| | | Volume 508 Number 7494 | | | | nature | | The science that matters. Every week. | | | | | | | | | | |  | | | Genomic know-how® — it's how experiments succeed. You need answers to complex biological questions. We have deep expertise across a wide range of technologies to help you get it right the first time. At EA | Quintiles, our experienced scientists leverage innovative bioinformatics and methodologies to give you the genomic information you need to succeed. genomicknowhow.com | | | | | | | | Jump to the content that matters to you | | | | | | | | | | | | Specials - Outlook: Schizophrenia | | | | | | Schizophrenia is a condition experienced by over 0.5% of the world's population at some time in their lives, and has a more debilitating impact on sufferers than most psychiatric illnesses, as well as a disproportionate societal impact. This special issue highlights the state of play and opportunities for progress in understanding, diagnosing and treating the condition. ▼ more | | | | | | | | | | | | | A ring system detected around the Centaur (10199) Chariklo | | Observations of a stellar occultation by (10199) Chariklo, a Centaur-class outer-system asteroid orbiting between Saturn and Uranus, reveal that it has a ring system, a feature previously observed only for the four giant planets. Chariklo, with a diameter of about 250 km, has two dense rings separated by a small gap, probably due to the presence of a an unseen kilometre-size satellite. This surprising discovery suggests that planetary rings are much more common than previously thought. | | | | | | | | | | | | | Highly siderophile elements in Earth's mantle as a clock for the Moon-forming impact | | Various chronometers have been used to estimate the age of the Moon but the results differ widely because of the varying assumptions required in the calculation of the so-called model ages. Seth Jacobson et al. use an alternative approach. They run a large number of numerical simulations, some based on early Moon-forming events, others on later events. They then arrive at a model-independent correlation between the formation age of the Moon and the amount of mass accreted by the Earth since then, the so-called Late Veneer. The authors calculate that the Moon-forming impact was a late event, occurring some 40 million years after formation of the Solar System. | | | | | | | | | | | | | Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers | | Tumours often display a complex subclonal organization. In a mouse model of breast cancer initiated by Wnt signalling, Allison Cleary et al. show that some tumours are biclonal — composed of basal and luminal clones with distinct genetic alterations. Clones cooperate to maintain the cancer: when Wnt production is blocked, basal cells carrying Hras mutations recruit other Wnt-producing cells to restore tumour growth. These findings shed light on the complex cellular interactions in heterogeneous tumours that may prove important for therapeutic strategies. | | | | | | | | | | | | | | | | | | | | | | In this week's podcast: This week, using the immune system to attack cancer, mapping the prenatal brain, and fifty years on from the discovery of an ancient human species, 'handy man' Homo habilis. Plus, our favourite entries to Nature's snappy sci-fi story competition, MicroFutures. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Brace for impacts ▶ | | | | The latest instalment of the Fifth Assessment Report from the Intergovernmental Panel on Climate Change lays out the state of the world — and the challenges ahead. | | | | | | | | | | | | Natural decline ▶ | | | | Few biology degrees still feature natural history. Is the naturalist a species in crisis? | | | | | | | | | | | | Brain waves ▶ | | | | Above the ‘big neuroscience’ commotion, literature plays its part. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | El Niño tests forecasters ▶ | | | | As hints emerge of a major weather event this year, poor data could thwart attempts to improve predictions. | | | | | | | | | | | | | | | | | | | | | | | | Cosmology: Polar star ▶ | | | | After years of work in the Antarctic, John Kovac and his team have captured strong evidence for a long-held theory about the Universe’s birth. | | | | | | | | | | | | | | | | | | | | | | | | Policy: Free Indian science ▶ | | | | As elections begin in India, Mathai Joseph and Andrew Robinson call for an end to the stultifying bureaucracy that has held back the nation's science for decades. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Synapse elimination and learning rules co-regulated by MHC class I H2-Db ▶ | | | | Hanmi Lee, Barbara K. Brott, Lowry A. Kirkby et al. | | | | This study reveals a role for the MHC class I molecule H2-Db in retinogeniculate synapse elimination; expression of this immune system molecule in neurons lacking it is sufficient to rescue proper synapse pruning, as well as the segregation of eye-specific circuits in mice. | | | | | | | | | | Endosomes are specialized platforms for bacterial sensing and NOD2 signalling ▶ | | | | Norihiro Nakamura, Jennie R. Lill, Qui Phung et al. | | | | This study shows that two endo-lysosomal peptide transporters, SLC15A3 and SLC15A4, are preferentially expressed by dendritic cells, especially after TLR stimulation. The transporters mediate the egress of bacterially derived components, such as the NOD2 cognate ligand muramyl dipeptide (MDP), and are selectively required for NOD2 responses to endosomally derived MDP. | | | | | | | | | | A mesoscale connectome of the mouse brain ▶ | | | | Seung Wook Oh, Julie A. Harris, Lydia Ng et al. | | | | This study reports a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. | | | | | | | | | | | | MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool ▶ | | | | Helge Gad, Tobias Koolmeister, Ann-Sofie Jemth et al. | | | | In order to find a general treatment for cancer, this study found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule inhibitors of MTH1, TH287 and TH588 in the presence of these inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in patient-derived mouse xenograft models. | | | | | | | | | | | | Transcriptional landscape of the prenatal human brain ▶ | | | | Jeremy A. Miller, Song-Lin Ding, Susan M. Sunkin et al. | | | | A spatially resolved transcriptional atlas of the mid-gestational developing human brain has been created using laser-capture microdissection and microarray technology, providing a comprehensive reference resource which also enables new hypotheses about the nature of human brain evolution and the origins of neurodevelopmental disorders. | | | | | | | | | | | | Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy ▶ | | | | Kilian V. M. Huber, Eidarus Salah, Branka Radic et al. | | | | A chemoproteomic screen is used here to identify MTH1 as the target of SCH51344, an experimental RAS-dependent cancer drug; a further search for inhibitors revealed (S)-crizotinib as a potent MTH1 antagonist, which suppresses tumour growth in animal models of colon cancer, and could be part of a new class of anticancer drugs. | | | | | | | | | | | | | | | | Sensory stimulation shifts visual cortex from synchronous to asynchronous states ▶ | | | | Andrew Y. Y. Tan, Yuzhi Chen, Benjamin Scholl et al. | | | | Intracellular recordings distinguish between mechanisms that can account for variability in primary visual cortex of alert primates, consistent with a scheme in which spiking is driven by infrequent synchronous events during fixation, with sensory stimulation shifting the cortex to an asynchronous state. | | | | | | | | | | | | T-cell activation by transitory neo-antigens derived from distinct microbial pathways ▶ | | | | Alexandra J. Corbett, Sidonia B. G. Eckle, Richard W. Birkinshaw et al. | | | | Activation of mucosal-associated invariant T (MAIT) cells is shown to require key genes encoding an early intermediate in bacterial riboflavin synthesis, 5-amino-6-d-ribitylaminouracil; this reacts non-enzymatically with metabolites to form short-lived antigens that are captured and stabilized by MR1 for presentation to MAIT cells. | | | | | | | | | | | | | | | | | | | | Capillary pericytes regulate cerebral blood flow in health and disease ▶ | | | | Catherine N. Hall, Clare Reynell, Bodil Gesslein et al. | | | | Neuronal activity relaxes pericytes, leading to capillary dilation and increased blood flow, before arterioles dilate, suggesting that pericytes initiate blood-oxygen-level-dependent (BOLD) functional imaging signals; pericytes constrict and die in rigor in ischaemia, which will cause a long-lasting blood flow decrease after stroke, and damage the bloodbrain barrier. | | | | | | | | | | | | Mechanism of Tc toxin action revealed in molecular detail ▶ | | | | Dominic Meusch, Christos Gatsogiannis, Rouslan G. Efremov et al. | | | | High-resolution structures of the Photorhabdus luminescens TcA toxin subunit and the entire Tc toxin complex reveal important new insights into Tc complex structure and function. | | | | | | | | | | | | Poly(A)-tail profiling reveals an embryonic switch in translational control ▶ | | | | Alexander O. Subtelny, Stephen W. Eichhorn, Grace R. Chen et al. | | | | A new high-throughput sequencing method to determine mRNA poly(A)-tail length enabled studies of individual RNAs across species and developmental stages to investigate the role of poly(A) length in translational regulation; the relationship between poly(A) length and translational efficiency shown in early embryo systems does not occur later in development, a finding that explains different regulatory consequences of microRNAs acting at different developmental times. | | | | | | | | | | | | | | | | | | | | | | | | XBP1 