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

Facing up to flu The potential for mutant-flu research to improve public health any time soon has been exaggerated. Timely production of sufficient vaccine remains the biggest challenge. Gas and air Natural-gas operations could leak enough methane to tarnish their clean image. Hypocritical oaths History judges some research as unethical, despite approval at the time. Finding the true value of US climate science A new strategy for addressing climate change takes a realistic approach to the challenge of making science useful, says Ryan Meyer. Evolution: Glad rags for a blind mole Golden moles have a blue-green sheen to their coats that is a rare example of iridescence in mammals, report Matthew Shawkey at the University of Akron in Ohio and his colleagues.The group conducted the first detailed study of iridescent outer hairs and non-iridescent downy Marine metagenomics: Sequencing from scratch Although most microorganisms cannot currently be cultured, their genomes may soon be accessible.Until now, metagenomic analyses have been able to identify only dominant members of a microbial community or those sequenced previously. Virginia Armbrust and her group at the University of Washington in Seattle Materials: Printing tiny coiled antennas Typically, the largest circuit component in wireless electronic devices such as mobile phones is the antenna, which sends and receives electromagnetic waves. The tiniest antennas available are made up of wires twisted into three-dimensional coils to save on space while maintaining high radiation efficiency and Networks: Patchy communication People tend to communicate with each other in bursts, exchanging clusters of messages over short time periods, and following these up with longer gaps in communication. But are these patterns simply the result of a tendency to talk more during the day and the working Cancer drugs: Chemo spans generations Some commonly used cancer drugs not only generate mutations in treated mice, but scar the genomes of their offspring as well.Radiation is known to cause genomic instability, leading to mutations that are passed down to the first- and even second-generation progeny of exposed mice. Human Evolution: Hobbit small, but not stunted Evidence is mounting for the argument that the 'hobbit' of Flores Island was not the same species as modern humans.The first of the 17,000-year-old Homo floresiensis fossils were discovered in 2003; since then there has been fierce debate over whether they represent a Astronomy: Core-collapse and star formation When massive stars accumulate more iron than their centres can hold, they explode in what is known as a core-collapse supernova. Such supernovae enrich the surrounding environment with elements, seeding the formation of other stars. Astronomers have linked the number of core-collapse supernovae in a Palaeontology: Early bird was black The plumage of the world's first known bird contained at least some black, researchers report.A team led by Ryan Carney at Brown University in Providence, Rhode Island, examined a fossilized feather (pictured) from the bird Archaeopteryx, which lived 150 million years Nanotechnology: Electrons explain zeolite complexity A potentially useful catalyst with a porous structure akin to that of nanoscale Swiss cheese has had its structure revealed by electron crystallography.Zeolites are microporous aluminosilicates with many applications, but their small size and the intergrowth of their crystals can make it difficult to Nuclear energy: Testing the waters for radionuclides Highly read on pubs.acs.org in DecemberA relatively reassuring study about radioactive particles released into the ocean as a result of the accident at Japan's Fukushima Daiichi nuclear power plant last March has proved popular reading.Ken Buesseler at the Woods Hole Oceanographic Institution Seven days: 3–9 February 2012 The week in science: hope for drilling breakthrough to Antarctic lake; AstraZeneca’s neuroscience cuts; and how land-grabs threaten Africa’s sustainable development. Air sampling reveals high emissions from gas field Methane leaks during production may offset climate benefits of natural gas. Fission power back on NASA’s agenda Space-technology report prioritizes nuclear propulsion. Lab flu may not aid vaccines Game-changing vaccine technologies are needed to strengthen global pandemic defences. Japan finds a key to unlock philanthropy Latest Kavli centre beats legal hurdle to using endowments. Drug bests cystic-fibrosis mutation First treatment to tackle protein behind the disease wins approval — but only a small fraction of patients will benefit. Duplicate-grant case puts funders under pressure Critics call for tighter checks to stop researchers being funded twice for the same work. Human experiments: First, do harm In the 1940s, US doctors deliberately infected thousands of Guatemalans with venereal diseases. The wound is still raw. Policy: Adaptations of avian flu virus are a cause for concern Members of the US National Science Advisory Board for Biosecurity explain its recommendations on the communication of experimental work on H5N1 influenza. H5N1: Flu transmission work is urgent Yoshihiro Kawaoka explains that research on transmissible avian flu viruses needs to continue if pandemics are to be prevented. Q&A: Reasons for proposed redaction of flu paper US National Science Advisory Board for Biosecurity explains recommendation to publish H5N1 work in a form that withholds essential data. Primate cognition: Copy that The past decade has seen a revolution in our perception of primates' social brains, says Christian Keysers. Books in brief It is no accident that the Holocaust and the Manhattan Project occurred at the same time, says science writer Gordon Fraser. Adolf Hitler's policies created a diaspora of exceptional Jewish physicists, who realized both the potential of atomic weaponry and the ambitions of the Nazi History: Impractical magic A biography of alchemist John Dee sidesteps his impact on science, suggests Philip Ball. Palaeontology: Beyond the Jurassic Brian Switek winds his way through prehistory at Utah's rehoused museum of natural history. Whaling: Quota trading won't work Anti-whaling organizations are often presented as conservationists (Nature481, 114; 2012). But for conservation efforts to advance, we need to resolve the differences between animal welfare, which is concerned with individuals, and environmental conservation, which focuses on maintaining populations, species and Policy-making: Scientists cannot compete as lobbyists Suggestions that scientists should run for political office or campaign to promote their work are counterproductive and ultimately self-defeating (Nature480, 153; 201110.1038/480153a). Science needs a permanent pipeline into policy, not temporary windows cracked open by individual researchers.Lobbying takes Marine management: Expand Australia's sustainable fisheries We do not believe that marine protected areas (MPAs) currently offer effective conservation in Australia. They do not address pollution or climate change (Nature480, 151–152; 201110.1038/480151b), and overfishing there has largely been rectified. MPAs are also inadequate Public health: Use snail ecology to assess dam impact It is not yet clear whether dam construction in the Mekong Basin will increase the impact of schistosomiasis in the region (A. R.BlaazerNature479, 478; 201110.1038/479478a). We need a better understanding of the parasite's transmission ecology to improve Asian medicine: A way to compare data To help to integrate traditional Asian medicine with Western medicine (S.Cameronet al. Nature482, 35; 201210.1038/482035a), the World Health Organization (WHO) is developing common systems for collecting statistics from both. This information — known as the International Biostatistics: Revealing analysis As the challenges of analysing genomic data evolve, statistical expertise has become more valuable than ever. Friend or foe? It is difficult to balance the benefits of collaboration and competition, argues Lydia Murray. Functional genomics: The changes that count As more mutations are found across the genome, geneticists are focusing on learning which ones are likely to cause human disease, and how. The interruption Grinding halt. Thermodynamics: The fridge gate Logic gates are the elementary building blocks of computers. The finding that a single logic gate may drive a refrigerator is a beautiful demonstration that information-processing devices can have useful thermodynamic properties. Genetics: How intelligence changes with age An analysis of common genetic variants shows that hereditary factors that influence intelligence in childhood also affect it in old age. Such work could signal the end of the nature–nurture controversy. See Letter p.212 Extrasolar planets: An Earth-sized duo The first Earth-sized planets orbiting a Sun-like star outside the Solar System have at last been detected. The discovery paves the way to finding Earth-like worlds. See Letter p.195 Infectious disease: Genomics decodes drug action Drugs used to treat African sleeping sickness are outdated, and how they enter cells and exert biological effects is poorly understood. A genome-wide study using RNA interference provides valuable insight. See Letter p.232 Quantum optics: Controlling the light Means to access and manipulate X-rays have been developing at a slow pace. But quantum-optical effects in ensembles of nuclei offer a way to tackle the control of this energetic radiation. See Letter p.199 Cell biology: Destruction deconstructed Correctly dismantling a structure can be as challenging as assembling it. The architecture of the yeast proteasome reveals this enzyme's intricate machinery for protein degradation. See Article p.186 The Drosophila melanogaster Genetic Reference Panel A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, Complete subunit architecture of the proteasome regulatory particle The proteasome is the major ATP-dependent protease in eukaryotic cells, but limited structural information restricts a mechanistic understanding of its activities. The proteasome regulatory particle, consisting of the lid and base subcomplexes, recognizes and processes polyubiquitinated substrates. Here we used electron microscopy and a new A tidally distorted dwarf galaxy near NGC 4449 NGC 4449 is a nearby Magellanic irregular starburst galaxy with a B-band absolute magnitude of −18 and a prominent, massive, intermediate-age nucleus at a distance from Earth of 3.8 megaparsecs (ref. 3). It is wreathed in an extraordinary neutral hydrogen (H i) complex, which includes rings, shells and a counter-rotating core, spanning ∼90 kiloparsecs (kpc; refs 1, 4). NGC 4449 is relatively isolated, although an interaction with its nearest known companion—the galaxy DDO 125, some 40 kpc to the south—has been proposed as being responsible for the complexity of its H i structure. Here we report the presence of a dwarf galaxy companion to NGC 4449, namely NGC 4449B. This companion has a V-band absolute