Hot off the presses! Jun 17 Nature

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Latest Articles Include:

• Assessing assessment
  - Nature (London) 465(7300):845 (2010)
  Nature | Editorial Assessing assessment Journal name:NatureVolume:465,Page:845Date published:(17 June 2010)DOI:doi:10.1038/465845aPublished online16 June 2010 Transparency, education and communication are key to ensuring that appropriate metrics are used to measure individual scientific achievement. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The use of metrics to measure and assess scientific performance is a subject of deep concern, especially among younger scientists. In this issue, Nature begins what we hope will be an ongoing conversation on such measures and how they should be developed and used. All the metrics-related articles are collected at http://www.nature.com/metrics and are available for online comment. A poll of Nature's readers suggests that feelings about metrics are mixed (see page 860). Many researchers say that, in principle, they welcome the use of quantitative performance metrics because of the potential for clarity and objectivity. Yet they also worry that the hiring, promotion and tenure committees that control their fate will ignore crucial but hard-to-quantify aspects of scientific performance such as mentorship and collaboration building, and instead focus exclusively on a handful of easy-to-measure numbers related mostly to their publication and citation rates. "Administrators need to understand what the various metrics can and cannot tell them." Academic administrators contacted by Nature suggest that this fear may be exaggerated. Most institutions seem to take a gratifyingly nuanced approach to hiring and tenure decisions, relying less on numbers and more on wide-ranging, qualitative assessments of a candidate's performance made by experts in the relevant field. Yet such enlightened nuancing cannot be taken for granted. Numbers can be surprisingly seductive, and evaluation committees need to guard against letting a superficial precision undermine their time-consuming assessment of a scientist's full body of work. This is particularly true in countries such as Britain, where metrics-heavy national assessments of universities can trickle down, so that individuals feel more rewarded for quantity than for quality — and change their behaviour to match. New measures of scientific impact are being developed all the time (see page 864), in part driven by government agencies looking to quantify the results they are getting for their investment. Such innovation is to be encouraged. But researchers must be mindful of how and why the metrics they are making are being used. When one person in this field was interviewed by Nature, he expressed a keen interest in reading our News Feature on how metrics are used for individual assessment, and to what extent, because he had no evidence with which to answer these questions himself. This isn't an optimal situation, to put it mildly. There needs to be much more discussion between specialists such as social scientists, economists and scientometricians to ensure that metrics development goes hand-in-hand with a discussion of what the metrics are for, and how they are affecting people. Only then can good suggestions be made about how to improve the system (see page 870). Academic administrators, conversely, need to understand what the various metrics can and cannot tell them. Many measures — including the classic 'impact factor' that attempts to describe a journal's influence — were not designed to assess individual scientists. Yet people still sometimes try to apply them in that way. Given that scientometricians continue to devise metrics of ever-increasing sophistication, universities and scientific societies need to help decision-makers keep abreast. Setting a good example is the European Summer School for Scientometrics, a programme that is being inaugurated in Berlin on 16–18 June and will run in Vienna from 2011. It promises a science-based approach to tutoring on the merits and pitfalls of various metrics. Institutions must also ensure that they give their researchers a clear and complete picture of how assessments are made. This can be awkward — one dean said that he was reluctant to list the qualities he looked for in tenure applications because this could encourage list-ticking behaviour rather than innovation in his faculty. But transparency is essential: no matter how earnestly evaluation committees say that they are assessing the full body of a scientist's work, not being open about the criteria breeds the impression that a fixed number of publications is a strict requirement, that teaching is undervalued and that service to the community is worthless. Such impressions do more than breed discontent — they alter the way that scientists behave. To promote good science, those doors must be opened wide. Additional data
• A DNA education
  - Nature (London) 465(7300):845 (2010)
  Nature | Editorial A DNA education Journal name:NatureVolume:465,Pages:845–846Date published:(17 June 2010)DOI:doi:10.1038/465845bPublished online16 June 2010 Taking personal genetic testing into the classroom brings ethical and legal sensitivities to the fore. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Although personalized genetic testing is still very new and controversial, its increasing use in health care seems inevitable — a trend that makes it essential to give consumers and physicians a better education in the technology's strengths and weaknesses. That was the rationale behind an announcement made last month by the College of Letters and Science at the University of California, Berkeley. This year, instead of sending its incoming students a book for later discussion in class, the college will send them a kit to swab their DNA. If they so choose, students can send in their sample to be analysed for three common gene variants that indicate how an individual metabolizes alcohol, lactose (found in dairy products) and folic acid, a vitamin common in leafy green vegetables. The impulse behind Berkeley's announcement was commendable. But officials there were too hasty in designing the programme, as evidenced by the firestorm of criticism it triggered and the changes the university has instituted in response. For example, each student's kit will now include not just details of the measures being taken to safeguard and anonymize the data and descriptions of the genes to be tested, as originally planned, but also information about the ethical and legal issues