| | | Volume 512 Number 7512 | | | | nature | | The science that matters. Every week. | | | | | | | | | | |  | | | EPIGENETICS FUNDING OPPORTUNITY - EpiCypher is offering FIVE FULLY-FUNDED Epigenetic Peptide Array Screening & Services Grants. Apply online today or call 855-374-2461. | | | | | | | | Jump to the content that matters to you | | | | | | | | | | | | | | | Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide | | Introduced in Europe in 1957 as a mild sedative, thalidomide was used in pregnant women as a treatment for morning sickness. This led to the birth of thousands of children with multiple defects and the drug was withdrawn in 1962. Since then thalidomide and its derivatives have emerged as treatments for the cancer multiple myeloma and the associated disorder 5q-dysplasia. Nicolas Thomä and colleagues present the crystal structure of the primary target of thalidomide, an enzyme complex called DDB1-CRBN, bound to thalidomide and to its related drugs, lenalidomide and pomalidomide. The structures show that these drugs have dual function, both interfering and cooperating with DDB1-CRBN activity, which may explain their dramatically diverse clinical effects. | | | | | | | | | | | | | Controlled synthesis of single-chirality carbon nanotubes | | The electronic properties of single-walled carbon nanotubes (SWCNTs) are extraordinarily sensitive to their precise structure. To fully exploit their technological potential, a method of producing isomerically pure SWCNTs is needed. Juan Ramon Sanchez-Valencia et al. have combined synthetic chemistry with materials engineering to develop a strategy that, with further optimization, could provide a route to nanotube-based materials for use in light detectors, photovoltaics, field effect transistors and sensors. The technique requires only modest temperatures and is fully compatible with today's complementary metal oxide semiconductor technologies. | | | | | | | | | | | | | A global ocean inventory of anthropogenic mercury based on water column measurements | | Mercury is a toxic trace metal that accumulates in aquatic organisms and whose emissions to the environment have increased significantly as a result of mining and fossil fuel combustion. Carl Lamborg and colleagues measured mercury levels during expeditions to the Atlantic, Pacific, Southern and Arctic Oceans. Their findings suggest that human disturbances to the global mercury cycle have led to an approximately 150% increase in the amount of mercury in thermocline waters and have more than tripled the mercury content of surface waters. | | | | | | | | | | | | | | | | | | | In this week's podcast: corralling carbon nanotubes, a chemist's dream machine, and an exhibition about an artist who fakes scientific discoveries. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Home-brew tests need regulation ▶ | | | | A US proposal to regulate medical diagnostics from individual labs reflects the tests’ growing complexity. Such guidance should be welcomed, not resisted. | | | | | | | | | | | | | | | | | | | | | | | | Seven days: 1–7 August 2014 ▶ | | | | The week in science: Death of top Japanese stem-cell scientist; instruments picked for Mars rover; and drought tightens grip on California. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Culture: Artistic alchemy ▶ | | | | Philip Ball unveils the scientific iconography in Albrecht Dürer's enigmatic engraving Melencolia I. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | X-ray structure of the mouse serotonin 5-HT3 receptor ▶ | | | | Ghérici Hassaine, Cédric Deluz, Luigino Grasso et al. | | | | The first X-ray crystal structure of the mouse serotonin 5-HT3 receptor, a pentameric ligand-gated ion channel, is similar to those of other Cys-loop receptors — though here electron density for part of the cytoplasmic domain, which is important for trafficking, synaptic localization, and modulation by cytoplasmic proteins, but not visible in previous structures, is also described. | | | | | | | | | | | | Structural mechanism of glutamate receptor activation and desensitization ▶ | | | | Joel R. Meyerson, Janesh Kumar, Sagar Chittori et al. | | | | Cryo-electron microscopy is used to visualize the AMPA receptor GluA2 and the kainate receptor GluK2 in several functional states — having access to so many different structural states has enabled the authors to propose a molecular model for the gating cycle of glutamate receptors. | | | | | | | | | | | | | | | | Mechanism of Dis3l2 substrate recognition in the Lin28–let-7 pathway ▶ | | | | Christopher R. Faehnle, Jack Walleshauser, Leemor Joshua-Tor | | | | The structure of mouse Dis3l2 bound to an oligoU substrate shows a funnel-like substrate-binding site with the RNA being fed into the active site along a path that is distinct from that seen in the related catalytic subunit of the exosome — 12 uracils of the oligoU-tailed RNA are recognized in a complex network of interactions, suggesting the basis for target specificity. | | | | | | | | | | | | | | | | | | | | Required enhancer–matrin-3 network interactions for a homeodomain transcription program ▶ | | | | Dorota Skowronska-Krawczyk, Qi Ma, Michal Schwartz et al. | | | | The POU homeodomain transcription factor Pit1 is required for pituitary development; here Pit1-occupied enhancers are shown to interact with the nuclear architecture components matrin-3 and Satb1, and this association is required for activation of Pit1-regulated enhancers and coding target genes. | | | | | | | | | | | | | | | | Noncoding RNA transcription targets AID to divergently transcribed loci in B