Top Module Empty

Bookmark Us




Home arrow eTOCs/Podcasts
eTOCs/Podcasts
Nature - Issue - nature.com science feeds
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.

Nature
  • Breeding controls
    Scientists must help to inform regulators wrestling with how to handle the next generation of genetically engineered crops.

  • Under appeal
    Don?t get too excited about that successful appeal against a grant rejection.

  • Destination Venus
    Findings from the Akatsuki mission should rekindle interest in Earth?s closest neighbour.

  • Origins of the obesity pandemic can be analysed
    Statistical and biological methods are available to probe why the prevalence of obesity has risen more in some countries than in others, says John Frank.

  • Geology: Fluid flow in landslides
    Vibrations that ripple through rocks as they tumble downhill explain why some landslides travel farther than expected. The finding could help towns to better prepare for landslide hazards.In 'long runout' landslides, falling rocks can move tens to hundreds of kilometres on flat land ?

  • Genetics: Disease mutations but no disease
    An analysis of genetic data from more than half a million people has uncovered 13 individuals who have disease-causing mutations but are healthy.Mendelian diseases such as cystic fibrosis begin in childhood, can be caused by a single mutation and lack effective treatments. Rong Chen

  • Ecology: Catfish face migration barriers
    Amazonian catfish make the longest known freshwater migrations, covering thousands of kilometres, but their epic voyages are threatened by new dams.Brachyplatystoma catfish can measure up to three metres in length, and are top predators. To study their migrations, Fabrice Duponchelle of the Institute

  • Astronomy: Black-hole disk launches jet
    Scientists have caught one of the best glimpses yet of a jet of plasma streaming from the black hole at the heart of a distant galaxy.Intense magnetic fields around black holes are thought to launch these beams, which travel nearly at the speed of

  • Anthropology: War uncommon in prehistoric Japan
    Hunter-gatherers living in Japan thousands of years ago were not particularly violent, adding weight to a contentious idea that violence and warfare were not the norm in early history.Hisashi Nakao at Yamaguchi University in Japan and his colleagues analysed published data on the skeletal

  • Microbiology: Salmonella live on thanks to toxin
    A toxin protein secreted by typhoid-causing bacteria seems to keep infected hosts alive, allowing the bacteria to persist in the body.Salmonella enterica Typhi (S. Typhi), which causes typhoid fever in humans but not in mice, produces a DNA-damaging protein. To study

  • Astrochemistry: Sugars made in simulated space
    A key sugar found in DNA has been created in the laboratory under conditions similar to those around comets.Ribose forms the backbone of DNA and RNA, but its ancient origin remains a mystery. Cornelia Meinert and Uwe Meierhenrich of the University of Nice Sophia

  • Heart disease: Molecule melts away cholesterol
    The next weapon against heart disease could be a compound that is currently used to make drugs more soluble.In atherosclerosis, plaques containing crystallized cholesterol clog up blood vessels. Eicke Latz of the University Hospital in Bonn, Germany, and his colleagues tested a compound called

  • Biochemistry: Bioplastic made from glucose
    Researchers have combined three biochemical pathways to produce a biodegradable plastic from glucose in the laboratory.Some industrial chemicals are made by microorganisms in bioreactors, but reengineering the organisms' metabolic pathways to boost yields is challenging, so researchers are keen to find cell-free production methods.

  • Neuroimmunology: Protein linked to immune privilege
    A protein found in neurons helps to limit inflammation in the central nervous system (CNS), contributing to the system's specialized immune environment.The CNS can stave off excessive inflammation. This 'immune privilege' has been attributed to the blood?brain barrier that restricts the entry of certain

  • The week in science: 8?14 April 2016
    Human embryos made HIV-resistant; reusable rocket lands on ship; Pfizer calls off merger with Allergan.

  • Fears rise over yellow fever?s next move
    Scientists warn vaccine stocks would be overwhelmed in the event of large urban outbreaks.

  • Rescued Japanese spacecraft delivers first results from Venus
    Streaked acidic clouds and a bow shape in the atmosphere are among Akatsuki?s findings.

  • Gene-editing surges as US rethinks regulations
    Committee begins study to guide oversight of modified organisms.

  • How one lab challenged a grant rejection and won ?5 million
    A British scientist successfully appealed against an unfavourable grant review ? but the road to victory can be paved with challenges.

  • Human mind excels at quantum physics game
    Revelation could have implications for how scientists approach quantum physics.

  • Cocktails for cancer with a measure of immunotherapy
    The next frontier in cancer immunotherapy lies in combining it with other treatments. Scientists are trying to get the mix just right.