magnitude of −13.4 and a half-light radius of 2.7 kpc, with a full extent of around 8 kpc. It is in a transient stage of tidal disruption, similar to that of the Sagittarius dwarf near the Milky Way. NGC 4449B exhibits a striking S-shaped morphology that has been predicted for disrupting galaxies but has hitherto been seen only in a dissolving globular cluster. We also detect an additional arc or disk ripple embedded in a two-component stellar halo, including a component extending twice as far as previously known, to about 20 kpc from the galaxy’s centre. Two Earth-sized planets orbiting Kepler-20 Since the discovery of the first extrasolar giant planets around Sun-like stars, evolving observational capabilities have brought us closer to the detection of true Earth analogues. The size of an exoplanet can be determined when it periodically passes in front of (transits) its parent star, causing a decrease in starlight proportional to its radius. The smallest exoplanet hitherto discovered has a radius 1.42 times that of the Earth’s radius (R⊕), and hence has 2.9 times its volume. Here we report the discovery of two planets, one Earth-sized (1.03R⊕) and the other smaller than the Earth (0.87R⊕), orbiting the star Kepler-20, which is already known to host three other, larger, transiting planets. The gravitational pull of the new planets on the parent star is too small to measure with current instrumentation. We apply a statistical method to show that the likelihood of the planetary interpretation of the transit signals is more than three orders of magnitude larger than that of the alternative hypothesis that the signals result from an eclipsing binary star. Theoretical considerations imply that these planets are rocky, with a composition of iron and silicate. The outer planet could have developed a thick water vapour atmosphere. Electromagnetically induced transparency with resonant nuclei in a cavity The manipulation of light–matter interactions by quantum control of atomic levels has had a profound impact on optical sciences. Such manipulation has many applications, including nonlinear optics at the few-photon level, slow light, lasing without inversion and optical quantum information processing. The critical underlying technique is electromagnetically induced transparency, in which quantum interference between transitions in multilevel atoms renders an opaque medium transparent near an atomic resonance. With the advent of high-brilliance, accelerator-driven light sources such as storage rings or X-ray lasers, it has become attractive to extend the techniques of optical quantum control to the X-ray regime. Here we demonstrate electromagnetically induced transparency in the regime of hard X-rays, using the 14.4-kiloelectronvolt nuclear resonance of the Mössbauer isotope iron-57 (a two-level system). We exploit cooperative emission from ensembles of the nuclei, which are embedded in a low-finesse cavity and excited by synchrotron radiation. The spatial modulation of the photonic density of states in a cavity mode leads to the coexistence of superradiant and subradiant states of nuclei, respectively located at an antinode and a node of the cavity field. This scheme causes the nuclei to behave as effective three-level systems, with two degenerate levels in the excited state (one of which can be considered metastable). The radiative coupling of the nuclear ensembles by the cavity field establishes the atomic coherence necessary for the cancellation of resonant absorption. Because this technique does not require atomic systems with a metastable level, electromagnetically induced transparency and its applications can be transferred to the regime of nuclear resonances, establishing the field of nuclear quantum optics. Thresholdless nanoscale coaxial lasers The effects of cavity quantum electrodynamics (QED), caused by the interaction of matter and the electromagnetic field in subwavelength resonant structures, have been the subject of intense research in recent years. The generation of coherent radiation by subwavelength resonant structures has attracted considerable interest, not only as a means of exploring the QED effects that emerge at small volume, but also for its potential in applications ranging from on-chip optical communication to ultrahigh-resolution and high-throughput imaging, sensing and spectroscopy. One such strand of research is aimed at developing the ‘ultimate’ nanolaser: a scalable, low-threshold, efficient source of radiation that operates at room temperature and occupies a small volume on a chip. Different resonators have been proposed for the realization of such a nanolaser—microdisk and photonic bandgap resonators, and, more recently, metallic, metallo-dielectric and plasmonic resonators. But progress towards realizing the ultimate nanolaser has been hindered by the lack of a systematic approach to scaling down the size of the laser cavity without significantly increasing the threshold power required for lasing. Here we describe a family of coaxial nanostructured cavities that potentially solve the resonator scalability challenge by means of their geometry and metal composition. Using these coaxial nanocavities, we demonstrate the smallest room-temperature, continuous-wave telecommunications-frequency laser to date. In addition, by further modifying the design of these coaxial nanocavities, we achieve thresholdless lasing with a broadband gain medium. In addition to enabling laser applications, these nanoscale resonators should provide a powerful platform