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Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising concl


Eye in the sky offers clearest vision of Earth


The world’s latest carbon-monitoring satellite has advanced our understanding of how the planet functions. US politicians should take note.

Science must examine the future of work


As automation changes employment, researchers should gather the evidence to help map the implications.

Blue is in the eye of the bee-holder


Flowers have evolved an ingenious way to attract pollinators.

Give researchers a lifetime word limit


Brian C. Martinson imagines how rationing the number of publications a scientist could put out might improve the scientific literature.

Epic star collision, asteroid fly-by and journal resignations


The week in science: 13–19 October 2017.

Colliding stars spark rush to solve cosmic mysteries


Stellar collision confirms theoretical predictions about the periodic table.

Japanese research leaders warn about national science decline


Concern mounts over budget cuts and other changes that undermine basic science.

Trump EPA begins push to overturn Obama-era climate regulation


The agency's plan to reverse limits on greenhouse-gas emissions is likely to draw legal challenges.

New definitions of scientific units are on the horizon


Metrologists are poised to change how scientists measure the Universe.

FDA advisers back gene therapy for rare form of blindness


Therapy that targets disease-causing mutations could become the first of its kind approved for use in the United States.

The future of work


Digital technologies are upending the workforce. The right research can tell us how.

The shape of work to come
Three ways that the digital revolution is reshaping workforces around the world.

Lessons from history for the future of work


Global comparisons of previous social and economic upheavals suggest that what is to come depends on where you are now, argues Robert C. Allen.

Reboot for the AI revolution


As artificial intelligence puts many out of work, we must forge new economic, social and educational systems, argues Yuval Noah Harari.

The second Renaissance


Ian Goldin calls on scientists to help society to weather the disruptive transformations afoot.

Archaeology: The wonder of the pyramids


Andrew Robinson enjoys a volume rounding up research on the complex at Giza, Egypt.

Books in brief


Barbara Kiser reviews five of the week's best science picks.

History: Five millennia of Indian science


James Poskett applauds a show celebrating discovery on the subcontinent, from zero to the boson.

Federal funding: Stifled by budgets, not irrelevance


Daniel Sarewitz constructs a stereotype of scientists who are left to their own devices and whose research is disconnected from potential applications (Nature547, 139; 10.1038/547139a2017). As president of the Federation of American Societies for Experimental Biology (FASEB), I argue

Ornithology: Danish dairy farmer delivers data coup


Neither the name Peder V. Thellesen nor the Danish Ornithological Society Journal will resonate with most Nature readers. In a striking example of citizen science, the Danish journal has just published 45 years of Thellesen's breeding data from his studies of starlings (

Open data: Spot data glitches before publication


Deposition of raw data into publicly available databases — now a condition of publication in many journals (Nature537, 138; 10.1038/537138a2016) — needs to involve more than just another checkbox for the senior author. Before accepting a manuscript, journals should

PhD students: living wage key to diversity


In our view, your report on side jobs for scientists paints a naive and insensitive picture of the financial and social realities facing many graduate students and other early-career researchers (Nature549, 297–299; 10.1038/nj7671-297a2017). For a group already

PhD students: side jobs are no solution


As a graduate student at a US university, I object strongly to any implication that PhD students should take other jobs on top of their already demanding research (Nature549, 297–299; 10.1038/nj7671-297a2017). That is not, nor should it

Flexible working: Science in the gig economy


Will the future of research rely on independent workers who perform short-term jobs? Labour researchers and freelance scientists share their views.

Breaking and entering


Escape is not an option.

Genetics: The hexanucleotide hex


For years, researchers missed the most common genetic cause of ALS. Now they're on an accelerated track to treat it.

Non-Familial ALS: A tangled web


Research ranging in scale from cells to populations is rapidly closing in on what goes awry in the body in 'non-familial' ALS, and what environmental factors might contribute.