surrounding genetic testing. In addition, the university has modified a contest that accompanies the programme: the prize will no longer be a full genetic test conducted by a commercial testing company, which could be perceived as an endorsement of such firms, but will instead be cash. Finally, organizers have decided to hold off revealing the tests' results until just before a lecture at which the benefits and limits of genetic testing, as well as the three chosen genes, will be discussed in ! detail. They will also give an accompanying lecture on the ethical and social dimensions of genetic testing. And students will be able to seek private counselling about their results if they wish. Although it was wise of Berkeley to make these improvements, concerns remain. The university contends, for example, that there will be no pressure on students to participate in the genetic testing. Not only will they be told it is entirely optional, but students — or in the case of those under 18 years of age, their parents — will sign an informed consent document. Moreover, faculty members will never learn which students participated and which did not. But critics still worry about indirect pressure: the very fact that the kits are being sent to all of the college's incoming students could give them the impression that their participation is expected, in which case their choice may not feel so free. A telling contrast in approach has been provided by Stanford University in Palo Alto, California, which announced a similar course designed for medical students shortly after Berkeley announced its programme. Recognizing the potential for controversy from the outset, Stanford officials first appointed a task force of basic scientists, clinicians, legal professionals, genetic counsellors, ethicists and students who spent a year designing precautions against coercion and conflicts of interest by the institution, and working out access to counselling. The result is a well-thought-out programme — which also includes a research component designed to test a commonly held belief: do students truly learn better when the information presented to them is of personal relevance? That said, the Berkeley and Stanford programmes are both still experimental. No one has all the answers to the issues they raise, which is why designing such curricula will involve constant refinement and evolution. It is shortsighted for critics to oppose such endeavours on the grounds that experts don't yet know how to interpret genetic information or how to integrate it into medical care. That is changing rapidly — and these two programmes are only the beginning of a long conversation that needs to happen on campuses worldwide. Additional data
• Skyrmion makeover
  - Nature (London) 465(7300):846 (2010)
  Nature | Editorial Skyrmion makeover Journal name:NatureVolume:465,Page:846Date published:(17 June 2010)DOI:doi:10.1038/465846aPublished online16 June 2010 Celebrating the treasures of topological twists. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Sometimes a scientific idea falls into obscurity as researchers turn their attention elsewhere, yet contains such mathematical beauty that it is revived again and again. Such is the story of the skyrmion: a concept that has had several makeovers since it was first formulated in the late 1950s by the British physicist Tony Hilton Royle Skyrme. One way to visualize a skyrmion is to imagine a sphere studded with arrows pointing towards its centre. Then take away the sphere, project the arrows onto a plane while keeping their orientations fixed, and admire a twisting configuration. This texture is best defined mathematically as a 'topological' spatial feature that, like the twist in a Möbius strip, is preserved under continuous deformation. But the skyrmion turned out to be more than pure mathematics: in 1962, Skyrme found that it could explain how subatomic particles such as neutrons and protons exist as discrete entities emerging from a continuous nuclear field. This was a problem that had been worrying some of the highest-profile physicists of the day. In the Skyrme model it was intuitively explained by imagining such particles as stable geometric twists in an otherwise flat background, much like whirlpools in a mass of water. It was an imaginative and satisfying solution — and one that was overlooked for a decade or two. This was probably at least in part because of the advent of another big idea in particle physics in the 1960s: quarks. It may also have had something to do with Skyrme's modesty and lack of ambition to gain far-reaching acceptance for his ideas. The Skyrme model was finally embraced by particle physicists in the 1980s, only to be overshadowed a second time by an even bolder idea: string theory. In that same decade, however, an unexpected revival of skyrmions was already brewing, thanks to the discovery of a new kind of electronic system known as a quantum Hall device — the subject of two Nobel prizes, and the basis of a revolution in condensed-matter physics. Quantum Hall devices exhibit very unusual quantum effects, which show up as ultraprecise jumps in electronic current when a magnetic field is applied. Slowly, the understanding emerged that these quantum effects were best described in terms of topological features. This was a natural home for skyrmions and they were predicted and detected electronically in quantum Hall devices by the mid-1990s. A flurry of activity ensued in the field. As research topics do, the phenomenon eventually went out of fashion — again. But in recent years, skyrmions have made yet another comeback. The field of condensed-matter physics is abuzz with excitement about topological states of matter in a range of systems besides quantum Hall devices. Moreover, there is an ambitious agenda to exploit these topological features for practical applications: it is thought that they hold the key to a whole new range of robust electronic and magnetic functions and possibly also to quantum computation. In this issue, skyrmions are vividly brought to life in the stunning electron-microscope images of textures of swirling magnetization in a magnetic material (see Figures 1e and f on page 902). After re-emerging from the depths of obscurity several times over, the spotlight is back on skyrmions. And a reader can only wonder what other neglected gems of mathematical ideas are tucked away in the literature, awaiting a creative scientist to recognize their value to the physical world? Additional data
• Biology: Sniffer sharks
  - Nature (London) 465(7300):848 (2010)
  