  • Cancer therapy: an evolved approach
    Tumours are subject to the same rules of natural selection as any other living thing. Clinicians are now putting that knowledge to use.

  • Physics: Unite to build a quantum Internet
    Advances in quantum communication will come from investment in hybrid technologies, explain Stefano Pirandola and Samuel L. Braunstein.

  • CRISPR: Pursuit of profit poisons collaboration
    The CRISPR?Cas9 patent battle demonstrates how overzealous efforts to commercialize technology can damage science, writes Jacob S. Sherkow.

  • Ornithology: Oology unshelled
    John M. Marzluff extols a rich history of ornithology's debt to egg collecting.

  • Books in brief
    Barbara Kiser reviews five of the week's best science picks.

  • Evolution: Taxonomies of cognition
    Joan B. Silk examines Frans de Waal's treatise on the evolution of animal intelligence.

  • Modelling: Climate costing is politics not science
    Nicholas Stern argues that today's integrated assessment models for quantifying the economic and societal impacts of climate change are inadequate (Nature530, 407?409;10.1038/530407a2016). We disagree with his view on the superiority of more complex models such as

  • Pollinators: Europe must block hornet invasion
    Another notable omission from the European Union's list of invasive alien species that are targeted for action is the Asian yellow-legged hornet, Vespa velutina nigrithorax (see J.Perglet al. Nature531, 173; 10.1038/531173d2016). Since its arrival in Europe

  • Animal models: Software for study design falls short
    Online software that can improve the design of animal studies is welcome, but it should not replace specialist advice (see Nature531, 128; 10.1038/531128a2016).Animals are complex biological systems. Their organs and tissues have variable and dynamic functions and morphology in

  • Research data: Silver lining to irreproducibility
    There is room for improvement in how science is done and reported, but something can often be learned from irreproducible experiments. The situation may not be as dire as some headlines imply.It is crucial to include caveats when citing analyses of reproducibility. For example,

  • Religion: Social cooperation among agnostics
    Benjamin Grant Purzycki and colleagues suggest that religion helps to explain cooperation in large societies (Nature530, 327?330; 10.1038/nature169802016). In my view, knowledge of others' reputations forms a more stable basis for cooperation.A network with redundant connections

  • Lloyd Shapley (1923?2016)
    A founding father of game theory.

  • Biomedical research: Privacy rules
    Researchers must unpick a tangle of regulations to work with personal health data.

  • Trade talk: Serial solver
    How mathematician Cristiano Malossi came to work for IBM.

  • Incursions
    Report from the front line.

  • Correction
    In the News story ?Controversial dark-matter claim faces ultimate test? (Nature532, 14?15; 2016), the last paragraph was amended to better reflect Katherine Freese?s views on the DAMA collaboration?s results.

  • Correction
    In the essay 'Getting the circulation going' (Nature531, 443?446; 2016), William McDonough was said to have studied under John Lyle; in fact, they collaborated.

  • Animal behaviour: Some begging is actually bragging
    A meta-analysis of 143 bird species finds huge variation in parental responses to chicks' begging signals, and shows that parental strategies depend on environmental factors, such as the predictability and quality of food supplies.

  • Cancer genomics: Hard-to-reach repairs
    Two studies find that the molecular machinery that initiates gene transcription prevents repair proteins from accessing DNA, resulting in increased mutation rates at sites of transcription-factor binding. See Letters p.259 & p.264

  • Regeneration: Not everything is scary about a glial scar
    After spinal-cord injury, cells called astrocytes form a scar that is thought to block neuronal regeneration. The finding that the scar promotes regrowth of long nerve projections called axons challenges this long-held dogma. See Article p.195

  • Physics: Quantum problems solved through games
    Humans are better than computers at performing certain tasks because of their intuition and superior visual processing. Video games are now being used to channel these abilities to solve problems in quantum physics. See Letter p.210

  • 50 & 100 Years Ago
    50 Years AgoEngineers get the rough end of the stick even in countries where they are more esteemed than in ours ... You fire off a rocket and a satellite moves successfully around the world. That is a scientific triumph. On the other hand,

  • Neuroinflammation: Surprises from the sanitary engineers
    In mammals, microglial cells of the central nervous system are responsible for the normal clearance of dead brain cells. TAM-receptor proteins have now been found to mediate this function. See Letter p.240

  • Geochemistry: How rain affects rock and rivers
    An analysis of the evolution of river channels on Hawaii's Big Island shows that a key factor is the effect of local rainfall on bedrock strength ? rather than its effect on river discharge, as is often assumed. See Letter p.223