cells ▶ | | | | Evangelos Pefanis, Jiguang Wang, Gerson Rothschild et al. | | | | The 11-subunit RNA exosome is thought to regulate the mammalian noncoding transcriptome; here, a mouse model is generated in which the essential Exosc3 subunit of the RNA exosome in B cells is conditionally deleted, revealing a link between sites of genomic RNA exosome function and AID-mediated chromosomal translocations. | | | | | | | | | | | | Inappropriate p53 activation during development induces features of CHARGE syndrome ▶ | | | | Jeanine L. Van Nostrand, Colleen A. Brady, Heiyoun Jung et al. | | | | Inappropriate activation of the tumour-suppressor protein p53 during development can promote phenotypes similar to those of CHARGE syndrome, suggesting that p53 activation not only has a beneficial function in suppressing cancer but also a deleterious function in promoting developmental syndromes. | | | | | | | | | | | | CRISPR-mediated direct mutation of cancer genes in the mouse liver ▶ | | | | Wen Xue, Sidi Chen, Hao Yin et al. | | | | CRISPR plasmids targeting Pten and p53, alone and in combination, are delivered by hydrodynamic injection to the liver; the CRISPR-mediated mutations phenocopy the effects of deletions using Cre–LoxP technology, allowing the direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new approach for rapid development of liver cancer models and functional genomics. | | | | | | | | | | | | | | | | Convergence of terrestrial plant production across global climate gradients ▶ | | | | Sean T. Michaletz, Dongliang Cheng, Andrew J. Kerkhoff et al. | | | | Net primary production is affected by temperature and precipitation, but whether this is a direct kinetic effect on plant metabolism or an indirect ecological effect mediated by changes in plant age, plant biomass or growing season length is unclear — this study develops metabolic scaling theory to be able to answer this question and applies it to a global data set of plant productivity, concluding that it is indirect effects that explain the influence of climate on productivity, which is characterized by a common scaling relationship across climate gradients. | | | | | | | | | | | | Replaying evolutionary transitions from the dental fossil record ▶ | | | | Enni Harjunmaa, Kerstin Seidel, Teemu Häkkinen et al. | | | | Gradual changes that occur to mammalian tooth morphology across evolutionary time were modelled in vitro and in vivo by modulation of signalling pathways in the mouse, and computer modelling was used to provide further analysis of the parameters influencing tooth morphology. | | | | | | | | | | | | Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide ▶ | | | | Eric S. Fischer, Kerstin Böhm, John R. Lydeard et al. | | | | The crystal structures of thalidomide and its derivatives bound to the E3 ligase subcomplex DDB1–CRBN are shown; these drugs are found to have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins. | | | | | | | | | | | | | | | | Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys ▶ | | | | James B. Whitney, Alison L. Hill, Srisowmya Sanisetty et al. | | | | Reservoirs of virus infection represent the most important reason why HIV-1 cannot be cured with current antiretroviral drugs; now the refractory viral reservoir is shown to be seeded as early as 3 days after infection in a monkey model, even before the virus is detected in the blood. | | | | | | | | | | | | Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms ▶ | | | | Lorena Arranz, Abel Sánchez-Aguilera, Daniel Martín-Pérez et al. | | | | Myeloproliferative neoplasms are caused by mutations in the haematopoietic stem cell (HSC) compartment, and here the authors show that the HSC niche contributes to the pathogenesis; sympathetic innervation of mesenchymal stem cells (MSCs) is reduced in the bone marrow of patients, which leads to reduced MSC numbers and increased mutant HSC expansion, and restoring sympathetic regulation of MSCs with neuroprotective/sympathomimetic drugs prevents mutant HSC expansion. | | | | | | | | | | | | | | | | Putative cis-regulatory drivers in colorectal cancer ▶ | | | | Halit Ongen, Claus L. Andersen, Jesper B. Bramsen et al. | | | | Examination of allele-specific expression identifies 71 genes with excess somatic cis-regulatory effects in colorectal cancer (CRC), and 1,693 and 948 expression quantitative trait loci (eQTLs) in normal samples and tumours, respectively (with 36% of tumour eQTLs exclusive to CRC); tumour-specific eQTLs are more enriched for low CRC genome-wide association study P values and accumulate more somatic mutations than shared eQTLs, suggesting a role as germline-derived cancer regulatory drivers. | | | | | | | | | | | | Genome-scale functional characterization of Drosophila developmental enhancers in vivo ▶ | | | | Evgeny Z. Kvon, Tomas Kazmar, Gerald Stampfel et al. | | | | Systematically assaying the activity of 7,705 candidate enhancers during Drosophila embryogenesis shows that nearly half are active in the embryo and display dynamic spatial patterns during development; enhancer activity is matched to expression patterns of putative target genes and predictive cis-regulatory motifs are identified. | | | | | | | | | | | | Enhancer loops appear stable during development and are associated with paused polymerase ▶ | | | | Yad Ghavi-Helm, Felix A. Klein, Tibor Pakozdi et al. | | | | A high-resolution map of enhancer three-dimensional contacts during Drosophila embryogenesis shows that although local regulatory interactions are frequent, long-range interactions are also very common; unexpectedly, most interactions appear unchanged between tissues and across development and are formed prior to gene expression, indicating that transcription initiates from preformed enhancer–promoter loops, which are associated with paused polymerase. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Brief Communications Arising | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |  | | | Nature Outlook Epilepsy
