equilibrium theory of island biogeography is the basis for estimating extinction rates and a pillar of conservation science. The default strategy for conserving biodiversity is the designation of nature reserves, treated as islands in an inhospitable sea of human activity. Despite the profound influence of islands on conservation theory and practice, their mainland analogues, forest fragments in human-dominated landscapes, consistently defy expected biodiversity patterns based on island biogeography theory. Countryside biogeography is an alternative framework, which recognizes that the fate of the world’s wildlife will be decided largely by the hospitality of agricultural or countryside ecosystems. Here we directly test these biogeographic theories by comparing a Neotropical countryside ecosystem with a nearby island ecosystem, and show that each supports similar bat biodiversity in fundamentally different ways. The island ecosystem conforms to island biogeographic predictions of bat species loss, in which the water matrix is not habitat. In contrast, the countryside ecosystem has high species richness and evenness across forest reserves and smaller forest fragments. Relative to forest reserves and fragments, deforested countryside habitat supports a less species-rich, yet equally even, bat assemblage. Moreover, the bat assemblage associated with deforested habitat is compositionally novel because of predictable changes in abundances by many species using human-made habitat. Finally, we perform a global meta-analysis of bat biogeographic studies, spanning more than 700 species. It generalizes our findings, showing that separate biogeographic theories for countryside and island ecosystems are necessary. A theory of countryside biogeography is essential to conservation strategy in the agricultural ecosystems that comprise roughly half of the global land surface and are likely to increase even further.

  • Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases

  • Lipopolysaccharide from Gram-negative bacteria is sensed in the host cell cytoplasm by a non-canonical inflammasome pathway that ultimately results in caspase-11 activation and cell death. In mouse macrophages, activation of this pathway requires the production of type-I interferons, indicating that interferon-induced genes have a critical role in initiating this pathway. Here we report that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the non-canonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria. We show that guanylate-binding proteins are recruited to intracellular bacterial pathogens and are necessary to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus allowing the detection of their lipopolysaccharide by a yet unknown lipopolysaccharide sensor. Moreover, recognition of the lysed vacuole by the danger sensor galectin-8 initiates the uptake of bacteria into autophagosomes, which results in a reduction of caspase-11 activation. These results indicate that host-mediated lysis of pathogen-containing vacuoles is an essential immune function and is necessary for efficient recognition of pathogens by inflammasome complexes in the cytosol.

  • A Palaeozoic shark with osteichthyan-like branchial arches

  • The evolution of serially arranged, jointed endoskeletal supports internal to the gills—the visceral branchial arches—represents one of the key events in early jawed vertebrate (gnathostome) history, because it provided the morphological basis for the subsequent evolution of jaws. However, until now little was known about visceral arches in early gnathostomes, and theories about gill arch evolution were driven by information gleaned mostly from both modern cartilaginous (chondrichthyan) and bony (osteichthyan) fishes. New fossil discoveries can profoundly affect our understanding of evolutionary history, by revealing hitherto unseen combinations of primitive and derived characters. Here we describe a 325 million year (Myr)-old Palaeozoic shark-like fossil that represents, to our knowledge, the earliest identified chondrichthyan in which the complete gill skeleton is three-dimensionally preserved in its natural position. Its visceral arch arrangement is remarkably osteichthyan-like, suggesting that this may represent the common ancestral condition for crown gnathostomes. Our findings thus reinterpret the polarity of some arch features of the crown jawed vertebrates and invert the classic hypothesis, in which modern sharks retain the ancestral condition. This study underscores the importance of early chondrichthyans in resolving the evolutionary history of jawed vertebrates.

  • Listeria monocytogenes exploits efferocytosis to promote cell-to-cell spread

  • Efferocytosis, the process by which dying or dead cells are removed by phagocytosis, has an important role in development, tissue homeostasis and innate immunity. Efferocytosis is mediated, in part, by receptors that bind to exofacial phosphatidylserine (PS) on cells or cellular debris after loss of plasma membrane asymmetry. Here we show that a bacterial pathogen, Listeria monocytogenes, can exploit efferocytosis to promote cell-to-cell spread during infection. These bacteria can escape the phagosome in host cells by using the pore-forming toxin listeriolysin O (LLO) and two phospholipase C enzymes. Expression of the cell surface protein ActA allows L. monocytogenes to activate host actin regulatory factors and undergo actin-based motility in the cytosol, eventually leading to formation of actin-rich protrusions at the cell surface. Here we show that protrusion formation is associated with plasma membrane damage due to LLO’s pore-forming activity. LLO also promotes the release of bacteria-containing protrusions from the host cell, generating membrane-derived vesicles with exofacial PS. The PS-binding receptor TIM-4 (encoded by the Timd4 gene) contributes to efficient cell-to-cell spread by L. monocytogenes in macrophages in vitro and growth of these bacteria is impaired in Timd4−/− mice. Thus, L. monocytogenes promotes its dissemination in a host by exploiting efferocytosis. Our results indicate that PS-targeted therapeutics may be useful in the fight against infections by L. monocytogenes and other bacteria that use similar strategies of cell-to-cell spread during infection.

  • Oncogene-like induction of cellular invasion from centrosome amplification

  • Centrosome amplification has long been recognized as a feature of human tumours; however, its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumours, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumour progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behaviour is similar to that induced by overexpression of the breast cancer oncogene ERBB2 (ref. 4) and indeed enhances invasiveness triggered by ERBB2. Our data indicate that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell–cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.

  • NRROS negatively regulates reactive oxygen species during host defence and autoimmunity

  • Reactive oxygen species (ROS) produced by phagocytes are essential for host defence against bacterial and fungal infections. Individuals with defective ROS production machinery develop chronic granulomatous disease. Conversely, excessive ROS can cause collateral tissue damage during inflammatory processes and therefore needs to be tightly regulated. Here we describe a protein, we termed negative regulator of ROS (NRROS), which limits ROS generation by phagocytes during inflammatory responses. NRROS expression in phagocytes can be repressed by inflammatory signals. NRROS-deficient phagocytes produce increased ROS upon inflammatory challenges, and mice lacking NRROS in their phagocytes show enhanced bactericidal activity against Escherichia coli and Listeria monocytogenes. Conversely, these mice develop severe experimental autoimmune encephalomyelitis owing to oxidative tissue damage in the central nervous system. Mechanistically, NRROS is localized to the endoplasmic reticulum, where it directly interacts with nascent NOX2 (also known gp91phox and encoded by Cybb) monomer, one of the membrane-bound subunits of the NADPH oxidase complex, and facilitates the degradation of NOX2 through the endoplasmic-reticulum-associated degradation pathway. Thus, NRROS provides a hitherto undefined mechanism for regulating ROS prodution—one that enables phagocytes to produce higher amounts of ROS, if required to control invading pathogens, while minimizing unwanted collateral tissue damage.

  • Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq

  • The mammalian lung is a highly branched network in which the distal regions of the bronchial tree transform during development into a densely packed honeycomb of alveolar air sacs that mediate gas exchange. Although this transformation has been studied by marker expression analysis and fate-mapping, the mechanisms that control the progression of lung progenitors along distinct lineages into mature alveolar cell types are still incompletely known, in part because of the limited number of lineage markers and the effects of ensemble averaging in conventional transcriptome analysis experiments on cell populations. Here we show that single-cell transcriptome analysis circumvents these problems and enables direct measurement of the various cell types and hierarchies in the developing lung. We used microfluidic single-cell RNA sequencing (RNA-seq) on 198 individual cells at four different stages encompassing alveolar differentiation to measure the transcriptional states which define the developmental and cellular hierarchy of the distal mouse lung epithelium. We empirically classified cells into distinct groups by using an unbiased genome-wide approach that did not require a priori knowledge of the underlying cell types or the previous purification of cell populations. The results confirmed the basic outlines of the classical model of epithelial cell-type diversity in the distal lung and led to the discovery of many previously unknown cell-type markers, including transcriptional regulators that discriminate between the different populations. We reconstructed the molecular steps during maturation of bipotential progenitors along both alveolar lineages and elucidated the full life cycle of the alveolar type 2 cell lineage. This single-cell genomics approach is applicable to any developing or mature tissue to robustly delineate molecularly distinct cell types, define progenitors and lineage hierarchies, and identify lineage-specific regulatory factors.

  • Focused specificity of intestinal TH17 cells towards commensal bacterial antigens

  • T-helper-17 (TH17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis. They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota. Segmented filamentous bacteria (SFB) are sufficient to induce TH17 cells and to promote TH17-dependent autoimmune disease in animal models. However, the specificity of TH17 cells, the mechanism of their induction by distinct bacteria, and the means by which they foster tissue-specific inflammation remain unknown. Here we show that the T-cell antigen receptor (TCR) repertoire of intestinal TH17 cells in SFB-colonized mice has minimal overlap with that of other intestinal CD4+ T cells and that most TH17 cells, but not other T cells, recognize antigens encoded by SFB. T cells with antigen receptors specific for SFB-encoded peptides differentiated into RORγt-expressing TH17 cells, even if SFB-colonized mice also harboured a strong TH1 cell inducer, Listeria monocytogenes, in their intestine. The match of T-cell effector function with antigen specificity is thus determined by the type of bacteria that produce the antigen. These findings have significant implications for understanding how commensal microbiota contribute to organ-specific autoimmunity and for developing novel mucosal vaccines.

  • Electrochemistry: Catalysis at the boundaries

  • Copper-based materials have been found that efficiently convert carbon monoxide and water to ethanol using electricity. The discovery is a major advance towards storing renewable energy in the form of a liquid fuel.

  • Infection biology: Nibbled to death

  • Trogocytosis, a process in which one cell 'takes a bite' out of another, had previously been seen only in immune cells. But the phenomenon has now been found in Entamoeba histolytica, as a way for this parasite to kill host cells.

  • Organic chemistry: Catalysis marches on

  • A fresh take on an established chemical reaction has solved a long-standing problem in organic synthesis: how to prepare single mirror-image isomers of groups known as isolated quaternary stereocentres.

  • Synthetic biology: Biocircuits in synchrony

  • Cellular biocircuit design has taken a major step forward. The circuit reuses the cell's own protein-degradation system to synchronize the expression of two synthetic modules throughout an entire bacterial population.

  • Enantioselective construction of remote quaternary stereocentres

  • A catalytic and enantioselective intermolecular Heck-type reaction of trisubstituted-alkenyl alcohols with aryl boronic acids provides direct access to quaternary stereocentres remote from a carbonyl group.

  • Copper is required for oncogenic BRAF signalling and tumorigenesis

  • The BRAF kinase is mutated, typically Val 600→Glu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers. BRAFV600E phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma, an effect that is increased when administered together with a BRAFV600E inhibitor. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu–MEK1 interaction. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAFV600E-driven signalling and tumorigenesis in mice and human cell settings. Conversely, a MEK1–MEK5 chimaera that phosphorylated ERK1/2 independently of Cu or an active ERK2 restored the tumour growth of murine cells lacking Ctr1. Cu chelators used in the treatment of Wilson diseasedecreased tumour growth of human or murine cells transformed by BRAFV600E or engineered to be resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAFV600E mutation.

  • Electroreduction of carbon monoxide to liquid fuel on oxide-derived nanocrystalline copper

  • The electrochemical conversion of CO2 and H2O into liquid fuel is ideal for high-density renewable energy storage and could provide an incentive for CO2 capture. However, efficient electrocatalysts for reducing CO2 and its derivatives into a desirable fuel are not available at present. Although many catalysts can reduce CO2 to carbon monoxide (CO), liquid fuel synthesis requires that CO is reduced further, using H2O as a H+ source. Copper (Cu) is the only known material with an appreciable CO electroreduction activity, but in bulk form its efficiency and selectivity for liquid fuel are far too low for practical use. In particular, H2O reduction to H2 outcompetes CO reduction on Cu electrodes unless extreme overpotentials are applied, at which point gaseous hydrocarbons are the major CO reduction products. Here we show that nanocrystalline Cu prepared from Cu2O (‘oxide-derived Cu’) produces multi-carbon oxygenates (ethanol, acetate and n-propanol) with up to 57% Faraday efficiency at modest potentials (–0.25 volts to –0.5 volts versus the reversible hydrogen electrode) in CO-saturated alkaline H2O. By comparison, when prepared by traditional vapour condensation, Cu nanoparticles with an average crystallite size similar to that of oxide-derived copper produce nearly exclusive H2 (96% Faraday efficiency) under identical conditions. Our results demonstrate the ability to change the intrinsic catalytic properties of Cu for this notoriously difficult reaction by growing interconnected nanocrystallites from the constrained environment of an oxide lattice. The selectivity for oxygenates, with ethanol as the major product, demonstrates the feasibility of a two-step conversion of CO2 to liquid fuel that could be powered by renewable electricity.