  • Hourglass fermions
    Spatial symmetries in crystals may be distinguished by whether they preserve the spatial origin. Here we study spatial symmetries that translate the origin by a fraction of the lattice period, and find that these non-symmorphic symmetries protect an exotic surface fermion whose dispersion relation is

  • Astrocyte scar formation aids central nervous system axon regeneration
    Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic

  • Modulation of tissue repair by regeneration enhancer elements
    How tissue regeneration programs are triggered by injury has received limited research attention. Here we investigate the existence of enhancer regulatory elements that are activated in regenerating tissue. Transcriptomic analyses reveal that leptin b (lepb) is highly induced in regenerating hearts and

  • A map of the large day?night temperature gradient of a super-Earth exoplanet
    Over the past decade, observations of giant exoplanets (Jupiter-size) have provided key insights into their atmospheres, but the properties of lower-mass exoplanets (sub-Neptune) remain largely unconstrained because of the challenges of observing small planets. Numerous efforts to observe the spectra of super-Earths?exoplanets with masses of one to ten times that of Earth?have so far revealed only featureless spectra. Here we report a longitudinal thermal brightness map of the nearby transiting super-Earth 55 Cancri e (refs 4, 5) revealing highly asymmetric dayside thermal emission and a strong day?night temperature contrast. Dedicated space-based monitoring of the planet in the infrared revealed a modulation of the thermal flux as 55 Cancri e revolves around its star in a tidally locked configuration. These observations reveal a hot spot that is located 41??12 degrees east of the substellar point (the point at which incident light from the star is perpendicular to the surface of the planet). From the orbital phase curve, we also constrain the nightside brightness temperature of the planet to 1,380??400 kelvin and the temperature of the warmest hemisphere (centred on the hot spot) to be about 1,300 kelvin hotter (2,700??270 kelvin) at a wavelength of 4.5 micrometres, which indicates inefficient heat redistribution from the dayside to the nightside. Our observations are consistent with either an optically thick atmosphere with heat recirculation confined to the planetary dayside, or a planet devoid of atmosphere with low-viscosity magma flows at the surface.

  • Exploring the quantum speed limit with computer games
    Humans routinely solve problems of immense computational complexity by intuitively forming simple, low-dimensional heuristic strategies. Citizen science (or crowd sourcing) is a way of exploiting this ability by presenting scientific research problems to non-experts. ?Gamification??the application of game elements in a non-game context?is an effective tool with which to enable citizen scientists to provide solutions to research problems. The citizen science games Foldit, EteRNA and EyeWire have been used successfully to study protein and RNA folding and neuron mapping, but so far gamification has not been applied to problems in quantum physics. Here we report on Quantum Moves, an online platform gamifying optimization problems in quantum physics. We show that human players are able to find solutions to difficult problems associated with the task of quantum computing. Players succeed where purely numerical optimization fails, and analyses of their solutions provide insights into the problem of optimization of a more profound and general nature. Using player strategies, we have thus developed a few-parameter heuristic optimization method that efficiently outperforms the most prominent established numerical methods. The numerical complexity associated with time-optimal solutions increases for shorter process durations. To understand this better, we produced a low-dimensional rendering of the optimization landscape. This rendering reveals why traditional optimization methods fail near the quantum speed limit (that is, the shortest process duration with perfect fidelity). Combined analyses of optimization landscapes and heuristic solution strategies may benefit wider classes of optimization problems in quantum physics and beyond.

  • Direct observation of dynamic shear jamming in dense suspensions
    Liquid-like at rest, dense suspensions of hard particles can undergo striking transformations in behaviour when agitated or sheared. These phenomena include solidification during rapid impact, as well as strong shear thickening characterized by discontinuous, orders-of-magnitude increases in suspension viscosity. Much of this highly non-Newtonian behaviour has recently been interpreted within the framework of a jamming transition. However, although jamming indeed induces solid-like rigidity, even a strongly shear-thickened state still flows and thus cannot be fully jammed. Furthermore, although suspensions are incompressible, the onset of rigidity in the standard jamming scenario requires an increase in particle density. Finally, whereas shear thickening occurs in the steady state, impact-induced solidification is transient. As a result, it has remained unclear how these dense suspension phenomena are related and how they are connected to jamming. Here we resolve this by systematically exploring both the steady-state and transient regimes with the same experimental system. We demonstrate that a fully jammed, solid-like state can be reached without compression and instead purely with shear, as recently proposed for dry granular systems. This state is created by transient shear-jamming fronts, which we track directly. We also show that shear stress, rather than shear rate, is the key control parameter. From these findings we map out a state diagram with particle density and shear stress as variables. We identify discontinuous shear thickening with a marginally jammed regime just below the onset of full, solid-like jamming. This state diagram provides a unifying framework, compatible with prior experimental and simulation results on dense suspensions, that connects steady-state and transient behaviour in terms of a dynamic shear-jamming process.

  • Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals
    An important goal of modern organic chemistry is to develop new catalytic strategies for enantioselective carbon?carbon bond formation that can be used to generate quaternary stereogenic centres. Whereas considerable advances have been achieved by exploiting polar reactivity, radical transformations have been far less successful. This is despite the fact that open-shell intermediates are intrinsically primed for connecting structurally congested carbons, as their reactivity is only marginally affected by steric factors. Here we show how the combination of photoredox and asymmetric organic catalysis enables enantioselective radical conjugate additions to ?,?-disubstituted cyclic enones to obtain quaternary carbon stereocentres with high fidelity. Critical to our success was the design of a chiral organic catalyst, containing a redox-active carbazole moiety, that drives the formation of iminium ions and the stereoselective trapping of photochemically generated carbon-centred radicals by means of an electron-relay mechanism. We demonstrate the generality of this organocatalytic radical-trapping strategy with two sets of open-shell intermediates, formed through unrelated light-triggered pathways from readily available substrates and photoredox catalysts?this method represents the application of iminium ion activation (a successful catalytic strategy for enantioselective polar chemistry) within the realm of radical reactivity.

  • Chemical weathering as a mechanism for the climatic control of bedrock river incision
    Feedbacks between climate, erosion and tectonics influence the rates of chemical weathering reactions, which can consume atmospheric CO2 and modulate global climate. However, quantitative predictions for the coupling of these feedbacks are limited because the specific mechanisms by which climate controls erosion are poorly understood. Here we show that climate-dependent chemical weathering controls the erodibility of bedrock-floored rivers across a rainfall gradient on the Big Island of Hawai?i. Field data demonstrate that the physical strength of bedrock in streambeds varies with the degree of chemical weathering, which increases systematically with local rainfall rate. We find that incorporating the quantified relationships between local rainfall and erodibility into a commonly used river incision model is necessary to predict the rates and patterns of downcutting of these rivers. In contrast to using only precipitation-dependent river discharge to explain the climatic control of bedrock river incision, the mechanism of chemical weathering can explain strong coupling between local climate and river incision.

  • Ritual human sacrifice promoted and sustained the evolution of stratified societies
    Evidence for human sacrifice is found throughout the archaeological record of early civilizations, the ethnographic records of indigenous world cultures, and the texts of the most prolific contemporary religions. According to the social control hypothesis, human sacrifice legitimizes political authority and social class systems, functioning to stabilize such social stratification. Support for the social control hypothesis is largely limited to historical anecdotes of human sacrifice, where the causal claims have not been subject to rigorous quantitative cross-cultural tests. Here we test the social control hypothesis by applying Bayesian phylogenetic methods to a geographically and socially diverse sample of 93 traditional Austronesian cultures. We find strong support for models in which human sacrifice stabilizes social stratification once stratification has arisen, and promotes a shift to strictly inherited class systems. Whilst evolutionary theories of religion have focused on the functionality of prosocial and moral beliefs, our results reveal a darker link between religion and the evolution of modern hierarchical societies.

  • Post-invasion demography of prehistoric humans in South America
    As the last habitable continent colonized by humans, the site of multiple domestication hotspots, and the location of the largest Pleistocene megafaunal extinction, South America is central to human prehistory. Yet remarkably little is known about human population dynamics during colonization, subsequent expansions, and domestication. Here we reconstruct the spatiotemporal patterns of human population growth in South America using a newly aggregated database of 1,147 archaeological sites and 5,464 calibrated radiocarbon dates spanning fourteen thousand to two thousand years ago (ka). We demonstrate that, rather than a steady exponential expansion, the demographic history of South Americans is characterized by two distinct phases. First, humans spread rapidly throughout the continent, but remained at low population sizes for 8,000 years, including a 4,000-year period of ?boom-and-bust? oscillations with no net growth. Supplementation of hunting with domesticated crops and animals had a minimal impact on population carrying capacity. Only with widespread sedentism, beginning ~5?ka, did a second demographic phase begin, with evidence for exponential population growth in cultural hotspots, characteristic of the Neolithic transition worldwide. The unique extent of humanity?s ability to modify its environment to markedly increase carrying capacity in South America is therefore an unexpectedly recent phenomenon.