Perspective: Don't keep it in the family


Let's start describing ALS on the basis of its cause, not on whether someone obtained a relevant family history, says Ammar Al-Chalabi.

Fundraising: The Ice Bucket Challenge delivers


In 2014, millions of people doused themselves in icy water to raise money for ALS. Was it worth it?

Machine learning: Calculating disease


Machine learning might identify patients earlier, predict their outcomes better, and assign them more efficiently to appropriate clinical trials.

Research round-up


Drug therapy: On the treatment trail for ALS


The disease remains incurable but there are signs of hope on the horizon.

Perspective: Untangling the ALS X-Files


Richard Bedlack explains how an open mind led him to some unusual places and unexpected lessons

Artificial intelligence: Learning to play Go from scratch


An artificial-intelligence program called AlphaGo Zero has mastered the game of Go without any human data or guidance. A computer scientist and two members of the American Go Association discuss the implications. See Article p.354

Cancer treatment: Bacterial snack attack deactivates a drug


Tumour cells can develop intrinsic adaptations that make them less susceptible to chemotherapy. It emerges that extrinsic bacterial action can also enable tumour cells to escape the effects of drug treatment.

50 & 100 Years Ago


50 Years AgoOur society is crimogenic, in that our social structure produces most crime, which must therefore be regarded as one “normal” response to social stimuli. For an adequate understanding of its causation, and of appropriate remedial action, we must therefore rely primarily on

Computer science: Data analysis meets quantum physics


A technique that combines machine learning and quantum computing has been used to identify the particles known as Higgs bosons. The method could find applications in many areas of science. See Letter p.375

Cancer biology: Genome jail-break triggers lockdown


A pro-inflammatory response, the senescence-associated secretory phenotype, can affect development, ageing and cancer. It emerges that one trigger for this response is the presence of DNA in the cytoplasm. See Letter p.402

Biochemistry: Complex assistance for DNA invasion


Repair of broken DNA is vital for genome stability and to prevent the development of cancer. Research shows how the tumour-suppressor protein BRCA1 promotes a DNA-repair pathway called homologous recombination. See Article p.360

Neurobiology: Domains to the rescue for Rett syndrome


Rett syndrome is a brain disorder caused by disrupted forms of the protein MECP2, but how MECP2 loss affects the brain is unknown. A mouse study now implicates key domains of the protein and offers therapeutic insights. See Letter p.398

DNA sequencing at 40: past, present and future


This review commemorates the 40th anniversary of DNA sequencing, a period in which we have already witnessed multiple technological revolutions and a growth in scale from a few kilobases to the first human genome, and now to millions of human and a myriad of other

Mastering the game of Go without human knowledge


A long-standing goal of artificial intelligence is an algorithm that learns, tabula rasa, superhuman proficiency in challenging domains. Recently, AlphaGo became the first program to defeat a world champion in the game of Go. The tree search in AlphaGo evaluated positions and selected moves

BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing


The tumour suppressor complex BRCA1–BARD1 functions in the repair of DNA double-stranded breaks by homologous recombination. During this process, BRCA1–BARD1 facilitates the nucleolytic resection of DNA ends to generate a single-stranded template for the recruitment of another tumour suppressor complex, BRCA2–PALB2, and the recombinase RAD51.