  • Rapid and tunable post-translational coupling of genetic circuits

  • One promise of synthetic biology is the creation of genetic circuitry that enables the execution of logical programming in living cells. Such‘wet programming’ is positioned to transform a wide and diverse swathe of biotechnology ranging from therapeutics and diagnostics to water treatment strategies. Although progress in the development of a library of genetic modules continues apace, a major challenge for their integration into larger circuits is the generation of sufficiently fast and precise communication between modules. An attractive approach is to integrate engineered circuits with host processes that facilitate robust cellular signalling. In this context, recent studies have demonstrated that bacterial protein degradation can trigger a precise response to stress by overloading a limited supply of intracellular proteases. Here we use protease competition to engineer rapid and tunable coupling of genetic circuits across multiple spatial and temporal scales. We characterize coupling delay times that are more than an order of magnitude faster than standard transcription-factor-based coupling methods (less than 1 min compared with ∼20–40 min) and demonstrate tunability through manipulation of the linker between the protein and its degradation tag. We use this mechanism as a platform to couple genetic clocks at the intracellular and colony level, then synchronize the multi-colony dynamics to reduce variability in both clocks. We show how the coupled clock network can be used to encode independent environmental inputs into a single time series output, thus enabling frequency multiplexing (information transmitted on a common channel by distinct frequencies) in a genetic circuit context. Our results establish a general framework for the rapid and tunable coupling of genetic circuits through the use of native ‘queueing’ processes such as competitive protein degradation.

  • Trogocytosis by Entamoeba histolytica contributes to cell killing and tissue invasion

  • Entamoeba histolytica is the causative agent of amoebiasis, a potentially fatal diarrhoeal disease in the developing world. The parasite was named“histolytica” for its ability to destroy host tissues, which is probably driven by direct killing of human cells. The mechanism of human cell killing has been unclear, although the accepted model was that the parasites use secreted toxic effectors to kill cells before ingestion. Here we report the discovery that amoebae kill by ingesting distinct pieces of living human cells, resulting in intracellular calcium elevation and eventual cell death. After cell killing, amoebae detach and cease ingestion. Ingestion of human cell fragments is required for cell killing, and also contributes to invasion of intestinal tissue. The internalization of fragments of living human cells is reminiscent of trogocytosis (from Greek trogo, nibble) observed between immune cells, but amoebic trogocytosis differs because it results in death. The ingestion of live cell material and the rejection of corpses illuminate a stark contrast to the established model of dead cell clearance in multicellular organisms. These findings change the model for tissue destruction in amoebiasis and suggest an ancient origin of trogocytosis as a form of intercellular exchange.

  • High-throughput screening of a CRISPR/Cas9 library for functional genomics in human cells

  • Targeted genome editing technologies are powerful tools for studying biology and disease, and have a broad range of research applications. In contrast to the rapid development of toolkits to manipulate individual genes, large-scale screening methods based on the complete loss of gene expression are only now beginning to be developed. Here we report the development of a focused CRISPR/Cas-based (clustered regularly interspaced short palindromic repeats/CRISPR-associated) lentiviral library in human cells and a method of gene identification based on functional screening and high-throughput sequencing analysis. Using knockout library screens, we successfully identified the host genes essential for the intoxication of cells by anthrax and diphtheria toxins, which were confirmed by functional validation. The broad application of this powerful genetic screening strategy will not only facilitate the rapid identification of genes important for bacterial toxicity but will also enable the discovery of genes that participate in other biological processes.

  • Homologue engagement controls meiotic DNA break number and distribution

  • DNA double-stranded breaks (DSBs) are shown to form in greater numbers in yeast cells lacking ZMM proteins, which are traditionally regarded as acting strictly downstream of DSB formation; these findings shed light on how cells balance the beneficial and deleterious outcomes of DSB formation.

  • Plate tectonics, damage and inheritance

  • The initiation of plate tectonics on Earth is a critical event in our planet’s history. The time lag between the first proto-subduction (about 4 billion years ago) and global tectonics (approximately 3 billion years ago) suggests that plates and plate boundaries became widespread over a period of 1 billion years. The reason for this time lag is unknown but fundamental to understanding the origin of plate tectonics. Here we suggest that when sufficient lithospheric damage (which promotes shear localization and long-lived weak zones) combines with transient mantle flow and migrating proto-subduction, it leads to the accumulation of weak plate boundaries and eventually to fully formed tectonic plates driven by subduction alone. We simulate this process using a grain evolution and damage mechanism with a composite rheology (which is compatible with field and laboratory observations of polycrystalline rocks), coupled to an idealized model of pressure-driven lithospheric flow in which a low-pressure zone is equivalent to the suction of convective downwellings. In the simplest case, for Earth-like conditions, a few successive rotations of the driving pressure field yield relic damaged weak zones that are inherited by the lithospheric flow to form a nearly perfect plate, with passive spreading and strike-slip margins that persist and localize further, even though flow is driven only by subduction. But for hotter surface conditions, such as those on Venus, accumulation and inheritance of damage is negligible; hence only subduction zones survive and plate tectonics does not spread, which corresponds to observations. After plates have developed, continued changes in driving forces, combined with inherited damage and weak zones, promote increased tectonic complexity, such as oblique subduction, strike-slip boundaries that are subparallel to plate motion, and spalling of minor plates.

  • Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors

  • Touch submodalities, such as flutter and pressure, are mediated by somatosensory afferents whose terminal specializations extract tactile features and encode them as action potential trains with unique activity patterns. Whether non-neuronal cells tune touch receptors through active or passive mechanisms is debated. Terminal specializations are thought to function as passive mechanical filters analogous to the cochlea’s basilar membrane, which deconstructs complex sounds into tones that are transduced by mechanosensory hair cells. The model that cutaneous specializations are merely passive has been recently challenged because epidermal cells express sensory ion channels and neurotransmitters; however, direct evidence that epidermal cells excite tactile afferents is lacking. Epidermal Merkel cells display features of sensory receptor cells and make ‘synapse-like’ contacts with slowly adapting type I (SAI) afferents. These complexes, which encode spatial features such as edges and texture, localize toskin regions with high tactile acuity, including whisker follicles, fingertips and touch domes. Here we show that Merkel cells actively participate in touch reception in mice. Merkel cells display fast, touch-evoked mechanotransduction currents. Optogenetic approaches in intact skin show that Merkel cells are both necessary and sufficient for sustained action-potential firing in tactile afferents. Recordings from touch-dome afferents lacking Merkel cells demonstrate that Merkel cells confer high-frequency responses to dynamic stimuli and enable sustained firing. These data are the first, to our knowledge, to directly demonstrate a functional, excitatory connection between epidermal cells and sensory neurons. Together, these findings indicate that Merkel cells actively tune mechanosensory responses to facilitate high spatio-temporal acuity. Moreover, our results indicate a division of labour in the Merkel cell–neurite complex: Merkel cells signal static stimuli, such as pressure, whereas sensory afferents transduce dynamic stimuli, such as moving gratings. Thus, the Merkel cell–neurite complex is an unique sensory structure composed of two different receptor cell types specialized for distinct elements of discriminative touch.

  • Protective mucosal immunity mediated by epithelial CD1d and IL-10

  • The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9), decreased epithelial CD1d expression—as observed in inflammatory bowel disease—may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP), as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.