• Ecology: Rise of the sources
  - Nature (London) 465(7300):848 (2010)
  
• Microbiology: A strain on the relationship
  - Nature (London) 465(7300):848 (2010)
  
• Chemistry: Potent potato power
  - Nature (London) 465(7300):848 (2010)
  
• Ecology: A watery grave
  - Nature (London) 465(7300):848 (2010)
  
• Extrasolar planets: Planets form quickly
  - Nature (London) 465(7300):848 (2010)
  
• Chemistry: Iodine improvement
  - Nature (London) 465(7300):849 (2010)
  
• Microbial ecology: Sated snakes
  - Nature (London) 465(7300):849 (2010)
  
• Materials science: Noodly appendages
  - Nature (London) 465(7300):849 (2010)
  
• Evolutionary genetics: Vive la digits
  - Nature (London) 465(7300):849 (2010)
  
• Journal club
  - Nature (London) 465(7300):849 (2010)
  
• News briefing: 11–17 June 2010
  - Nature (London) 465(7300):850 (2010)
  The week in science. This article is best viewed as a PDF Policy|Business|Events|People|Funding watch|The week ahead|Number crunch|Sound bites Genetic tests marketed directly to consumers are medical devices, the US Food and Drug Administration (FDA) has decided. On 10 June it told five companies that the tests must therefore gain regulatory approval before they can be marketed — but did not ask that the tests be taken off the market. The FDA sent letters to Navigenics, 23andMe and deCODE Genetics, which sell the tests, together with the sequencing company Illumina and Knome, which offers whole-genome sequencing. See also Editorial, page 845. The European Science Foundation (ESF) is planning to merge with EUROHORCS, a group made up of the heads of Europe's national research councils. The two organizations will combine leadership and resources to form a body provisionally titled the European Research Organisation (ERO). The aim is for this group to be more active in driving European research priorities and strategic concepts such as the European Research Area, which seeks the free movement of researchers and funding across national borders. Almost two weeks of interim climate talks in Bonn, Germany, ended on 11 June with little progress towards an international climate deal. No agreement was reached between rich and poor countries on the content of a negotiation text for the United Nations climate summit later this year in Cancun, Mexico. Negotiations continue in Bonn in August. The US Senate voted 53–47 on 10 June against a resolution by Lisa Murkowski (Republican, Alaska) to block the US Environmental Protection Agency (EPA) from implementing climate regulations under the Clean Air Act. It was the first major climate vote in the Senate in two years, although it was largely symbolic because the resolution stood little chance of passing the House of Representatives or the White House. Senate Democrats are still hoping to bring up climate legislation this summer, but if Congress fails to act, the EPA expects to begin rolling out new climate regulations next year. See go.nature.com/m58gPT for more. NASA has told contractors to scale back work on a suite of rockets to carry astronauts to the Moon — even though Congress has not agreed to the cutback. In the presidential budget request in February, NASA announced plans to cancel the rockets, called Constellation, in favour of supporting rockets developed by commercial companies. But members of Congress, who must authorize and pay for the switch, have resisted. NASA administrator Charles Bolden sent a letter to Kay Bailey Hutchison (Republican, Texas), a key senator, on 9 June saying that he was trying to "pace, rather than terminate" contractual work. A new United Nations organization will monitor the planet's natural resources. The Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) was approved by representatives in Busan, South Korea, last week. See page 859 for more. The International Federation of Pharmaceutical Manufacturers and Associations has adopted new guidelines governing the publication of clinical-trial results. The policy calls for the industry to publish the results of late-stage, phase III clinical trials in peer-reviewed journals, regardless of the outcome of trials, and to acknowledge any ghostwriters (who are hired to work on papers without being credited as authors). But some researchers say that the guidelines, announced on 10 June, do not go far enough and may have little effect because they are voluntary. See go.nature.com/6kAcsW for more. Computing and technology giant IBM is to open a research laboratory in Brazil, it announced on 8 June. The centre would be the company's ninth global research laboratory, its first new one for 12 years, and its first in South America. It is already hiring scientists for the lab, which will be home to more than 100 researchers; costs and the precise location were not disclosed. Research will focus on natural-resource discovery, semiconductors and the logistics of managing 'human systems' at large-scale events such as the Olympics. A patent covering cancer-related mutations in the BRCA1 gene has again come under fire, this time in Australia. On 8 June, the Melbourne-based law firm Maurice Blackburn, together with the patient-advocacy group