Human TRPML1 channel structures in open and closed conformations


Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human

A parts-per-billion measurement of the antiproton magnetic moment


Precise comparisons of the fundamental properties of matter–antimatter conjugates provide sensitive tests of charge–parity–time (CPT) invariance, which is an important symmetry that rests on basic assumptions of the standard model of particle physics. Experiments on mesons, leptons and baryons have compared different properties of matter–antimatter conjugates with fractional uncertainties at the parts-per-billion level or better. One specific quantity, however, has so far only been known to a fractional uncertainty at the parts-per-million level: the magnetic moment of the antiproton, . The extraordinary difficulty in measuring with high precision is caused by its intrinsic smallness; for example, it is 660 times smaller than the magnetic moment of the positron. Here we report a high-precision measurement of in units of the nuclear magneton μN with a fractional precision of 1.5 parts per billion (68% confidence level). We use a two-particle spectroscopy method in an advanced cryogenic multi-Penning trap system. Our result  = −2.7928473441(42)μN (where the number in parentheses represents the 68% confidence interval on the last digits of the value) improves the precision of the previous best measurement by a factor of approximately 350. The measured value is consistent with the proton magnetic moment, μp = 2.792847350(9)μN, and is in agreement with CPT invariance. Consequently, this measurement constrains the magnitude of certain CPT-violating effects to below 1.8 × 10−24 gigaelectronvolts, and a possible splitting of the proton–antiproton magnetic moments by CPT-odd dimension-five interactions to below 6 × 10−12 Bohr magnetons.

Solving a Higgs optimization problem with quantum annealing for machine learning


The discovery of Higgs-boson decays in a background of standard-model processes was assisted by machine learning methods. The classifiers used to separate signals such as these from background are trained using highly unerring but not completely perfect simulations of the physical processes involved, often resulting in incorrect labelling of background processes or signals (label noise) and systematic errors. Here we use quantum and classical annealing (probabilistic techniques for approximating the global maximum or minimum of a given function) to solve a Higgs-signal-versus-background machine learning optimization problem, mapped to a problem of finding the ground state of a corresponding Ising spin model. We build a set of weak classifiers based on the kinematic observables of the Higgs decay photons, which we then use to construct a strong classifier. This strong classifier is highly resilient against overtraining and against errors in the correlations of the physical observables in the training data. We show that the resulting quantum and classical annealing-based classifier systems perform comparably to the state-of-the-art machine learning methods that are currently used in particle physics. However, in contrast to these methods, the annealing-based classifiers are simple functions of directly interpretable experimental parameters with clear physical meaning. The annealer-trained classifiers use the excited states in the vicinity of the ground state and demonstrate some advantage over traditional machine learning methods for small training datasets. Given the relative simplicity of the algorithm and its robustness to error, this technique may find application in other areas of experimental particle physics, such as real-time decision making in event-selection problems and classification in neutrino physics.

Ion sieving in graphene oxide membranes via cationic control of interlayer spacing


Graphene oxide membranes—partially oxidized, stacked sheets of graphene—can provide ultrathin, high-flux and energy-efficient membranes for precise ionic and molecular sieving in aqueous solution. These materials have shown potential in a variety of applications, including water desalination and purification, gas and ion separation, biosensors, proton conductors, lithium-based batteries and super-capacitors. Unlike the pores of carbon nanotube membranes, which have fixed sizes, the pores of graphene oxide membranes—that is, the interlayer spacing between graphene oxide sheets (a sheet is a single flake inside the membrane)—are of variable size. Furthermore, it is difficult to reduce the interlayer spacing sufficiently to exclude small ions and to maintain this spacing against the tendency of graphene oxide membranes to swell when immersed in aqueous solution. These challenges hinder the potential ion filtration applications of graphene oxide membranes. Here we demonstrate cationic control of the interlayer spacing of graphene oxide membranes with ångström precision using K+, Na+, Ca2+, Li+ or Mg2+ ions. Moreover, membrane spacings controlled by one type of cation can efficiently and selectively exclude other cations that have larger hydrated volumes. First-principles calculations and ultraviolet absorption spectroscopy reveal that the location of the most stable cation adsorption is where oxide groups and aromatic rings coexist. Previous density functional theory computations show that other cations (Fe2+, Co2+, Cu2+, Cd2+, Cr2+ and Pb2+) should have a much stronger cation–π interaction with the graphene sheet than Na+ has, suggesting that other ions could be used to produce a wider range of interlayer spacings.