  • Piezo2 is required for Merkel-cell mechanotransduction

  • How we sense touch remains fundamentally unknown. The Merkel cell–neurite complex is a gentle touch receptor in the skin that mediates slowly adapting responses of Aβ sensory fibres to encode fine details of objects. This mechanoreceptor complex was recognized to have an essential role in sensing gentle touch nearly 50 years ago. However, whether Merkel cellsor afferent fibres themselves sense mechanical force is still debated, and the molecular mechanism of mechanotransduction is unknown. Synapse-like junctions are observed between Merkel cells and associated afferents, and yet it is unclear whether Merkel cells are inherently mechanosensitive or whether they can rapidly transmit such information to the neighbouring nerve. Here we show that Merkel cells produce touch-sensitive currents in vitro. Piezo2, a mechanically activated cation channel, is expressed in Merkel cells. We engineered mice deficient in Piezo2 in the skin, but not in sensory neurons, and show that Merkel-cell mechanosensitivity completely depends on Piezo2. In these mice, slowly adapting responses in vivo mediated by the Merkel cell–neurite complex show reduced static firing rates, and moreover, the mice display moderately decreased behavioural responses to gentle touch. Our results indicate that Piezo2 is the Merkel-cell mechanotransduction channel and provide the first line of evidence that Piezo channels have a physiological role in mechanosensation in mammals. Furthermore, our data present evidence for a two-receptor-site model, in which both Merkel cells and innervating afferents act together as mechanosensors. The two-receptor system could provide this mechanoreceptor complex with a tuning mechanism to achieve highly sophisticated responses to a given mechanical stimulus.

  • Cell biology: The stressful influence of microbes

  • An investigation into cellular stress responses reveals how cell compartments called mitochondria use information about the surrounding metabolites and microorganisms to protect themselves from damage.

  • T-cell activation by transitory neo-antigens derived from distinct microbial pathways

  • T cells discriminate between foreign and host molecules by recognizing distinct microbial molecules, predominantly peptides and lipids. Riboflavin precursors found in many bacteria and yeast also selectively activate mucosal-associated invariant T (MAIT) cells, an abundant population of innate-like T cells in humans. However, the genesis of these small organic molecules and their mode of presentation to MAIT cells by the major histocompatibility complex (MHC)-related protein MR1 (ref. 8) are not well understood. Here we show that MAIT-cell activation requires key genes encoding enzymes that form 5-amino-6-d-ribitylaminouracil (5-A-RU), an early intermediate in bacterial riboflavin synthesis. Although 5-A-RU does not bind MR1 or activate MAIT cells directly, it does form potent MAIT-activating antigens via non-enzymatic reactions with small molecules, such as glyoxal and methylglyoxal, which are derived from other metabolic pathways. The MAIT antigens formed by the reactions between 5-A-RU and glyoxal/methylglyoxal were simple adducts, 5-(2-oxoethylideneamino)-6-d-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), respectively, which bound to MR1 as shown by crystal structures of MAIT TCR ternary complexes. Although 5-OP-RU and 5-OE-RU are unstable intermediates, they became trapped by MR1 as reversible covalent Schiff base complexes. Mass spectra supported the capture by MR1 of 5-OP-RU and 5-OE-RU from bacterial cultures that activate MAIT cells, but not from non-activating bacteria, indicating that these MAIT antigens are present in a range of microbes. Thus, MR1 is able to capture, stabilize and present chemically unstable pyrimidine intermediates, which otherwise convert to lumazines, as potent antigens to MAIT cells. These pyrimidine adducts are microbial signatures for MAIT-cell immunosurveillance.

  • Caenorhabditis elegans pathways that surveil and defend mitochondria

  • Mitochondrial function is challenged by toxic by-products of metabolism as well as by pathogen attack. Caenorhabditis elegans normally responds to mitochondrial dysfunction with activation of mitochondrial-repair, drug-detoxification and pathogen-response pathways. Here, from a genome-wide RNA interference (RNAi) screen, we identified 45 C. elegans genes that are required to upregulate detoxification, pathogen-response and mitochondrial-repair pathways after inhibition of mitochondrial function by drug-induced or genetic disruption. Animals defective in ceramide biosynthesis are deficient in mitochondrial surveillance, and addition of particular ceramides can rescue the surveillance defects. Ceramide can also rescue the mitochondrial surveillance defects of other gene inactivations, mapping these gene activities upstream of ceramide. Inhibition of the mevalonate pathway, either by RNAi or statin drugs, also disrupts mitochondrial surveillance. Growth of C. elegans with a significant fraction of bacterial species from their natural habitat causes mitochondrial dysfunction. Other bacterial species inhibit C. elegans defence responses to a mitochondrial toxin, revealing bacterial countermeasures to animal defence.

  • Synapse elimination and learning rules co-regulated by MHC class I H2-Db

  • This study reveals a role for the MHC class I molecule H2-Db in retinogeniculate synapse elimination; expression of this immune system molecule in neurons lacking it is sufficient to rescue proper synapse pruning, as well as the segregation of eye-specific circuits in mice.

  • Mid-latitude interhemispheric hydrologic seesaw over the past 550,000 years

  • An interhemispheric hydrologic seesaw—in which latitudinal migrations of the Intertropical Convergence Zone (ITCZ) produce simultaneous wetting (increased precipitation) in one hemisphere and drying in the other—has been discovered in some tropical and subtropical regions. For instance, Chinese and Brazilian subtropical speleothem(cave formations such as stalactites and stalagmites) records show opposite trends in time series of oxygen isotopes (a proxy for precipitation variability) at millennial to orbital timescales, suggesting that hydrologic cycles were antiphased in the northerly versus southerly subtropics. This tropical to subtropical hydrologic phenomenon is likely to be an initial and important climatic response to orbital forcing. The impacts of such an interhemispheric hydrologic seesaw on higher-latitude regions and the global climate system, however, are unknown. Here we show that the antiphasing seen inthe tropical records is also present in both hemispheres of the mid-latitude western Pacific Ocean. Our results are based on a new 550,000-year record of the growth frequency of speleothems from the Korean peninsula, which we compare to Southern Hemisphere equivalents. The Korean data are discontinuous and derived from 24 separate speleothems, but still allow the identification of periods of peak speleothem growth and, thus, precipitation. The clear hemispheric antiphasing indicates that the sphere of influence of the interhemispheric hydrologic seesaw over the past 550,000 years extended at least to the mid-latitudes, such as northeast Asia, and that orbital-timescale ITCZ shifts can have serious effects on temperate climate systems. Furthermore, our result implies that insolation-driven ITCZ dynamics may provoke water vapour and vegetation feedbacks in northern mid-latitude regions and could have regulated global climate conditions throughout the late Quaternary ice age cycles.

  • Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy

  • Autophagy, the process by which proteins and organelles are sequestered in double-membrane structures called autophagosomes and delivered to lysosomes for degradation, is critical in diseases such as cancer and neurodegeneration. Much of our understanding of this process has emerged from analysis of bulk cytoplasmic autophagy, but our understanding of how specific cargo, including organelles, proteins or intracellular pathogens, are targeted for selective autophagy is limited. Here we use quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins in human cells, including cargo receptors. Like known cargo receptors, nuclear receptor coactivator 4 (NCOA4) was highly enriched in autophagosomes, and associated with ATG8 proteins that recruit cargo–receptor complexes into autophagosomes. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species but is degraded via autophagy to release iron through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin led to decreased bioavailable intracellular iron. This work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy), which is critical for iron homeostasis, and provides a resource for further dissection of autophagosomal cargo–receptor connectivity.

  • Endosomes are specialized platforms for bacterial sensing and NOD2 signalling

  • The detection of microbial pathogens involves the recognition of conserved microbial components by host cell sensors such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). TLRs are membrane receptors that survey the extracellular environment for microbial infections, whereas NLRs are cytosolic complexes that detect microbial products that reach the cytosol. Upon detection, both sensor classes trigger innate inflammatory responses and allow the engagement of adaptive immunity. Endo-lysosomes are the entry sites for a variety of pathogens, and therefore the sites at which the immune system first senses their presence. Pathogens internalized by endocytosis are well known to activate TLRs 3 and 7–9 that are localized to endocytic compartments and detect ligands present in the endosomal lumen. Internalized pathogens also activate sensors in the cytosol such as NOD1 and NOD2 (ref. 2), indicating that endosomes also provide for the translocation of bacterial components across the endosomal membrane. Despite the fact that NOD2 is well understood to have a key role in regulating innate immune responses and that mutations at the NOD2 locus are a common risk factor in inflammatory bowel disease and possibly other chronic inflammatory states, little is known about how its ligands escape from endosomes. Here we show that two endo-lysosomal peptide transporters, SLC15A3 and SLC15A4, are preferentially expressed by dendritic cells, especially after TLR stimulation. The transporters mediate the egress of bacterially derived components, such as the NOD2 cognate ligand muramyl dipeptide (MDP), and are selectively required for NOD2 responses to endosomally derived MDP. Enhanced expression of the transporters also generates endosomal membrane tubules characteristic of dendritic cells, which further enhanced the NOD2-dependent response to MDP. Finally, sensing required the recruitment of NOD2 and its effector kinase RIPK2 (refs 8, 9) to the endosomal membrane, possibly by forming a complex with SLC15A3 or SLC15A4. Thus, dendritic cell endosomes are specialized platforms for both the lumenal and cytosolic sensing of pathogens.

  • Sensory stimulation shifts visual cortex from synchronous to asynchronous states

  • In the mammalian cerebral cortex, neural responses are highly variable during spontaneous activity and sensory stimulation. To explain this variability, the cortex of alert animals has been proposed to be in an asynchronous high-conductance state in which irregular spiking arises from the convergence of large numbers of uncorrelated excitatory and inhibitory inputs onto individual neurons. Signatures of this state are that a neuron’s membrane potential (Vm) hovers just below spike threshold, and its aggregate synaptic input is nearly Gaussian, arising from many uncorrelated inputs. Alternatively, irregular spiking could arise from infrequent correlated input events that elicit large fluctuations in Vm (refs 5, 6). To distinguish between these hypotheses, we developed a technique to perform whole-cell Vm measurements from the cortex of behaving monkeys, focusing on primary visual cortex (V1) of monkeys performing a visual fixation task. Here we show that, contrary to the predictions of an asynchronous state, mean Vm during fixation was far from threshold (14 mV) and spiking was triggered by occasional large spontaneous fluctuations. Distributions of Vm values were skewed beyond that expected for a range of Gaussian input, but were consistent with synaptic input arising from infrequent correlated events. Furthermore, spontaneous fluctuations in Vm were correlated with the surrounding network activity, as reflected in simultaneously recorded nearby local field potential. Visual stimulation, however, led to responses more consistent with an asynchronous state: mean Vm approached threshold, fluctuations became more Gaussian, and correlations between single neurons and the surrounding network were disrupted. These observations show that sensory drive can shift a common cortical circuitry from a synchronous to an asynchronous state.

  • FXR is a molecular target for the effects of vertical sleeve gastrectomy

  • Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are the most effective therapy for the treatment of obesity; now bile acids, and the presence of the nuclear bile acid receptor FXR, are shown to underpin the mechanism of VSG action, and the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced if FXR is absent.

  • Nuclear reprogramming by interphase cytoplasm of two-cell mouse embryos

  • Successful mammalian cloning using somatic cell nuclear transfer (SCNT) into unfertilized, metaphase II (MII)-arrested oocytes attests to the cytoplasmic presence of reprogramming factors capable of inducing totipotency in somatic cell nuclei. However, these poorly defined maternal factors presumably decline sharply after fertilization, as the cytoplasm of pronuclear-stage zygotes is reportedly inactive. Recent evidence suggests that zygotic cytoplasm, if maintained at metaphase, can also support derivation of embryonic stem (ES) cells after SCNT, albeit at low efficiency. This led to the conclusion that critical oocyte reprogramming factors present in the metaphase but not in the interphase cytoplasm are‘trapped’ inside the nucleus during interphase and effectively removed during enucleation. Here we investigated the presence of reprogramming activity in the cytoplasm of interphase two-cell mouse embryos (I2C). First, the presence of candidate reprogramming factors was documented in both intact and enucleated metaphase and interphase zygotes and two-cell embryos. Consequently, enucleation did not provide a likely explanation for the inability of interphase cytoplasm to induce reprogramming. Second, when we carefully synchronized the cell cycle stage between the transplanted nucleus (ES cell, fetal fibroblast or terminally differentiated cumulus cell) and the recipient I2C cytoplasm, the reconstructed SCNT embryos developed into blastocysts and ES cells capable of contributing to traditional germline and tetraploid chimaeras. Last, direct transfer of cloned embryos, reconstructed with ES cell nuclei, into recipients resulted in live offspring. Thus, the cytoplasm of I2C supports efficient reprogramming, with cell cycle synchronization between the donor nucleus and recipient cytoplasm as the most critical parameter determining success. The ability to use interphase cytoplasm inSCNT could aid efforts to generate autologous human ES cells for regenerative applications, as donated or discarded embryos are more accessible than unfertilized MII oocytes.

  • Cystathionineγ-lyase deficiency mediates neurodegeneration in Huntington’s disease

  • Huntington’s disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington’s disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington’s disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington’s disease tissues, which may mediate Huntington’s disease pathophysiology. The defect occurs at the transcriptional level and seems toreflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington’s disease tissues and in intact mouse models of Huntington’s disease, suggesting therapeutic potential.