Stigmatization of people with epilepsy continues in certain parts of the world and though lack of funding limits epilepsy research, new ways to treat and manage seizures are on the horizon. Access the Outlook free online for six months. Produced with support of an independent medical education grant from Sunovion Pharmaceuticals Inc. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Inappropriate p53 activation during development induces features of CHARGE syndrome ▶ | | | | Jeanine L. Van Nostrand, Colleen A. Brady, Heiyoun Jung et al. | | | | Inappropriate activation of the tumour-suppressor protein p53 during development can promote phenotypes similar to those of CHARGE syndrome, suggesting that p53 activation not only has a beneficial function in suppressing cancer but also a deleterious function in promoting developmental syndromes. | | | | | | | | | | | | CRISPR-mediated direct mutation of cancer genes in the mouse liver ▶ | | | | Wen Xue, Sidi Chen, Hao Yin et al. | | | | CRISPR plasmids targeting Pten and p53, alone and in combination, are delivered by hydrodynamic injection to the liver; the CRISPR-mediated mutations phenocopy the effects of deletions using Cre–LoxP technology, allowing the direct mutation of tumour suppressor genes and oncogenes in the liver using the CRISPR/Cas system, which presents a new approach for rapid development of liver cancer models and functional genomics. | | | | | | | | | | | | | | | | Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide ▶ | | | | Eric S. Fischer, Kerstin Böhm, John R. Lydeard et al. | | | | The crystal structures of thalidomide and its derivatives bound to the E3 ligase subcomplex DDB1–CRBN are shown; these drugs are found to have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins. | | | | | | | | | | | | Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms ▶ | | | | Lorena Arranz, Abel Sánchez-Aguilera, Daniel Martín-Pérez et al. | | | | Myeloproliferative neoplasms are caused by mutations in the haematopoietic stem cell (HSC) compartment, and here the authors show that the HSC niche contributes to the pathogenesis; sympathetic innervation of mesenchymal stem cells (MSCs) is reduced in the bone marrow of patients, which leads to reduced MSC numbers and increased mutant HSC expansion, and restoring sympathetic regulation of MSCs with neuroprotective/sympathomimetic drugs prevents mutant HSC expansion. | | | | | | | | | | | | | | | | Putative cis-regulatory drivers in colorectal cancer ▶ | | | | Halit Ongen, Claus L. Andersen, Jesper B. Bramsen et al. | | | | Examination of allele-specific expression identifies 71 genes with excess somatic cis-regulatory effects in colorectal cancer (CRC), and 1,693 and 948 expression quantitative trait loci (eQTLs) in normal samples and tumours, respectively (with 36% of tumour eQTLs exclusive to CRC); tumour-specific eQTLs are more enriched for low CRC genome-wide association study P values and accumulate more somatic mutations than shared eQTLs, suggesting a role as germline-derived cancer regulatory drivers. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Formation of monatomic metallic glasses through ultrafast liquid quenching ▶ | | | | Li Zhong, Jiangwei Wang, Hongwei Sheng et al. | | | | Metallic liquids of single elements have been successfully vitrified to their glassy states by achieving an ultrafast quenching rate in a new experimental design, of which the process has been monitored and studied by a combination of in situ transmission electron microscopy and atoms-to-continuum computer modelling. | | | | | | | | | | | | | | | | | | | | Tunable spin–spin interactions and entanglement of ions in separate potential wells ▶ | | | | A. C. Wilson, Y. Colombe, K. R. Brown et al. | | | | The ability of individual ions trapped in separate potential wells to simulate spin–spin interactions is demonstrated by tuning the Coulomb interaction between two ions, independently controlling their local wells and entangling their internal states with a fidelity of approximately 0.82. | | | | | | | | | | | | Controlled synthesis of single-chirality carbon nanotubes ▶ | | | | Juan Ramon Sanchez-Valencia, Thomas Dienel, Oliver Gröning et al. | | | | Present preparation methods fail to meet fully the demand for structurally pure single-walled carbon nanotubes; surface-catalysed cyclodehydrogenation reactions are now shown to convert precursor molecules deposited on a platinum(111) surface into ultrashort nanotube seeds that can then be grown further into defect-free and structurally pure single-walled carbon nanotubes of single chirality. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | A global ocean inventory of anthropogenic mercury based on water column measurements ▶ | | | | Carl H. Lamborg, Chad R. Hammerschmidt, Katlin L. Bowman et al. | | | | GEOTRACES sampling of deep water from the Atlantic, Pacific and Southern oceans allows an estimate of the amount (tripled in surface waters) and distribution (two-thirds increase in water less than a thousand metres deep) of anthropogenic mercury accumulating in the global ocean. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | CALL FOR PAPERS
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