  • A neuronal circuit for colour vision based on rod?cone opponency
    In bright light, cone-photoreceptors are active and colour vision derives from a comparison of signals in cones with different visual pigments. This comparison begins in the retina, where certain retinal ganglion cells have ?colour-opponent? visual responses?excited by light of one colour and suppressed by another colour. In dim light, rod-photoreceptors are active, but colour vision is impossible because they all use the same visual pigment. Instead, the rod signals are thought to splice into retinal circuits at various points, in synergy with the cone signals. Here we report a new circuit for colour vision that challenges these expectations. A genetically identified type of mouse retinal ganglion cell called JAMB (J-RGC), was found to have colour-opponent responses, OFF to ultraviolet (UV) light and ON to green light. Although the mouse retina contains a green-sensitive cone, the ON response instead originates in rods. Rods and cones both contribute to the response over several decades of light intensity. Remarkably, the rod signal in this circuit is antagonistic to that from cones. For rodents, this UV-green channel may play a role in social communication, as suggested by spectral measurements from the environment. In the human retina, all of the components for this circuit exist as well, and its function can explain certain experiences of colour in dim lights, such as a ?blue shift? in twilight. The discovery of this genetically defined pathway will enable new targeted studies of colour processing in the brain.

  • TAM receptors regulate multiple features of microglial physiology
    Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson?s disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.

  • The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression
    Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle?its cognate receptor?was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

  • sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance
    Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in ?-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.

  • Reductive carboxylation supports redox homeostasis during anchorage-independent growth
    Cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM). Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells. Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS.

  • Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes
    Promoters are DNA sequences that have an essential role in controlling gene expression. While recent whole cancer genome analyses have identified numerous hotspots of somatic point mutations within promoters, many have not yet been shown to perturb gene expression or drive cancer development. As such, positive selection alone may not adequately explain the frequency of promoter point mutations in cancer genomes. Here we show that increased mutation density at gene promoters can be linked to promoter activity and differential nucleotide excision repair (NER). By analysing 1,161 human cancer genomes across 14 cancer types, we find evidence for increased local density of somatic point mutations within the centres of DNase I-hypersensitive sites (DHSs) in gene promoters. Mutated DHSs were strongly associated with transcription initiation activity, in which active promoters but not enhancers of equal DNase I hypersensitivity were most mutated relative to their flanking regions. Notably, analysis of genome-wide maps of NER shows that NER is impaired within the DHS centre of active gene promoters, while XPC-deficient skin cancers do not show increased promoter mutation density, pinpointing differential NER as the underlying cause of these mutation hotspots. Consistent with this finding, we observe that melanomas with an ultraviolet-induced DNA damage mutation signature show greatest enrichment of promoter mutations, whereas cancers that are not highly dependent on NER, such as colon cancer, show no sign of such enrichment. Taken together, our analysis has uncovered the presence of a previously unknown mechanism linking transcription initiation and NER as a major contributor of somatic point mutation hotspots at active gene promoters in cancer genomes.

  • Nucleotide excision repair is impaired by binding of transcription factors to DNA
    Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears to be greatly variable across the genome due to variations in chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally are unknown, such as a role for DNA-binding proteins, for example. Here we demonstrate that the rate of somatic mutations in melanomas is highly increased at active transcription factor binding sites and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of DNA mutations at the protein binding sites. This finding has important implications for our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

  • Corrigendum: Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart
    Nature523, 226?230 (2015); doi:10.1038/nature14582In this Letter we omitted to include the accession number for our RNA-seq data. The data are deposited in the Sequence Read Archive database under the accession number SRP060713. Also, in our

  • Corrigendum: Mapping tree density at a global scale
    Nature525, 201?205 (2015); doi:10.1038/nature14967In the first boldface paragraph of this Article, the global number of trees should be approximately ?1.30 trillion? (rather than ?1.39 trillion?) for tropical and subtropical forests and ?0.66 trillion? (rather than ?0.61

  • Retraction: The structure of complement C3b provides insights into complement activation and regulation
    Nature444, 221?225 (2006); doi:10.1038/nature05258This Letter is retracted by Nature. This follows an investigation by the University of Alabama at Birmingham, Alabama, USA, of structures deposited into the Protein Data Bank under accession 2HR0 by H.


© 2016 The Pawson Lab
Joomla! is Free Software released under the GNU/GPL License.