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Volume 471 Issue 7339, 24 March 2011

Transgenic zebrafish carrying the human oncogene BRAF(V600E), the most common mutation in melanoma patients, provide a convenient model for melanoma. Two papers from Leonard Zon and colleagues demonstrate the potential of this system in the study of cancer genetics and in drug development. Ceol et al. screen for genes that cooperate with mutated BRAF, and identify SETDB1 as capable of accelerating melanoma formation in fish. The gene is found in a region that is frequently amplified in human melanomas, and its gene product, SETDB1, is a histone methylating enzyme that is often overexpressed in those melanomas. This work establishes SETDB1 as an important oncogene. White et al. find expression of a gene signature in melanoma-susceptible zebrafish embryos that is indicative of disrupted differentiation of neural crest progenitors. A chemical screen identifies leflunomide, an immunomodulatory drug used to treat rheumatoid arthritis, as an inhibitor of neural crest stem cells. Leflunomide has antimelanoma activity in human melanoma xenografts and might prove useful as an anticancer drug, particularly in combination with BRAF inhibitors. On the cover, a heavily pigmented zebrafish expressing both SETDB1 and BRAF-V600E in its melanocytes. Credit: Yariv Houvras.

Editorial

  • For now, Japan's scientists have higher priorities than rebuilding their research infrastructure, but when they do get to it, they will need help from the international scientific community.

    Editorial

    Advertisement

  • British readers should help to change libel laws that suppress global scientific discussion.

    Editorial
  • Conference of science journalists can strengthen ties between the Arab world and the West.

    Editorial
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World View

  • Fission power must remain a crucial part of the energy mix until renewable energy technologies can be scaled up, argues Charles D. Ferguson.

    • Charles Ferguson
    World View
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Research Highlights

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Seven Days

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News

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News Feature

  • The race to detect dark matter has yielded mostly confusion. But the larger, more sensitive detectors being built could change that picture soon.

    • Adam Mann
    News Feature
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Comment

  • On the 50th anniversary of the first attempt to drill into Earth's mantle, Damon Teagle and Benoît Ildefonse say that what was once science fiction is now possible.

    • Damon Teagle
    • Benoît Ildefonse
    Comment
  • Madeleine C. Thomson and colleagues call on climate and health researchers, policy-makers and practitioners to work together to tackle infectious diseases.

    • Madeleine C. Thomson
    • Stephen J. Connor
    • Abere Mihretie
    Comment
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Books & Arts

  • A 90-year cohort study hints that personality plays a unexpected part in lifespan, finds Marten Lagergren.

    • Marten Lagergren
    Books & Arts
  • Emma Marris is gripped by an account of our love-hate relationship with extinct megafauna.

    • Emma Marris
    Books & Arts
  • W. F. Bynum enjoys a history of three revolutionary moments in health care.

    • W. F. Bynum
    Books & Arts
  • A new staging of Frankenstein plays up the monster but draws no morals about science, finds Philip Ball.

    • Philip Ball
    Books & Arts
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Correspondence

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News & Views

  • Metathesis reactions can be used to make carbon–carbon double bonds — bar one isomeric class. By using new catalysts and balancing out the stabilities of intermediates in the reaction, the elusive isomers can be made. See Article p.461

    • Daesung Lee
    News & Views
  • Anticancer therapies can impair male fertility. Whereas men can opt to freeze their sperm before treatment, young boys don't produce mature sperm and so lack this choice. Work in mice offers hope for such patients. See Letter p.504

    • Marco Seandel
    • Shahin Rafii
    News & Views
  • Genome-wide association studies are often criticized for providing little insight of immediate physiological relevance. The finding of one such study, which implicates a signalling molecule in schizophrenia, is welcome news. See Letter p.499

    • Hugh D. Piggins
    News & Views
  • The surface warming due to emissions of black-carbon aerosols over the second half of the twentieth century has been identified in observations. These findings will inform debate over the climatic effects of controlling such emissions.

    • Johannes Quaas
    News & Views
  • Early cell-lineage decisions during embryonic development differ between mice and cows. This finding calls for a re-examination of developmental variations across mammals, but does not undermine use of the mouse as a model organism.

    • Janet Rossant
    News & Views
  • The modENCODE project uses integrative analysis to annotate genomic elements in the fruitfly and a nematode worm. The first fly data have now been published. See Articles p.473 & p.480 & Letter p.527

    • Eileen E. M. Furlong
    News & Views
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Article

  • There are a large number of chemical transformations in which alkenes act as the reactants and/or the products of the reaction, but methods enabling the facile synthesis of 1,2-disubstituted Z alkenes are scarce. This paper describes catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously,and allylic amides, used thus far only in E-selective processes. The utility of this methodology is demonstrated by its use in syntheses of anti oxidant C18 (plasm)-16:0 (PC), found in electrically active tissues and implicated in Alzheimer's disease, and the potent immunostimulant KRN7000.