for the development of other QED devices and metamaterials in which atom–field interactions generate new functionalities. Supercontinent cycles and the calculation of absolute palaeolongitude in deep time Traditional models of the supercontinent cycle predict that the next supercontinent—‘Amasia’—will form either where Pangaea rifted (the ‘introversion’ model) or on the opposite side of the world (the ‘extroversion’ models). Here, by contrast, we develop an ‘orthoversion’ model whereby a succeeding supercontinent forms 90° away, within the great circle of subduction encircling its relict predecessor. A supercontinent aggregates over a mantle downwelling but then influences global-scale mantle convection to create an upwelling under the landmass. We calculate the minimum moment of inertia about which oscillatory true polar wander occurs owing to the prolate shape of the non-hydrostatic Earth. By fitting great circles to each supercontinent’s true polar wander legacy, we determine that the arc distances between successive supercontinent centres (the axes of the respective minimum moments of inertia) are 88° for Nuna to Rodinia and 87° for Rodinia to Pangaea—as predicted by the orthoversion model. Supercontinent centres can be located back into Precambrian time, providing fixed points for the calculation of absolute palaeolongitude over billion-year timescales. Palaeogeographic reconstructions additionally constrained in palaeolongitude will provide increasingly accurate estimates of ancient plate motions and palaeobiogeographic affinities. Genetic contributions to stability and change in intelligence from childhood to old age Understanding the determinants of healthy mental ageing is a priority for society today. So far, we know that intelligence differences show high stability from childhood to old age and there are estimates of the genetic contribution to intelligence at different ages. However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative. Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated individuals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years). We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated individuals. We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells Our understanding of Alzheimer’s disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer’s disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APPDp), two with sporadic Alzheimer’s disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APPDp patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1–40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APPDp and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer’s disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer’s disease, even though it can take decades for overt disease to manifest in patients. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation Transcription factors and chromatin modifiers are important in the programming and reprogramming of cellular states during development. Transcription factors bind to enhancer elements and recruit coactivators and chromatin-modifying enzymes to facilitate transcription initiation. During differentiation a subset of these enhancers must be silenced, but the mechanisms underlying enhancer silencing are poorly understood. Here we show that the histone demethylase lysine-specific demethylase 1 (LSD1; ref. 5), which demethylates histone H3 on Lys 4 or Lys 9 (H3K4/K9), is essential in decommissioning enhancers during the differentiation of mouse embryonic stem cells (ESCs). LSD1 occupies enhancers of active genes that are critical for control of the state of ESCs. However, LSD1 is not essential for the maintenance of ESC identity. Instead, ESCs lacking LSD1 activity fail to differentiate fully, and ESC-specific enhancers fail to undergo the histone demethylation events associated with differentiation. At active enhancers, LSD1 is a component of the NuRD (nucleosome remodelling and histone deacetylase) complex, which contains additional subunits that are necessary for ESC differentiation. We propose that the LSD1–NuRD complex decommissions enhancers of the pluripotency program during differentiation, which is essential for the complete shutdown of the ESC gene expression program and the transition to new cell states. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis. High-throughput decoding of antitrypanosomal drug efficacy and resistance The concept of disease-specific chemotherapy was developed a century ago. Dyes and arsenical compounds that displayed selectivity against trypanosomes were central to this work, and the drugs that emerged remain in use for treating human African trypanosomiasis (HAT). The importance of understanding the mechanisms underlying selective drug action and resistance for the development of improved HAT therapies has been recognized, but these mechanisms have remained largely unknown. Here we use all five current HAT drugs for genome-scale RNA interference target sequencing (RIT-seq) screens in Trypanosoma brucei, revealing the transporters, organelles, enzymes and metabolic pathways that function to facilitate antitrypanosomal drug action. RIT-seq profiling identifies both known drug importers and the only known pro-drug activator, and links more than fifty additional genes to drug action. A bloodstream stage-specific invariant surface glycoprotein (ISG75) family mediates suramin uptake, and the AP1 adaptin complex, lysosomal proteases and major lysosomal transmembrane protein, as well as spermidine and N-acetylglucosamine