Cancer Voices Australia in Sydney and a breast-cancer patient, filed a federal case against the patent's holders Myriad Genetics, headquartered in Salt Lake City, Utah, and Genetic Technologies of Melbourne. In March, a New York district court ruled that some claims in the same patent were invalid (see Nature, 464, 655; 2010). The University of California is considering a boycott of Nature Publishing Group (NPG) in response to what it says is a proposed 400% increase in subscription fees to the group's journals. Faculty members would be asked to stop submitting papers to and peer-reviewing for NPG journals, and to resign from its editorial boards, said a letter from the university's libraries, dated 4 June. NPG stated that California Digital Library has been on "a very large, unsustainable discount for many years". The dispute continues. See go.nature.com/2QpBzl for more. JAXA/AP Japanese scientists are hoping for their first peek at asteroid dust from a space capsule (pictured) that landed near Woomera, Australia, after being jettisoned by Japan's Hayabusa explorer, which returned to Earth on 13 June. The probe's seven-year mission to gather samples from the 535-metre-long asteroid Itokawa was the first round trip to a planetary body beyond the Moon. The capsule will be transported to a laboratory in Sagamihara, Japan; any captured dust could undergo preliminary analysis by the end of this week. See go.nature.com/vMkRSC for more. Japan's Ikaros space capsule unfurled its solar sail last week, beginning the disc-shaped craft's journey through deep space. The 7.5-micrometre thick, 200-square-metre polyimide sail aims to show for the first time that a spacecraft can be propelled by photons from the Sun. UNIV. CALIFORNIA, DAVIS Depressing images of oil-covered birds and marine animals (pictured, a turtle being treated at the University of California, Davis) marked a week in which official estimates for the amount of oil leaking into the Gulf of Mexico from BP's crippled well rose to between 25,000 and 40,000 barrels per day (4 million to 6.4 million litres). The previous estimate was between 12,000 and 19,000 barrels, itself raised from 5,000 barrels in May. BP says that it is currently capturing around 15,000 barrels of the total. Swiss solar-cell scientist Michael Grätzel has won the £800,000 (US$969,000) Millennium Technology Prize. Grätzel, of the Swiss Federal Institute of Technology in Lausanne, developed the technology of dye-sensitized solar cells, which use organic dyes rather than silicon to capture sunlight. First awarded in 2004, the biennial Millennium Prize styles itself as "the world's largest technology prize". Two runner-up prizes of £150,000 were awarded this year to Richard Friend of the University of Cambridge, UK, for his work on plastic electronics, and Stephen Furber of the University of Manchester, UK, designer of the ARM 32-bit RISC microprocessor. An attempt to quantify government funding for synthetic biology suggests that the United States has spent around US$430 million on the sector since 2005, whereas the European Union and three European countries (the Netherlands, the United Kingdom and Germany) have spent a total of around $160 million (see chart). SOURCE: WOODROW WILSON CENTER But the main lesson from the analysis, released on 4 June by the Woodrow Wilson International Center for Scholars in Washington DC, is that transparent and accurate numbers are hard to come by. "Although governments are funding synthetic biology, there is no easy way to determine the total amount of resources, both human and financial, that are being dedicated to it," the report notes. Analysts combed federal research grant databases for the term 'synthetic biology', and hope that research agencies will now be spurred to provide more comprehensive information than they could when first asked, says Todd Kuiken, a research associate at the Wilson Center. The report suggests that the US Department of Energy dominates agency spending, thanks to its push to develop new biofuels. And although 4% of US and 2% of European funds were apportioned to investigating the ethical, legal or societal implications of synthetic biology, no projects in the grant databases used funds for research on risk assessment. Approval of 'Europe 2020' — a ten-year economic strategy for the European Union — is expected at a meeting of the European Council in Brussels. The document's drafts suggest worthy targets for European research spending (see Nature 464, 142; 2010). → go.nature.com/R9Z3vJ A government- and industry-attended summit in Washington DC will review technical progress on scaling up production of advanced biofuels. It hopes to thrash out a global regulatory and financial framework to help commercialize the technology. → go.nature.com/8paTK5 A Western Pacific Geophysics meeting in Taipei, Taiwan, includes research on one of the Western Pacific's most devastating cyclones, 2009's Typhoon Morakot. → go.nature.com/WvNpR5 Percentage of Americans who don't remember hearing or reading anything in the news about the furore over climate e-mails in the past six months. Despite this, public belief in anthropogenic climate change has waned in the United States. Source: Stanford University poll; available at go.nature.com/ArgW19 Christiana Figueres, who will become UN climate chief on 8 July, told reporters on 9 June that governments should focus on incremental efforts to combat climate change, rather than a conclusive agreement. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Diseased cells fail to win approval