    • Simon J. Meek
    • Robert V. O’Brien
    • Amir H. Hoveyda
    Article
  • Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Using next-generation sequencing of several multiple myeloma genomes reveals that this disease involves mutations of genes involved in protein translation, histone methylation and blood coagulation. The study suggests that BRAF inhibitors should be evaluated in multiple myeloma clinical trials.

    • Michael A. Chapman
    • Michael S. Lawrence
    • Todd R. Golub
    Article Open Access
  • As part of the modENCODE initiative, which aims to characterize functional DNA elements in D. melanogaster and C. elegans, this study uses RNA-Seq, tiling microarrays and cDNA sequencing to explore the transcriptome in 30 distinct developmental stages of the fruitfly. Among the results are scores of new genes, coding and non-coding transcripts, as well as splicing and editing events.

    • Brenton R. Graveley
    • Angela N. Brooks
    • Susan E. Celniker
    Article
  • As part of the modENCODE initiative, which aims to characterize functional DNA elements in D. melanogaster and C. elegans, this study presents a genome-wide chromatin landscape of the fruitfly, based on 18 histone modifications. Nine prevalent chromatin states are described. Integrating these analyses with other data types reveals individual characteristics of different genomic elements. The work provides a resource of unprecedented scale for future experimental investigations.

    • Peter V. Kharchenko
    • Artyom A. Alekseyenko
    • Peter J. Park
    Article
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Letter

  • Quantum metrology aims to use entanglement and other quantum resources to improve precision measurement, resulting in Heisenberg limited sensitivity. However, theory suggests that interactions among particles may allow scaling beyond this limit. This study proves experimentally that this can occur in a nonlinear, non-destructive measurement of the magnetization of an atomic ensemble. The work shows that interparticle interactions could be a useful resource for quantum metrology, although the relative performance of nonlinear versus linear measurements has yet to be explored more generally.

    • M. Napolitano
    • M. Koschorreck
    • M. W. Mitchell
    Letter
  • Angle-resolved photoemission spectroscopy (ARPES) is widely used to study the electronic structure of a wide range of correlated materials. Time-resolved ARPES allows the study of the response of such electronic features on ultrafast timescales; this paper now adds an exciting new dimension by using high photon energies that allow the study of ultrafast dynamics at high momenta, where often the most interesting fundamental phenomena occur. The technique is applied to the charge density wave material 1T-TiSe2 and it is shown with stroboscopic imaging of the electronic band structure at high momentum that atomic-scale periodic long-range order collapses on a surprisingly short timescale of 20 femtoseconds.

    • Timm Rohwer
    • Stefan Hellmann
    • Michael Bauer
    Letter
  • This study reviews a large set of fault friction experiments and finds that a significant decrease in friction occurs at high slip rate. Extrapolating the experimental data to conditions typical of earthquake nucleation depths, it is concluded that faults are lubricated during earthquakes, irrespective of the fault rock composition or specific weakening mechanism involved.

    • G. Di Toro
    • R. Han
    • T. Shimamoto
    Letter
  • Substantial risk for schizophrenia is conferred by large copy number variants at a number of genomic loci. Here, a significant association between duplications on chromosome 7 and schizophrenia is reported. Importantly, microduplication analysis narrowed down the region to a region just upstream of a gene encoding vasoactive intestinal peptide receptor (VIPR2). Increased expression of VIPR2 in patients with schizophrenia implicates VIP signalling as a molecular mechanism underlying schizophrenia.

    • Vladimir Vacic
    • Shane McCarthy
    • Jonathan Sebat
    Letter
  • Reproducing the complex process of spermatogenesis in vitro might lead to the development of new diagnostic and therapeutic techniques for male infertility. This study establishes in vitro organ culture conditions that can support complete spermatogenesis in mice. The in-vitro-derived spermatids and sperm produced healthy and fertile mice, and testis tissue fragments used as a starting material for in vitro spermatogenesis could be cryopreserved for months and then resumed full spermatogenesis in vitro.

    • Takuya Sato
    • Kumiko Katagiri
    • Takehiko Ogawa
    Letter
  • Little is known about how nutritional cues are detected by quiescent neural stem cells (neuroblasts in Drosophila melanogaster) and how these signals are relayed to reactivate their cell cycle to exit quiescence. This study uses an integrative physiology approach to identify the relay mechanism regulating this nutritional checkpoint in neural progenitors. It is found that specific insulin-like peptides produced within the brain by glia bridge the amino-acid/TOR-dependent signal derived from the fat body with PI3K/TOR signalling in neuroblasts to induce exit from quiescent.

    • Rita Sousa-Nunes
    • Lih Ling Yee
    • Alex P. Gould
    Letter
  • Using a zebrafish model of melanoma, this study has searched for genes that can cooperate with mutated BRAF, a frequent oncogenic event in human melanomas. It is found that SETDB1 can accelerate melanoma formation in fish and resides in a region frequently amplified in human melanomas. SETDB1, a histone methylating enzyme, is also frequently overexpressed in human melanomas and functions at least in part by regulating the expression of HOX genes.

