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Volume 464 Issue 7291, 15 April 2010

Notch receptors are widely expressed transmembrane proteins through which mammalian cells communicate to regulate cell fate and growth, and defects in Notch signalling are linked to many cancers. Using phage display technology, a multi-department team at Genentech has produced synthetic antibodies that act as potent and specific antagonists of Notch1 and Notch2. The cover, by Gregóire Vion of Salamander Design Studios (www.grgwr.com), depicts communication between a ligand-expressing cell (right) stimulating Notch signalling in an adjacent cell. The receptor-cell membrane expresses Notches 1 and 2 (red and blue); action of a specific antagonist means that only the blue signal is transduced to the nucleus.

Editorial

  • A surprising US court decision highlights the need to modernize gene-patenting practices if patients are to benefit from advances in genetic research.

    Editorial

    Advertisement

  • Scientific competition is lacking in Japan, and efforts to increase it are not always best focused.

    Editorial
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Research Highlights

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Journal Club

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News

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News Feature

  • Databases could soon be flooded with genome sequences from 25,000 tumours. Heidi Ledford looks at the obstacles researchers face as they search for meaning in the data.

    • Heidi Ledford
    News Feature
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Column

  • Tough choices lie ahead in UK research policy, and they need to be debated openly in the general election campaign, says Colin Macilwain.

    • Colin Macilwain
    Column
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Correspondence

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Opinion

  • Twenty years on from the first pregnancies after preimplantation genetic diagnosis, Alan Handyside argues that informed prospective parents are largely good guides to the use of the thriving technology.

    • Alan Handyside
    Opinion
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Books & Arts

  • Our stereotypical view of mathematicians shifted during the Romantic era from worldly scholar to tortured soul, explains Jascha Hoffman.

    • Jascha Hoffman
    Books & Arts
  • While pursuing his doctorate in dynamical systems, John Sims was drawn to explore the connections between mathematics and art. Now curating a year-long series of maths–art shows at the Bowery Poetry Club in New York City, the conceptual artist explains the cultural significance of maths.

    • Jascha Hoffman
    Books & Arts
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News & Views

  • A study of failures in interconnected networks highlights the vulnerability of tightly coupled infrastructures and shows the need to consider mutually dependent network properties in designing resilient systems.

    • Alessandro Vespignani
    News & Views
  • A challenge in biology is to understand complex traits, which are influenced by many genetic variants. Studies in yeast provide the prospect of analysing such genetic variation in detail in other organisms, including humans.

    • David B. Goldstein
    • Mohamed A. F. Noor
    News & Views
  • The manufacture of proteins by ribosomes involves complex interactions of diverse nucleic-acid and protein ligands. Single-molecule studies allow us, for the first time, to follow the synthesis of full-length proteins in real time.

    • Susanne Brakmann
    News & Views
  • You have received a device that is claimed to produce random numbers, but you don't trust it. Can you check it without opening it? In some cases, you can, thanks to the bizarre nature of quantum physics.

    • Valerio Scarani
    News & Views
  • Cancer cells that invade other parts of the body do so by accumulating genomic aberrations. Analysis of the genomic differences between primary and metastatic tumours should aid the understanding of this process.

    • Joe Gray
    News & Views
  • To reduce parental care, just add water — that's the conclusion of an intriguing investigation into the extent of the motherly and fatherly devotion that different species of frog extend to their offspring.

    • Hanna Kokko
    • Michael Jennions
    News & Views
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Perspective

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Article

  • Massively parallel DNA sequencing allows entire genomes to be screened for genetic changes associated with tumour progression. Here, the genomes of four DNA samples from a 44-year-old African-American patient with basal-like breast cancer were analysed. The samples came from peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The findings indicate that cells with a distinct subset of the primary tumour mutation might be selected during metastasis and xenografting.

    • Li Ding
    • Matthew J. Ellis
    • Elaine R. Mardis

    Milestone:

    Article
  • Snakes are notoriously apt at generating 'thermal images' of predators or prey. The underlying physiology has been unclear, although in snakes such as pythons, vipers and boas, infrared signals are initially received by the pit organ. Here it is shown that pit-bearing snakes rely on heat detection by the ion channel TRPA1. This extends the sensory repertoire of the TRPA1 family of proteins, which detect chemical irritants in mammals and thermal variations in insects.