  - Nature (London) 465(7300):852 (2010)
  Consent form signed by clinic's donors falls short of 'high ethical standards' set by the NIH. Cells taken from embryos to test for inherited diseases can be used to generate cell lines for research.Medicalpicture/Alamy In the latest obstacle to expanding the number of embryonic stem-cell lines eligible for US federal funding, a National Institutes of Health (NIH) committee has unanimously rejected dozens of cell lines carrying mutations for specific diseases. The committee of advisers to NIH director Francis Collins ruled that the extremely broad language in the informed-consent form signed by donating couples does not meet ethical requirements. "We are sorry about the decision about these lines," says Collins, who must sign off on the 10 June vote. "Many of them contained interesting single-gene mutations, but if we have guidelines we have to stick to them in order to maintain credibility." Embryonic stem-cell lines that carry the recipe for an inherited disease are valued by researchers. This is because as the cells mature and specialize they should offer a detailed view of how a disease manifests itself in the earliest stages of life, and provide targets for drug testing. Of 67 lines so far approved for federal funding, just one — for Marfan syndrome, a rare connective-tissue disorder — is explicitly disease-specific. The 47 lines rejected last week, 42 of which carry mutations for specific diseases, were derived by the Reproductive Genetics Institute (RGI) in Chicago, a private fertility clinic that specializes in preimplantation genetic diagnosis (PGD). During PGD, one or two cells are removed from a very early stage embryo in order to establish whether it carries a particular mutation for an inherited disease; only embryos without the mutation are then implanted into the mother's womb. The RGI derived roughly 150 disease-specific stem-cell lines from leftover embryos between 2003 and 2008. All the donating couples agreed to the same broad informed-consent language, which effectively waived their right to sue the RGI in any forum at any time for reasons "related to our participation in this study". Such wording is deemed 'exculpatory' — meaning it requires people to waive rights that they would otherwise have — and is therefore forbidden under rules governing federally funded research. "The most valuable human embryonic stem-cell lines are those that model genetic disease." The possibility of using the RGI lines in federally funded research arose last year, when the Obama administration lifted a 2001 ban imposed by former president George Bush on federal support for work on new stem-cell lines. As a private clinic, the RGI was not barred from using exculpatory language, and it did follow the guidelines published by the NIH last July. The guidelines require cells eligible for federal funding to have come from leftover embryos that would otherwise have been discarded, and ban financial inducements to donors. They do not address exculpatory language. "Our assessment was not that RGI broke the applicable regulatory rules, but rather that their application did not meet the high ethical standards that are appropriate for federal funding of human embryonic stem-cell research," says Jeffrey Botkin, a professor of paediatrics at the University of Utah School of Medicine in Salt Lake City, who chairs the working group that guided the committee's decision. George Daley, a stem-cell researcher at the Children's Hospital Boston in Massachusetts, says he respects the NIH's decision and its ethical basis. But, he adds, "the most valuable human embryonic stem-cell lines are those that model genetic disease, and excluding the RGI lines means a significant lost opportunity to study these diseases." The lines voted down last week include cells carrying mutations that cause Huntington's disease, cystic fibrosis, inherited breast cancer, neurofibromatosis, Duchenne muscular dystrophy, tuberous sclerosis and sickle-cell anaemia. Clive Svendsen, the director of the Regenerative Medicine Institute at Cedars-Sinai Medical Center in Los Angeles, California, notes that work on most of the RGI lines has not been published, leaving their particular value unknown. But if they are biologically sound, he says, "they are very valuable". In that situation, "is this detrimental to the research community? Clearly the answer is yes". ADVERTISEMENT Botkin told the committee that "if feasible", getting the embryo donors to sign new consents, using a form with the offending language removed, "would adequately address our concerns". Oleg Verlinsky, the RGI's chief executive, told Nature that he has attempted to contact two of the consenting couples through