Organic long persistent luminescence


Long persistent luminescence (LPL) materials—widely commercialized as ‘glow-in-the-dark’ paints—store excitation energy in excited states that slowly release this energy as light. At present, most LPL materials are based on an inorganic system of strontium aluminium oxide (SrAl2O4) doped with europium and dysprosium, and exhibit emission for more than ten hours. However, this system requires rare elements and temperatures higher than 1,000 degrees Celsius during fabrication, and light scattering by SrAl2O4 powders limits the transparency of LPL paints. Here we show that an organic LPL (OLPL) system of two simple organic molecules that is free from rare elements and easy to fabricate can generate emission that lasts for more than one hour at room temperature. Previous organic systems, which were based on two-photon ionization, required high excitation intensities and low temperatures. By contrast, our OLPL system—which is based on emission from excited complexes (exciplexes) upon the recombination of long-lived charge-separated states—can be excited by a standard white LED light source and generate long emission even at temperatures above 100 degrees Celsius. This OLPL system is transparent, soluble, and potentially flexible and colour-tunable, opening new applications for LPL in large-area and flexible paints, biomarkers, fabrics, and windows. Moreover, the study of long-lived charge separation in this system should advance understanding of a wide variety of organic semiconductor devices.

Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex


All animals possess a repertoire of innate (or instinctive) behaviours, which can be performed without training. Whether such behaviours are mediated by anatomically distinct and/or genetically specified neural pathways remains unknown. Here we report that neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience. Oestrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents. We used microendoscopy to image Esr1+ neuronal activity in the VMHvl of male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles and to induce an attack response 24 h later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a ‘hard-wired’ system.

Establishment of mouse expanded potential stem cells


Mouse embryonic stem cells derived from the epiblast contribute to the somatic lineages and the germline but are excluded from the extra-embryonic tissues that are derived from the trophectoderm and the primitive endoderm upon reintroduction to the blastocyst. Here we report that cultures of expanded potential stem cells can be established from individual eight-cell blastomeres, and by direct conversion of mouse embryonic stem cells and induced pluripotent stem cells. Remarkably, a single expanded potential stem cell can contribute both to the embryo proper and to the trophectoderm lineages in a chimaera assay. Bona fide trophoblast stem cell lines and extra-embryonic endoderm stem cells can be directly derived from expanded potential stem cells in vitro. Molecular analyses of the epigenome and single-cell transcriptome reveal enrichment for blastomere-specific signature and a dynamic DNA methylome in expanded potential stem cells. The generation of mouse expanded potential stem cells highlights the feasibility of establishing expanded potential stem cells for other mammalian species.

Radically truncated MeCP2 rescues Rett syndrome-like neurological defects


Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome. The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader whose binding to chromatin primarily depends on 5-methylcytosine. Functionally, MeCP2 has been implicated in several cellular processes on the basis of its reported interaction with more than 40 binding partners, including transcriptional co-repressors (for example, the NCoR/SMRT complex), transcriptional activators, RNA, chromatin remodellers, microRNA-processing proteins and splicing factors. Accordingly, MeCP2 has been cast as a multi-functional hub that integrates diverse processes that are essential in mature neurons. At odds with the concept of broad functionality, missense mutations that cause Rett syndrome are concentrated in two discrete clusters coinciding with interaction sites for partner macromolecules: the methyl-CpG binding domain and the NCoR/SMRT interaction domain. Here we test the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/SMRT complex, by removing almost all amino-acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. We find that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions (approximately half of the native protein) are phenotypically near-normal; and those expressing a minimal MeCP2 additionally lacking a central domain survive for over one year with only mild symptoms. This minimal protein is able to prevent or reverse neurological symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. Thus, despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and co-repressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility.