  • Structure of the human P2Y12 receptor in complex with an antithrombotic drug

  • P2Y receptors (P2YRs), a family of purinergic G-protein-coupled receptors (GPCRs), are activated by extracellular nucleotides. There are a total of eight distinct functional P2YRs expressed in human, which are subdivided into P2Y1-like receptors and P2Y12-like receptors. Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo, which limits our understanding of this receptor family. P2Y12R regulates platelet activation and thrombus formation, and several antithrombotic drugs targeting P2Y12R—including the prodrugs clopidogrel (Plavix) and prasugrel (Effient) that are metabolized and bind covalently, and the nucleoside analogue ticagrelor (Brilinta) that acts directly on the receptor—have been approved for the prevention of stroke and myocardial infarction. However, limitations of these drugs (for example, a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors. Here we report the 2.6 Å resolution crystal structure of human P2Y12R in complex with a non-nucleotide reversible antagonist, AZD1283. The structure reveals a distinct straight conformation of helix V, which sets P2Y12R apart from all other known class A GPCR structures. With AZD1283 bound, the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic. Along with the details of the AZD1283-binding site, analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding. The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates.

  • Diversity and dynamics of the Drosophila transcriptome

  • A large-scale transcriptome analysis in Drosophila melanogaster, across tissues, cell types and conditions, provides insights into global patterns and diversity of transcription initiation, splicing, polyadenylation and non-coding RNA expression.

  • Disruption of Mediator rescues the stunted growth of a lignin-deficient Arabidopsis mutant

  • Lignin is a phenylpropanoid-derived heteropolymer important for the strength and rigidity of the plant secondary cell wall. Genetic disruption of lignin biosynthesis has been proposed as a means to improve forage and bioenergy crops, but frequently results in stunted growth and developmental abnormalities, the mechanisms of which are poorly understood. Here we show that the phenotype of a lignin-deficient Arabidopsis mutant is dependent on the transcriptional co-regulatory complex, Mediator. Disruption of the Mediator complex subunits MED5a (also known as REF4) and MED5b (also known as RFR1) rescues the stunted growth, lignin deficiency and widespread changes in gene expression seen in the phenylpropanoid pathway mutant ref8, without restoring the synthesis of guaiacyl and syringyl lignin subunits. Cell walls of rescued med5a/5b ref8 plants instead contain a novel lignin consisting almost exclusively of p-hydroxyphenyl lignin subunits, and moreover exhibit substantially facilitated polysaccharide saccharification. These results demonstrate that guaiacyl and syringyl lignin subunits are largely dispensable for normal growth and development, implicate Mediator in an active transcriptional process responsible for dwarfing and inhibition of lignin biosynthesis, and suggest that the transcription machinery and signalling pathways responding to cell wall defects may be important targets to include in efforts to reduce biomass recalcitrance.

  • miRNAs trigger widespread epigenetically activated siRNAs from transposons in Arabidopsis

  • In plants, post-transcriptional gene silencing (PTGS) is mediated by DICER-LIKE 1 (DCL1)-dependent microRNAs (miRNAs), which also trigger 21-nucleotide secondary short interfering RNAs (siRNAs) via RNA-DEPENDENT RNA POLYMERASE 6 (RDR6), DCL4 and ARGONAUTE 1 (AGO1), whereas transcriptional gene silencing (TGS) of transposons is mediated by 24-nucleotide heterochromatic (het)siRNAs, RDR2, DCL3 and AGO4 (ref. 4). Transposons can also give rise to abundant 21-nucleotide‘epigenetically activated’ small interfering RNAs (easiRNAs) in DECREASED DNA METHYLATION 1 (ddm1) and DNA METHYLTRANSFERASE 1 (met1) mutants, as well as in the vegetative nucleus of pollen grains and in dedifferentiated plant cell cultures. Here we show that easiRNAs in Arabidopsis thaliana resemble secondary siRNAs, in that thousands of transposon transcripts are specifically targeted by more than 50 miRNAs for cleavage and processing by RDR6. Loss of RDR6, DCL4 or DCL1 in a ddm1 background results in loss of 21-nucleotide easiRNAs and severe infertility, but 24-nucleotide hetsiRNAs arepartially restored, supporting an antagonistic relationship between PTGS and TGS. Thus miRNA-directed easiRNA biogenesis is a latent mechanism that specifically targets transposon transcripts, but only when they are epigenetically reactivated during reprogramming of the germ line. This ancient recognition mechanism may have been retained both by transposons to evade long-term heterochromatic silencing and by their hosts for genome defence.

  • Structural basis for translocation by AddAB helicase–nuclease and its arrest at χ sites

  • In bacterial cells, processing of double-stranded DNA breaks for repair by homologous recombination is dependent upon the recombination hotspot sequenceχ (Chi) and is catalysed by either an AddAB- or RecBCD-type helicase–nuclease (reviewed in refs 3, 4). These enzyme complexes unwind and digest the DNA duplex from the broken end until they encounter a χ sequence, whereupon they produce a 3′ single-stranded DNA tail onto which they initiate loading of the RecA protein. Consequently, regulation of the AddAB/RecBCD complex by χ is a key control point in DNA repair and other processes involving genetic recombination. Here we report crystal structures of Bacillus subtilis AddAB in complex with different χ-containing DNA substrates either with or without a non-hydrolysable ATP analogue. Comparison of these structures suggests a mechanism for DNA translocation and unwinding, suggests how the enzyme binds specifically to χ sequences, and explains how χ recognition leads to the arrest of AddAB (and RecBCD) translocation that is observed in single-molecule experiments.

  • Nectar secretion requires sucrose phosphate synthases and the sugar transporter SWEET9

  • Angiosperms developed floral nectaries that reward pollinating insects. Although nectar function and composition have been characterized, the mechanism of nectar secretion has remained unclear. Here we identify SWEET9 as a nectary-specific sugar transporter in three eudicot species: Arabidopsis thaliana, Brassica rapa (extrastaminal nectaries) and Nicotiana attenuata (gynoecial nectaries). We show that SWEET9 is essential for nectar production and can function as an efflux transporter. We also show that sucrose phosphate synthase genes, encoding key enzymes for sucrose biosynthesis, are highly expressed in nectaries and that their expression is also essential for nectar secretion. Together these data are consistent with a model in which sucrose is synthesized in the nectary parenchyma and subsequently secreted into the extracellular space via SWEET9, where sucrose is hydrolysed by an apoplasmic invertase to produce a mixture of sucrose, glucose and fructose. The recruitment of SWEET9 for sucrose export may have been a key innovation, and could have coincided with the evolution of core eudicots and contributed to the evolution of nectar secretion to reward pollinators.