their referring physicians. Both doctors refused to provide the couples' addresses, citing federal privacy law. Last week Verlinsky pronounced the situation "a nightmare". But he says that he will persevere. "We will try. We may get a few lines through out of the 47." The RGI had begun applications for another 31 disease-specific cell lines. But, Verlinsky says, "there's no point" in continuing with that process now, because the additional lines used the same consent form. Last December, Collins restricted federal funding for 27 lines from a Harvard University lab in Cambridge, limiting their use to work on pancreatic formation with the long-term goal of diabetes treatment. The consent form was an issue in this case as well: it had stipulated that the lines would be used for this purpose. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Intensive farming may ease climate change
  - Nature (London) 465(7300):853 (2010)
  Land saved from cultivation offsets carbon emissions. Modern farming practices have led to reduced carbon dioxide emissions.P. Whitaker/Reuters To many people, modern agriculture, with its industrial-scale farms and reliance on petroleum-based fertilizers, may seem a necessary evil — one that has fed a growing human population while causing untold damage to the environment. But the alternative may be worse, concludes a Stanford University study: a less-productive agricultural system would destroy even more wild land, drive up greenhouse-gas emissions and wreak havoc on biodiversity. The study's results suggest that further agricultural intensification will play a critical part in addressing global warming. In the study, researchers modelled the world as we know it, complete with the 'green revolution' and modern agricultural practices, and two alternative realities in which crop yields were kept at the levels of decades ago. Published on 14 June, the results show that increased greenhouse-gas emissions resulting from intensive farming are more than offset by the effects of land preservation, which keeps carbon sequestered in native soils, savannahs and forests (J. A. Burney et al. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0914216107; 2010). "In the beginning, we weren't even sure whether the carbon savings from land use would outweigh the increased agricultural emissions," says David Lobell, an agricultural scientist at Stanford University in California and a co-author on the study. After all, the fertilizers used in intensive farming increase emissions of greenhouse gases. All told, agriculture was responsible for 10–12% of global anthropogenic emissions in 2005. Yet the balance turns out to be favourable, says Lobell, "and the carbon savings are quite large". All other things being equal, the researchers found that agricultural advances between 1961 and 2005 spared a portion of land larger than Russia from development and reduced emissions by the equivalent of 590 gigatonnes of carbon dioxide — roughly a third of the total emitted since the start of the Industrial Revolution. Click for larger image The notion that increasing crop yields preserves forests and other native lands dates back to the father of the green revolution, the late US plant scientist Norman Borlaug, and is known as the Borlaug hypothesis. Lobell's team attempted to quantify that effect and to calculate the resulting reduction in greenhouse-gas emissions. Between 1961 and 2005, the global population increased by 111%, from 3.1 billion to 6.5 billion, but agricultural yields went up by 135% over the same period, according to the researchers. As a result, global cropland increased by just 27%, from 960 million to around 1.2 billion hectares. To work out how much land would be required to feed today's world using yesterday's technology, the researchers froze agricultural yields at 1961 levels and then allowed population and living standards to increase apace. Although emissions from fertilizer use were lower than in the real-world scenario, the amount of land required to grow food expanded by nearly 1.8 billion hectares. In a second scenario, both the yields and the standard of living were fixed at 1961 levels; the effects in terms of agricultural-land conversion and greenhouse-gas emissions were roughly half those of the first scenario but were still higher than actual impacts in the real-world analysis (see 'Greenhouse-gas emissions'). Finally, the team analysed the nearly US$1.2-trillion investment in agricultural research and development since 1961. Averaged over the study period, investments in agricultural yields reduced carbon emissions at a cost of around $4 per tonne of carbon dioxide equivalent, less than a quarter of the going price for emissions permits under Europe's carbon-trading scheme. ADVERTISEMENT The environmental benefits will accrue if yields continue to increase, say researchers. Last year, for example, a team from the Joint Global Change Research Institute in College Park, Maryland, analysed land-use scenarios and found that increasing yields could reduce emissions as much as could energy technologies such as wind and solar (M. Wise et al. Science 324, 1183–1186; 