    • Elena O. Gracheva
    • Nicholas T. Ingolia
    • David Julius
    Article
  • Single-molecule studies allow biological processes to be examined one molecule at a time, as they occur. Here, zero-mode waveguides have been used to concentrate reactions in zeptolitre-sized volumes, making it possible to study real-time translocation by the ribosome. The binding of transfer RNAs (tRNAs) to the ribosome could be followed; the results show that tRNA release from the exit site is uncoupled from tRNA binding to the aminoacyl-tRNA site.

    • Sotaro Uemura
    • Colin Echeverría Aitken
    • Joseph D. Puglisi
    Article
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Letter

  • Three exoplanets around the star HR 8799 have recently been discovered by differential imaging with large telescopes. In such cases, bright scattered starlight means that large angular offsets of the star are required for high-contrast imaging of the planets. Imaging at small angles requires a technique for reducing starlight and associated noise while still transmitting light from the planet. Here such a technique is described: all three HR 8799 planets have been detected using a vector vortex coronagraph on a small-aperture system.

    • E. Serabyn
    • D. Mawet
    • R. Burruss
    Letter
  • Here it is shown, both theoretically and experimentally, that non-local correlations between entangled quantum particles can be used for a new cryptographic application — the generation of certified private random numbers — that is impossible to achieve classically. The results have implications for future device-independent quantum information experiments and for addressing fundamental issues regarding the randomness of quantum theory.

    • S. Pironio
    • A. Acín
    • C. Monroe
    Letter
  • Modern networks are rarely independent, instead being coupled together with many others. Thus the failure of a small fraction of nodes in one network may lead to the complete fragmentation of a system of several interdependent networks. Here, a framework is developed for understanding the robustness of interacting networks subject to such 'cascading' failures. Surprisingly, a broader degree distribution increases the vulnerability of interdependent networks to random failure.

    • Sergey V. Buldyrev
    • Roni Parshani
    • Shlomo Havlin
    Letter
  • It has been thought that ocean temperatures during the early Palaeoarchaean era (around 3.5 billion years ago) were 55–85 °C. But a recent study indicated that the temperatures might be no higher than 40 °C. Here, studies are reported of the oxygen isotope compositions of phosphates in sediments from the 3.2–3.5-billion-year-old Barberton Greenstone Belt in South Africa. The findings indicate a well-developed phosphorus cycle and evolved biological activity in an Archaean ocean with temperatures of 26–35 °C.

    • Ruth E. Blake
    • Sae Jung Chang
    • Aivo Lepland
    Letter
  • The genome of the black truffle - one of the most popular truffles on the market - has been sequenced. This is the first genome of a symbiotic ascomycete to be analysed. Comparison with the genome of another ectomycorrhizal symbiotic fungus indicates that a genetic predisposition to symbiosis evolved differently in ascomycetes and basidiomycetes. The study also offers insight into fungal sex and fruiting.

    • Francis Martin
    • Annegret Kohler
    • Patrick Wincker
    Letter Open Access
  • Complex heritable traits — such as human height and many human diseases — are caused by multiple genetic loci, each with small effects. It is hard to identify such loci, however, because of a lack of statistical power. Now, a method has been developed to overcome this problem. The method has been applied to chemical resistance traits and mitochondrial function in yeast, and has identified loci for each of these phenotypes.

    • Ian M. Ehrenreich
    • Noorossadat Torabi
    • Leonid Kruglyak
    Letter
  • Hereditary hypotrichosis simplex is a rare form of hereditary hair loss in humans, where the hair follicle is miniaturized. Now, the gene involved has been identified, using genetic linkage analysis in three affected families. The gene, APCDD1, is expressed in human hair follicles. It encodes a previously unknown membrane-bound glycoprotein that inhibits signalling through the Wnt protein and functions upstream of β-catenin.

    • Yutaka Shimomura
    • Dritan Agalliu
    • Angela M. Christiano
    Letter
  • Primary cilia are tiny hair-like structures expressed on the surface of eukaryotic cells. They participate in a range of processes, such as sensing the extracellular environment and regulating signalling pathways during development. Here, a functional genomic screen is presented that used RNA interference to identify human genes involved in controlling ciliogenesis. Several positive and negative ciliogenesis modulators with broad-ranging functions were found.