promotes triple-negative breast cancer by controlling the HIF1 pathway ▶ | | | | Xi Chen, Dimitrios Iliopoulos, Qing Zhang et al. | | | | This study finds that triple-negative breast cancers (TNBC) show an increased basal level of endoplasmic reticulum stress and activation of the XBP1 branch of the unfolded protein response; furthermore, XBP1 promotes tumour formation of TNBC cell lines by interacting with and regulating HIF1. | | | | | | | | | | | | Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides ▶ | | | | Kvan Birsoy, Richard Possemato, Franziska K. Lorbeer et al. | | | | New apparatus is used to maintain proliferating cancer cells in low-glucose conditions, demonstrating that mitochondrial oxidative phosphorylation (OXPHOS) is essential for optimal proliferation in these conditions; the most sensitive cell lines are defective in OXPHOS upregulation and may therefore be sensitive to current antidiabetic drugs that inhibit OXPHOS. | | | | | | | | | | | | | | | | Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma ▶ | | | | Chong Sun, Liqin Wang, Sidong Huang et al. | | | | Patients with melanomas carrying an activating BRAF mutation respond to treatment with BRAF inhibitors although resistance to the inhibitor usually emerges; this resistance is shown to arise through increased expression of receptor tyrosine kinases such as EGFR; however, these changes decrease cell fitness and during a break from inhibitor treatment these cells are selected against, revealing that some patients who acquire EGFR expression may benefit from inhibitor re-treatment after a drug holiday. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Brief Communications Arising | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |  | | | Nature Genetics, Chinese Academy of Medical Sciences and Anhui Medical University are pleased to present:
Genome Variation in Precision Medicine May 15-17, 2014 Radegast Lake View Hotel Beijing Click here for more information or to register for this conference today! | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool ▶ | | | | Helge Gad, Tobias Koolmeister, Ann-Sofie Jemth et al. | | | | In order to find a general treatment for cancer, this study found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule inhibitors of MTH1, TH287 and TH588 in the presence of these inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in patient-derived mouse xenograft models. | | | | | | | | | | | | Endosomes are specialized platforms for bacterial sensing and NOD2 signalling ▶ | | | | Norihiro Nakamura, Jennie R. Lill, Qui Phung et al. | | | | This study shows that two endo-lysosomal peptide transporters, SLC15A3 and SLC15A4, are preferentially expressed by dendritic cells, especially after TLR stimulation. The transporters mediate the egress of bacterially derived components, such as the NOD2 cognate ligand muramyl dipeptide (MDP), and are selectively required for NOD2 responses to endosomally derived MDP. | | | | | | | | | | | | A mesoscale connectome of the mouse brain ▶ | | | | Seung Wook Oh, Julie A. Harris, Lydia Ng et al. | | | | This study reports a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. | | | | | | | | | | | | Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy ▶ | | | | Kilian V. M. Huber, Eidarus Salah, Branka Radic et al. | | | | A chemoproteomic screen is used here to identify MTH1 as the target of SCH51344, an experimental RAS-dependent cancer drug; a further search for inhibitors revealed (S)-crizotinib as a potent MTH1 antagonist, which suppresses tumour growth in animal models of colon cancer, and could be part of a new class of anticancer drugs. | | | | | | | | | | | | | | | | | | | | XBP1 promotes triple-negative breast cancer by controlling the HIF1 pathway ▶ | | | | Xi Chen, Dimitrios Iliopoulos, Qing Zhang et al. | | | | This study finds that triple-negative breast cancers (TNBC) show an increased basal level of endoplasmic reticulum stress and activation of the XBP1 branch of the unfolded protein response; furthermore, XBP1 promotes tumour formation of TNBC cell lines by interacting with and regulating HIF1. | | | | | | | | | | | | Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides ▶ | | | | Kvan Birsoy, Richard Possemato, Franziska K. Lorbeer et al. | | | | New apparatus is used to maintain proliferating cancer cells in low-glucose conditions, demonstrating that mitochondrial oxidative phosphorylation (OXPHOS) is essential for optimal proliferation in these conditions; the most sensitive cell lines are defective in OXPHOS upregulation and may therefore be sensitive to current antidiabetic drugs that inhibit OXPHOS. | | | | | | | | | | | | | | | | Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma ▶ | | | | Chong Sun, Liqin Wang, Sidong Huang et al. | | | | Patients with melanomas carrying an activating BRAF mutation respond to treatment with BRAF inhibitors although resistance to the inhibitor usually emerges; this resistance is shown to arise through increased expression of receptor tyrosine kinases such as EGFR; however, these changes decrease cell fitness and during a break from inhibitor treatment these cells are selected against, revealing that some patients who acquire EGFR expression may benefit from inhibitor re-treatment after a drug holiday. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | A ring system detected around the Centaur (10199) Chariklo ▶ | | | | F. Braga-Ribas, B. Sicardy, J. L. Ortiz et al. | | | | Observations of a stellar occultation by (10199) Chariklo, a minor body that orbits the Sun between Jupiter and Neptune, reveal that it has a ring system, a property previously observed only for the four giant planets of the Solar System. | | | | | | | | | | | | Efficient rotational cooling of Coulomb-crystallized molecular ions by a helium buffer gas ▶ | | | | A. K. Hansen, O. O. Versolato, . Kosowski et al. | | | | In combination with sympathetic cooling of translational degrees of freedom (leading to Coulomb crystallization), cooling of the rotational degrees of freedom of magnesium hydride ions using a helium buffer gas leads to temperatures in a tunable range from 60 kelvin down to about 7 kelvin for a single ion, the lowest such temperature so far recorded. | | | | | | | | | | | | Coherent control of the waveforms of recoilless -ray photons ▶ | | | | Farit Vagizov, Vladimir Antonov, Y. V. Radeonychev et al. | | | | The resonant interaction between -ray photons and an ensemble of nuclei with a periodically modulated resonant transition frequency can be used to control the waveforms of the photons coherently; for example, individual -ray photons can be converted into a coherent, ultrashort pulse train or into a double pulse. | | | | | | | | | | | | Highly siderophile elements in Earths mantle as a clock for the Moon-forming impact ▶ | | | | Seth A. Jacobson, Alessandro Morbidelli, Sean N. Raymond et al. | | | | A large number of N-body simulations of the giant-impact phase of planet formation, combined with the measured concentrations of highly siderophile elements in Earths mantle, reveal that the Moon must have formed at least 40 million years after the condensation of the first solids of the Solar System. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Mid-latitude interhemispheric hydrologic seesaw over the past 550,000 years ▶ | | | | Kyoung-nam Jo, Kyung Sik Woo, Sangheon Yi et al. | | | | Tropical and subtropical speleothems show that the latitudinal migration of the Intertropical Convergence Zone tends to produce increased precipitation in one hemisphere and drying in the other; now it is shown using speleothems from the Korean peninsula that this phenomenon extended to the mid-latitudes during the past 550,000 years. | | | | | | | | | | | | | | | | | | | | Highly siderophile elements in Earths mantle as a clock for the Moon-forming impact ▶ | | | | Seth A. Jacobson, Alessandro Morbidelli, Sean N. Raymond et al. | | | | A large number of N-body simulations of the giant-impact phase of planet formation, combined with the measured concentrations of highly siderophile elements in Earths mantle, reveal that the Moon must have formed at least 40 million years after the condensation of the first solids of the Solar System. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Genetics: Unravelling complexity ▶ | | | | A massive research collaboration is revealing hundreds of genes underlying schizophrenia risk, and may point the way to targeted treatments. | | | | | | | | | | | | | | | | | | | | Prevention: Before the break ▶ | | | | Paying attention to risk factors and warning signs could avert some cases of schizophrenia or at least better prepare people for what's to come. | | | | | | | | | | | | | | | | Ageing: Live faster, die younger ▶ | | | | People with schizophrenia show signs of accelerated ageing a phenomenon that could lead researchers to a deeper understanding of the disease. | | | | | | | | | | | | | | | | Perspective: Revealing molecular secrets ▶ | | | | The more we study the genetics of schizophrenia, says Steven E. Hyman, the more daunting and exciting are the challenges we see ahead. | | | | | | Produced with support from Otsuka Pharmaceutical Development and Commercialization, Inc. | | | | | | | | | | | | | | | | | | | | | | | | | | | | Cancer treatment: Sharp shooters ▶ | | | | Beams of charged particles can treat cancer more safely and effectively than X-rays. Physicists and biomedical researchers are working to refine the technology for wider use. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Careers related news & comment | | | | | | | | | | | | | | | | | | | | | | 
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