    • Craig J. Ceol
    • Yariv Houvras
    • Leonard I. Zon
    Letter
  • In a zebrafish model of melanoma driven by activated BRAF, this study finds expression of a gene signature indicative of disrupted terminal differentiation of neural crest progenitors. A chemical screen led to the identification of leflunomide as an inhibitor of neural crest stem cells. Leflunomide inhibits dihydroorotate dehydrogenase and thereby transcriptional elongation, including genes involved in neural crest development and melanoma growth. Leflunomide has anti-melanoma activity in the zebrafish model and human melanoma xenografts, and might prove useful as an anticancer drug.

    • Richard Mark White
    • Jennifer Cech
    • Leonard I. Zon
    Letter
  • Lung cancers with activating mutations in EGFR can be treated with EGFR inhibitors, but not all tumours respond and some develop resistance. In an RNAi screen, this study searches for modifiers of the EGFR inhibitor response. It is found that inhibition of FAS and NF-κB signalling enhances the response in vitro and in vivo. In a cohort of lung cancer patients treated with EGFR inhibitors, expression of the NF-κB inhibitor IκB is associated with a better response and longer survival, indicating that combining NF-κB pathway and EGFR inhibitors may prove clinically useful.

    • Trever G. Bivona
    • Haley Hieronymus
    • Charles L. Sawyers
    Letter
  • As part of the modENCODE initiative, which aims to characterize functional DNA elements in D. melanogaster and C. elegans, this study created a map of the regulatory part of the fruitfly genome. On the basis of the developmental dynamics of chromatin modifications, polymerase and transcription factor occupancy this work defines a vast array of putative regulatory elements, such as enhancers, promoters, insulators and silencers. This resource represents the first attempt at a comprehensive annotation of cis-regulatory elements in a metazoan genome.

    • Nicolas Nègre
    • Christopher D. Brown
    • Kevin P. White
    Letter
  • Two single-stranded DNA-binding proteins, POT1 and RPA, associate with telomeres. Binding of RPA to telomeres can activate a DNA damage response, so it was previously proposed that POT1 binds telomeres to prevent RPA association. Here, it is found that POT1–TPP1 cannot prevent RPA binding, and hnRNPA1 is identified as having this activity instead. In addition, it is shown that TERRA, a telomere-associated RNA, displaces hnRNPA1 and promotes POT1 binding after S phase, when replication is completed.

    • Rachel Litman Flynn
    • Richard C. Centore
    • Lee Zou
    Letter
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Feature

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Q&A

  • Computational biologist's fellowship will help him to explore developmental and evolutionary biology.

    • Virginia Gewin
    Q&A
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Career Brief

  • US legislation aims to help bring women to research.

    Career Brief
  • US biomedical research risks losing top talent, says NIH director.

    Career Brief
  • NASA launches website to draw female interest.

    Career Brief
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Futures

  • Flesh of my flesh.

    • Peter Roberts
    Futures
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Brief Communications Arising

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Outlook

  • Despite our relative wealth of knowledge about the causes of cancer, the disease persists — and the burden is worsening. Prevention demands political will, ample funding and a change in mindset.

    • Tiffany O'Callaghan
    Outlook
  • Vaccines are arguably our greatest medical achievement. But to what extent can they help prevent cancer?

    • Michael Eisenstein
    Outlook
  • Drugs to prevent cancer are clearly possible despite some early missteps, says Michael B. Sporn. Restoring the cooperative ethos of decades past will help get us there.

    • Michael B. Sporn
    Outlook
  • There's more to the genetic causes of cancer than sequence mutations. This added complexity could offer scientists an opportunity to tackle cancer even earlier.

    • Vicki Brower
    Outlook
  • The sooner a cancer is found, the better. New technologies are pushing the limits of detection — towards the frontier of prevention.

    • Neil Savage
    Outlook
  • Successful prevention requires attacking the causes, says Stephen S. Hecht—and the main target remains tobacco.

    • Stephen S. Hecht
    Outlook
  • Being able to determine an individual's chances of developing cancer will greatly improve risk management strategies and recruitment to clinical trials.

    • Vicki Brower
    Outlook
  • Finding the right food to help reduce our chances of cancer can be a maze. But ongoing studies and a little inventive cooking might point us in the right direction.

    • Sarah DeWeerdt
    Outlook
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Nature Outlook

  • Despite decades of research, cancer in all its guises still kills millions of people each year. The good news is that the more we understand about cancer, the more it appears to be avoidable — not just through smarter eating and healthier lifestyle choices but also with vaccines and chemopreventive drugs. However, a formidable set of scientific, institutional and cultural obstacles stands in the way.

    Nature Outlook
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