Cytoplasmic chromatin triggers inflammation in senescence and cancer


Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS–STING (cyclic GMP–AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin–cGAS–STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

Enhanced proofreading governs CRISPR–Cas9 targeting accuracy


The RNA-guided CRISPR–Cas9 nuclease from Streptococcus pyogenes (SpCas9) has been widely repurposed for genome editing. High-fidelity (SpCas9-HF1) and enhanced specificity (eSpCas9(1.1)) variants exhibit substantially reduced off-target cleavage in human cells, but the mechanism of target discrimination and the potential to further improve fidelity are unknown. Here, using single-molecule Förster resonance energy transfer experiments, we show that both SpCas9-HF1 and eSpCas9(1.1) are trapped in an inactive state when bound to mismatched targets. We find that a non-catalytic domain within Cas9, REC3, recognizes target complementarity and governs the HNH nuclease to regulate overall catalytic competence. Exploiting this observation, we design a new hyper-accurate Cas9 variant (HypaCas9) that demonstrates high genome-wide specificity without compromising on-target activity in human cells. These results offer a more comprehensive model to rationalize and modify the balance between target recognition and nuclease activation for precision genome editing.

Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3


The modulation of ion channel activity by lipids is increasingly recognized as a fundamental component of cellular signalling. The transient receptor potential mucolipin (TRPML) channel family belongs to the TRP superfamily and is composed of three members: TRPML1–TRPML3. TRPMLs are the major Ca2+-permeable channels on late endosomes and lysosomes (LEL). They regulate the release of Ca2+ from organelles, which is important for various physiological processes, including organelle trafficking and fusion. Loss-of-function mutations in the MCOLN1 gene, which encodes TRPML1, cause the neurodegenerative lysosomal storage disorder mucolipidosis type IV, and a gain-of-function mutation (Ala419Pro) in TRPML3 gives rise to the varitint–waddler (Va) mouse phenotype. Notably, TRPML channels are activated by the low-abundance and LEL-enriched signalling lipid phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), whereas other phosphoinositides such as PtdIns(4,5)P2, which is enriched in plasma membranes, inhibit TRPMLs. Conserved basic residues at the N terminus of the channel are important for activation by PtdIns(3,5)P2 and inhibition by PtdIns(4,5)P2. However, owing to a lack of structural information, the mechanism by which TRPML channels recognize PtdIns(3,5)P2 and increase their Ca2+ conductance remains unclear. Here we present the cryo-electron microscopy (cryo-EM) structure of a full-length TRPML3 channel from the common marmoset (Callithrix jacchus) at an overall resolution of 2.9 Å. Our structure reveals not only the molecular basis of ion conduction but also the unique architecture of TRPMLs, wherein the voltage sensor-like domain is linked to the pore via a cytosolic domain that we term the mucolipin domain. Combined with functional studies, these data suggest that the mucolipin domain is responsible for PtdIns(3,5)P2 binding and subsequent channel activation, and that it acts as a ‘gating pulley’ for lipid-dependent TRPML gating.

Structure of mammalian endolysosomal TRPML1 channel in nanodiscs


Transient receptor potential mucolipin 1 (TRPML1) is a cation channel located within endosomal and lysosomal membranes. Ubiquitously expressed in mammalian cells, its loss-of-function mutations are the direct cause of type IV mucolipidosis, an autosomal recessive lysosomal storage disease. Here we present the single-particle electron cryo-microscopy structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis analysis, the TRPML1 structure reveals that phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2) binds to the N terminus of the channel—distal from the pore—and the helix–turn–helix extension between segments S2 and S3 probably couples ligand binding to pore opening. The tightly packed selectivity filter contains multiple ion-binding sites, and the conserved acidic residues form the luminal Ca2+-blocking site that confers luminal pH and Ca2+ modulation on channel conductance. A luminal linker domain forms a fenestrated canopy atop the channel, providing several luminal ion passages to the pore and creating a negative electrostatic trap, with a preference for divalent cations, at the luminal entrance. The structure also reveals two equally distributed S4–S5 linker conformations in the closed channel, suggesting an S4–S5 linker-mediated PtdInsP2 gating mechanism among TRPML channels.