    • Joon Kim
    • Ji Eun Lee
    • Joseph G. Gleeson
    Letter
  • The four receptors of the Notch family are transmembrane proteins through which mammalian cells communicate to regulate cell fate and growth. Aberrant signalling through each receptor has been linked to disease, so the Notch pathway is a compelling drug target. But current drugs cannot distinguish between the different Notch proteins. Here, phage display technology has been used to generate highly specialized antibodies, enabling the functions of Notch1 and Notch2 to be discriminated in humans and mice.

    • Yan Wu
    • Carol Cain-Hom
    • Christian W. Siebel
    Letter
  • Cancer 'chemoprevention' uses substances to reverse, suppress or prevent the initial phase of carcinogenesis or the progression of neoplastic cells to cancer cells. Here it is shown that treatment with TRAIL proteins and all-trans-retinyl acetate can cause the death, in vitro and in vivo, of premalignant cells deficient in the adenomatous polyposis coli gene. Normal cells are unaffected. Selectively eliminating premalignant tumour cells in this way is thus an effective method for chemoprevention.

    • Ling Zhang
    • Xiaoyang Ren
    • Xiangwei Wu
    Letter
  • Analogues of migrastatin — a natural product secreted by Streptomyces — are potent inhibitors of tumour cell migration and metastasis. Here, the underlying mechanism is elucidated: these migrastatin analogues target and inhibit the activity of the actin-bundling protein fascin. Hence proteins such as fascin might present new molecular targets for cancer treatments.

    • Lin Chen
    • Shengyu Yang
    • Xin-Yun Huang
    Letter
  • It has previously been shown in mice and non-human primates that systemically delivered short RNA molecules can inhibit gene expression. Here it is shown that a short interfering RNA (siRNA) can be systemically delivered, using nanoparticles, to a solid tumour in humans. The siRNA mediates cleavage of its target mRNA, thereby also reducing levels of the encoded protein. This proof-of-principle study confirms the potential of this technology for treating human disease.

    • Mark E. Davis
    • Jonathan E. Zuckerman
    • Antoni Ribas
    Letter
  • Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome. Here it is shown that lincRNAs in the HOX genetic loci are dysregulated during breast cancer progression in human cells, and that expression levels of the lincRNA called HOTAIR can predict whether a tumour will metastasize. Moreover, enforced expression of HOTAIR can lead to altered patterns of binding of the PRC2 protein to the genome.

    • Rajnish A. Gupta
    • Nilay Shah
    • Howard Y. Chang
    Letter
  • Thermophilic bacteria and archaea use carbon dioxide or carbon monoxide as a starting material for making the organic substances used in cellular molecules. A central enzyme in this pathway has now been discovered, namely fructose 1,6-bisphosphate aldolase/phosphatase. This enzyme might represent the ancestral gluconeogenic enzyme.

    • Rafael F. Say
    • Georg Fuchs
    Letter
  • Most human gene promoters are embedded within CpG islands that lack DNA methylation and coincide with sites at which histone H3 lysine 4 is trimethylated (H3K4me3 sites). Here, a zinc-finger protein, Cfp1, is found to be associated with non-methylated CpG islands and H3K4me3 sites throughout the genome in the mouse brain. A primary function of non-methylated CpG islands might be to genetically determine the local chromatin modification state by interaction with Cfp1 and perhaps other CpG-binding proteins.

    • John P. Thomson
    • Peter J. Skene
    • Adrian Bird
    Letter
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Careers Q&A

  • Evolutionary geneticist Harmit Malik of the Fred Hutchinson Cancer Research Center in Seattle, Washington, has won the 2010 Vilcek Prize for Creative Promise in Biomedical Science for his work on the coevolution of humans and diseases.

    • Virginia Gewin
    Careers Q&A
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Career Brief

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Careers and Recruitment

  • Applying systems biology to cancer research has become a growth area for computationally minded scientists. Kelly Rae Chi tallies the possibilities.

    • Kelly Rae Chi
    Careers and Recruitment
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Futures

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