  • Identification of genomic alterations in oesophageal squamous cell cancer

  • Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide. Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (ggt;90%). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.

  • A new fossil species supports an early origin for toothed whale echolocation

  • Odontocetes (toothed whales, dolphins and porpoises) hunt and navigate through dark and turbid aquatic environments using echolocation; a key adaptation that relies on the same principles as sonar. Among echolocating vertebrates, odontocetes are unique in producing high-frequency vocalizations at the phonic lips, a constriction in the nasal passages just beneath the blowhole, and then using air sinuses and the melon to modulate their transmission. All extant odontocetes seem to echolocate; however, exactly when and how this complex behaviour—and its underlying anatomy—evolved is largely unknown. Here we report an odontocete fossil, Oligocene in age (approximately 28 Myr ago), from South Carolina (Cotylocara macei, gen. et sp. nov.) that has several features suggestive of echolocation: a dense, thick and downturned rostrum; air sac fossae; cranial asymmetry; and exceptionally broad maxillae. Our phylogenetic analysis places Cotylocara in a basal clade of odontocetes, leading us to infer that a rudimentary form of echolocation evolved in the early Oligocene, shortly after odontocetes diverged from the ancestors of filter-feeding whales (mysticetes). This was followed by enlargement of the facial muscles that modulate echolocation calls, which in turn led to marked, convergent changes in skull shape in the ancestors of Cotylocara, and in the lineage leading to extant odontocetes.

  • Inhibition of miR-25 improves cardiac contractility in the failing heart

  • Heart failure is characterized by a debilitating decline in cardiac function, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy. MicroRNAs (miRNAs) are dysregulated in heart failure but whether they control contractility or constitute therapeutic targets remains speculative. Using high-throughput functional screening of the human microRNAome, here we identify miRNAs that suppress intracellular calcium handling in heart muscle by interacting with messenger RNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a (also known as ATP2A2). Of 875 miRNAs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas adeno-associated virus 9 (AAV9)-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 markedly halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR oligonucleotide. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggest that it might be targeted therapeutically to restore function.

  • Haematopoietic stem cells require a highly regulated protein synthesis rate

  • Haematopoietic stem cells (HSCs) have a lower rate of protein synthesis in vivo than most other haematopoietic cells, and both increases and decreases in the rate of protein synthesis impair HSC function, demonstrating that HSC maintenance—and hence, cellular homeostasis—requires the rate of protein synthesis to be highly regulated.

  • Herbivores and nutrients control grassland plant diversity via light limitation

  • Human alterations to nutrient cycles and herbivore communities are affecting global biodiversity dramatically. Ecological theory predicts these changes should be strongly counteractive: nutrient addition drives plant species loss through intensified competition for light, whereas herbivores prevent competitive exclusion by increasing ground-level light, particularly in productive systems. Here we use experimental data spanning a globally relevant range of conditions to test the hypothesis that herbaceous plant species losses caused by eutrophication may be offset by increased light availability due to herbivory. This experiment, replicated in 40 grasslands on 6 continents, demonstrates that nutrients and herbivores can serve as counteracting forces to control local plant diversity through light limitation, independent of site productivity, soil nitrogen, herbivore type and climate. Nutrient addition consistently reduced local diversity through light limitation, and herbivory rescued diversity at sites where it alleviated light limitation. Thus, species loss from anthropogenic eutrophication can be ameliorated in grasslands where herbivory increases ground-level light.

  • Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus

  • Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.

  • Structure of a type IV secretion system

  • Bacterial type IV secretion systems translocate virulence factors into eukaryotic cells, distribute genetic material between bacteria and have shown potential as a tool for the genetic modification of human cells. Given the complex choreography of the substrate through the secretion apparatus, the molecular mechanism of the type IV secretion system has proved difficult to dissect in the absence of structural data for the entire machinery. Here we use electron microscopy to reconstruct the type IV secretion system encoded by the Escherichia coli R388 conjugative plasmid. We show that eight proteins assemble in an intricate stoichiometric relationship to form an approximately 3 megadalton nanomachine that spans the entire cell envelope. The structure comprises an outer membrane-associated core complex connected by a central stalk to a substantial inner membrane complex that is dominated by a battery of 12 VirB4 ATPase subunits organized as side-by-side hexameric barrels. Our results show a secretion system with markedly different architecture, and consequently mechanism, to other known bacterial secretion systems.

  • Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies

  • A longitudinal study of an individual patient developing neutralizing antibodies against HIV-1 (targeting the V1V2 region of gp120) reveals how such neutralizing antibodies develop and evolve over time, providing important insights relevant to vaccine development.

  • Apical constriction drives tissue-scale hydrodynamic flow to mediate cell elongation

  • Epithelial folding mediated by apical constriction converts flat epithelial sheets into multilayered, complex tissue structures and is used throughout development in most animals. Little is known, however, about how forces produced near the apical surface of the tissue are transmitted within individual cells to generate the global changes in cell shape that characterize tissue deformation. Here we apply particle tracking velocimetry in gastrulating Drosophila embryos to measure the movement of cytoplasm and plasma membrane during ventral furrow formation. We find that cytoplasmic redistribution during the lengthening phase of ventral furrow formation can be precisely described by viscous flows that quantitatively match the predictions of hydrodynamics. Cell membranes move with the ambient cytoplasm, with little resistance to, or driving force on, the flow. Strikingly, apical constriction produces similar flow patterns in mutant embryos that fail to form cells before gastrulation (‘acellular’ embryos), such that the global redistribution of cytoplasm mirrors the summed redistribution occurring in individual cells of wild-type embryos. Our results indicate that during the lengthening phase of ventral furrow formation, hydrodynamic behaviour of the cytoplasm provides the predominant mechanism transmitting apically generated forces deep into the tissue and that cell individualization is dispensable.

  • Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation

  • Haematopoietic stem and progenitor cells are maintained by special microenvironments known as niches in bone marrow. Many studies have identified diverse candidate cells that constitute niches for haematopoietic stem cells in the marrow, including osteoblasts, endothelial cells, Schwann cells,α-smooth muscle actin-expressing macrophages and mesenchymal progenitors such as CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells, stem cell factor-expressing cells, nestin-expressing cells and platelet-derived growth factor receptor-α (PDGFR-α)+Sca-1+CD45−Ter119− (PαS) cells. However, the molecular basis of the formation of the niches remains unclear. Here we find that the transcription factor Foxc1 is preferentially expressed in the adipo-osteogenic progenitor CAR cells essential for haematopoietic stem and progenitor cell maintenance in vivo in the developing and adult bone marrow. When Foxc1 was deleted in all marrow mesenchymal cells or CAR cells, from embryogenesis onwards, osteoblasts appeared normal, but haematopoietic stem and progenitor cells were markedly reduced and marrow cavities were occupied by adipocytes (yellow adipose marrow) with reduced CAR cells. Inducible deletion of Foxc1 in adult mice depleted haematopoietic stem and progenitor cells and reduced CXCL12 and stem cell factor expression in CAR cells but did not induce a change to yellow marrow. These data suggest a role for Foxc1 in inhibiting adipogenic processes in CAR progenitors. Foxc1might also promote CAR cell development, upregulating CXCL12 and stem cell factor expression. This study identifies Foxc1 as a specific transcriptional regulator essential for development and maintenance of the mesenchymal niches for haematopoietic stem and progenitor cells.

  • Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I

  • Ubiquitin (Ub) has important roles in a wide range of intracellular signalling pathways. In the conventional view, ubiquitin alters the signalling activity of the target protein through covalent modification, but accumulating evidence points to the emerging role of non-covalent interaction between ubiquitin and the target. In the innate immune signalling pathway of a viral RNA sensor, RIG-I, both covalent and non-covalent interactions with K63-linked ubiquitin chains (K63-Ubn) were shown to occur in its signalling domain, a tandem caspase activation and recruitment domain (hereafter referred to as 2CARD). Non-covalent binding of K63-Ubn to 2CARD induces its tetramer formation, a requirement for downstream signal activation. Here we report the crystal structure of the tetramer of human RIG-I 2CARD bound by three chains of K63-Ub2. 2CARD assembles into a helical tetramer resembling a‘lock-washer’, in which the tetrameric surface serves as a signalling platform for recruitment and activation of the downstream signalling molecule, MAVS. Ubiquitin chains are bound along the outer rim of the helical trajectory, bridging adjacent subunits of 2CARD and stabilizing the 2CARD tetramer. The combination of structural and functional analyses reveals that binding avidity dictates the K63-linkage and chain-length specificity of 2CARD, and that covalent ubiquitin conjugation of 2CARD further stabilizes the Ub–2CARD interaction and thus the 2CARD tetramer. Our work provides unique insights into the novel types of ubiquitin-mediated signal-activation mechanism, and previously unexpected synergism between the covalent and non-covalent ubiquitin interaction modes.

  • Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430

  • Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.

  • Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2

  • Hepatitis C virus (HCV) is a significant public health concern with approximately 160 million people infected worldwide. HCV infection often results in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. No vaccine is available and current therapies are effective against some, but not all, genotypes. HCV is an enveloped virus with two surface glycoproteins (E1 and E2). E2 binds to the host cell through interactions with scavenger receptor class B type I (SR-BI) and CD81, and serves as a target for neutralizing antibodies. Little is known about the molecular mechanism that mediates cell entry and membrane fusion, although E2 is predicted to be a class II viral fusion protein. Here we describe the structure of the E2 core domain in complex with an antigen-binding fragment (Fab) at 2.4 Å resolution. The E2 core has a compact, globular domain structure, consisting mostly of β-strands and random coil with two small α-helices. The strands are arranged in two, perpendicular sheets (A and B), which are held together by an extensive hydrophobic core and disulphide bonds. Sheet A has an IgG-like fold that is commonly found in viral and cellular proteins, whereas sheet B represents a novel fold. Solution-based studies demonstrate that the full-length E2 ectodomain has a similar globular architecture and does not undergo significant conformational or oligomeric rearrangements on exposure to low pH. Thus, the IgG-like fold is the only feature that E2 shares with class II membrane fusion proteins. These results provide unprecedented insights into HCV entry and will assist in developing an HCV vaccine and new inhibitors.

  • Eutrophication weakens stabilizing effects of diversity in natural grasslands

  • Studies of experimental grassland communities have demonstrated that plant diversity can stabilize productivity through species asynchrony, in which decreases in the biomass of some species are compensated for by increases in others. However, it remains unknown whether these findings are relevant to natural ecosystems, especially those for which species diversity is threatened by anthropogenic global change. Here we analyse diversity–stability relationships from 41 grasslands on five continents and examine how these relationships are affected by chronic fertilization, one of the strongest drivers of species loss globally. Unmanipulated communities with more species had greater species asynchrony, resulting in more stable biomass production, generalizing a result from biodiversity experiments to real-world grasslands. However, fertilization weakened the positive effect of diversity on stability. Contrary to expectations, this was not due to species loss after eutrophication but rather to an increase in the temporal variation of productivity in combination with a decrease in species asynchrony in diverse communities. Our results demonstrate separate and synergistic effects of diversity and eutrophication on stability, emphasizing the need to understand how drivers of global change interactively affect the reliable provisioning of ecosystem services in real-world systems.

  • A committed precursor to innate lymphoid cells

  • Innate lymphoid cells (ILCs) specialize in the rapid secretion of polarized sets of cytokines and chemokines to combat infection and promote tissue repair at mucosal barriers. Their diversity and similarities with previously characterized natural killer (NK) cells and lymphoid tissue inducers (LTi) have prompted a provisional classification of all innate lymphocytes into groups 1, 2 and 3 solely on the basis of cytokine properties, but their developmental pathways and lineage relationships remain elusive. Here we identify and characterize a novel subset of lymphoid precursors in mouse fetal liver and adult bone marrow that transiently express high amounts of PLZF, a transcription factor previously associated with NK T cell development, by using lineage tracing and transfer studies. PLZFhigh cells were committed ILC progenitors with multiple ILC1, ILC2 and ILC3 potential at the clonal level. They excluded classical LTi and NK cells, but included a peculiar subset of NK1.1+DX5− ‘NK-like’ cells residing in the liver. Deletion of PLZF markedly altered the development of several ILC subsets, but not LTi or NK cells. PLZFhigh precursors also expressed high amounts of ID2 and GATA3, as well as TOX, a known regulator of PLZF-independent NK and LTi lineages. These findings establish novel lineage relationships between ILC, NK and LTi cells, and identify the common precursor to ILCs, termed ILCP. They also reveal the broad, defining role of PLZF in the differentiation of innate lymphocytes.

  • Skilled reaching relies on a V2a propriospinal internal copy circuit

  • Cervical propriospinal neurons (PNs) form a genetically accessible subclass of V2a interneurons that convey both premotor output and precerebellar copy signals; their ablation in mice impairs reaching movements selectively, and activation of their internal copy projection recruits a rapid cerebellar feedback loop that modulates forelimb movement.

  • Brainstem nucleus MdV mediates skilled forelimb motor tasks

  • The authors use a combination of viral tracing and genetics to characterize the diversity of neurons projecting from mouse brainstem to motor neurons that control limb movements; in particular they discover that the medullary reticular formation ventral part (MdV) is functionally specialized for skilled forelimb motor control.
    Return To Top of the Page