biosynthesis, all contribute to suramin action. Further screens link ubiquinone availability to nitro-drug action, plasma membrane P-type H+-ATPases to pentamidine action, and trypanothione and several putative kinases to melarsoprol action. We also demonstrate a major role for aquaglyceroporins in pentamidine and melarsoprol cross-resistance. These advances in our understanding of mechanisms of antitrypanosomal drug efficacy and resistance will aid the rational design of new therapies and help to combat drug resistance, and provide unprecedented molecular insight into the mode of action of antitrypanosomal drugs. G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody G-protein-coupled receptors are the largest class of cell-surface receptors, and these membrane proteins exist in equilibrium between inactive and active states. Conformational changes induced by extracellular ligands binding to G-protein-coupled receptors result in a cellular response through the activation of G proteins. The A2A adenosine receptor (A2AAR) is responsible for regulating blood flow to the cardiac muscle and is important in the regulation of glutamate and dopamine release in the brain. Here we report the raising of a mouse monoclonal antibody against human A2AAR that prevents agonist but not antagonist binding to the extracellular ligand-binding pocket, and describe the structure of A2AAR in complex with the antibody Fab fragment (Fab2838). This structure reveals that Fab2838 recognizes the intracellular surface of A2AAR and that its complementarity-determining region, CDR-H3, penetrates into the receptor. CDR-H3 is located in a similar position to the G-protein carboxy-terminal fragment in the active opsin structure and to CDR-3 of the nanobody in the active β2-adrenergic receptor structure, but locks A2AAR in an inactive conformation. These results suggest a new strategy to modulate the activity of G-protein-coupled receptors. Gated regulation of CRAC channel ion selectivity by STIM1 Two defining functional features of ion channels are ion selectivity and channel gating. Ion selectivity is generally considered an immutable property of the open channel structure, whereas gating involves transitions between open and closed channel states, typically without changes in ion selectivity. In store-operated Ca2+ release-activated Ca2+ (CRAC) channels, the molecular mechanism of channel gating by the CRAC channel activator, stromal interaction molecule 1 (STIM1), remains unknown. CRAC channels are distinguished by a very high Ca2+ selectivity and are instrumental in generating sustained intracellular calcium concentration elevations that are necessary for gene expression and effector function in many eukaryotic cells. Here we probe the central features of the STIM1 gating mechanism in the human CRAC channel protein, ORAI1, and identify V102, a residue located in the extracellular region of the pore, as a candidate for the channel gate. Mutations at V102 produce constitutively active CRAC channels that are open even in the absence of STIM1. Unexpectedly, although STIM1-free V102 mutant channels are not Ca2+-selective, their Ca2+ selectivity is dose-dependently boosted by interactions with STIM1. Similar enhancement of Ca2+ selectivity is also seen in wild-type ORAI1 channels by increasing the number of STIM1 activation domains that are directly tethered to ORAI1 channels, or by increasing the relative expression of full-length STIM1. Thus, exquisite Ca2+ selectivity is not an intrinsic property of CRAC channels but rather a tuneable feature that is bestowed on otherwise non-selective ORAI1 channels by STIM1. Our results demonstrate that STIM1-mediated gating of CRAC channels occurs through an unusual mechanism in which permeation and gating are closely coupled. Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy Aneuploidy—the state of having uneven numbers of chromosomes—is a hallmark of cancer and a feature identified in yeast from diverse habitats. Recent studies have shown that aneuploidy is a form of large-effect mutation that is able to confer adaptive phenotypes under diverse stress conditions. Here we investigate whether pleiotropic stress could induce aneuploidy in budding yeast (Saccharomyces cerevisae). We show that whereas diverse stress conditions can induce an increase in chromosome instability, proteotoxic stress, caused by transient Hsp90 (also known as Hsp82 or Hsc82) inhibition or heat shock, markedly increased chromosome instability to produce a cell population with high karyotype diversity. The induced chromosome instability is linked to an evolutionarily conserved role for the Hsp90 chaperone complex in kinetochore assembly. Continued growth in the presence of an Hsp90 inhibitor resulted in the emergence of drug-resistant colonies with chromosome XV gain. This drug-resistance phenotype is a quantitative trait involving copy number increases of at least two genes located on chromosome XV. Short-term exposure to Hsp90 stress potentiated fast adaptation to unrelated cytotoxic compounds by means of different aneuploid chromosome stoichiometries. These findings demonstrate that aneuploidy is a form of stress-inducible mutation in eukaryotes, capable of fuelling rapid phenotypic evolution and drug resistance, and reveal a new role for Hsp90 in regulating the emergence of adaptive traits under stress. Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme–substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications.

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