2009). "Above all, this study underscores the purpose of agricultural research funding, especially in developing countries," says Andrew Balmford, a conservation scientist at the University of Cambridge, UK. Unless the world sees a second green revolution, some 1.5 billion to 2 billion additional hectares will need to be put into production by 2050 to feed a growing population, according to an ongoing analysis by David Tilman, an ecologist at the University of Minnesota in St Paul. Fortunately, there is plenty of cleared land that is underperforming and massive potential for boosting yields in developing countries, Tilman says. "If we want to save the Earth, we have to feed the world," Tilman adds."And it's these poorest countries that have the most to contribute." This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• MRI set to win reprieve from EU ban
  - Nature (London) 465(7300):854 (2010)
  Directive that limits workers' electromagnetic exposure aims for a compromise. EU legislation would have stopped workers getting close to MRI scanners during operation.Corbis/Photolibrary A controversial piece of European Union (EU) legislation that outlaws much routine brain and body imaging in research laboratories and clinics is on course for a revamp. The EU directive was designed to limit workers' exposure to electromagnetic fields (EMF) and was approved in 2004. But it was put on hold in 2007 after scientists and others said that it would stop them from carrying out important work without improving worker safety. The European Commission now says that it will propose new legislation by the end of this year that addresses these issues, and will allow magnetic resonance imaging (MRI) use to be exempted from binding exposure-limit values. "We know this is only a proposal," says Stephen Keevil, a medical physicist at King's College London. "But if the final directive turns out to be like this, then everything will be fine." The 2004 Physical Agents (EMF) Directive was originally designed to address health risks for those working in the electrical power and telecommunication industries, but it turned out to have a range of unintended consequences. Many sectors — medical, industrial and even military — claimed that the directive set occupational exposure limits that were overcautious and that would interfere with normal activities, including routine imaging, which is vital in both the clinic and the research lab. They also disputed the scientific data on which the limits had been based. The protests earned the directive the dubious distinction of being the only piece of EU legislation ever to have been put on ice. The original directive was scheduled to be incorporated into national legislation by 30 April 2008 — member states are normally obliged to implement EU directives within four years of their approval — but after the complaints this was delayed until April 2012 to allow time to consult stakeholders and, potentially, to propose revisions. The European Parliament and Council must sign up to any changes the commission proposes to make. "If the final directive turns out to be like this, then everything will be fine." Even with those extra years, the timetable for repair is tight. "We hoped to have our proposal for new legislation much earlier, but it all proved complicated," admits Georges Herbillon, the commission official responsible for drafting the new rules. "Our current timetable gives 16 months for the political approval and that should be enough." But the commission is already behind schedule and, he says, much further slippage would mean that the original directive would automatically come into effect on 1 May 2012. The directive covers the electromagnetic spectrum up to 300 GHz, the highest frequency of radio waves, but the disputes focus on the low-frequency range under 100 kHz, typically found in the vicinity of standard MRI machines. Many procedures require health or research workers to remain close to the scanner when it is running, to carry out procedures on people inside the scanner, for example. Decades of experience have produced no evidence of permanent adverse health effects, MRI scientists argue. Physical effects, such as a feeling of vertigo, or peripheral nerve stimulation resulting in a harmless twitch, may occasionally occur, but they are temporary. The original directive banned workers from staying close to a running scanner. The calculations used to estimate safe levels of exposure were based on recommendations of the International Commission on Non-Ionizing Radiation Protection (ICNIRP), a non-governmental organization recognized by the World Health Organization. But a report released this week by the European Science Foundation says that those recommendations are extrapolated from very limited experimental data with excessive caution. "It is nonsense — taking the precautionary principle too far," says Denis Le Bihan, director of the NeuroSpin neuroimaging project at the CEA-Saclay Centre near Paris, and a member of the expert group that prepared the report. ADVERTISEMENT In its latest consultation document, the commission says that when defining adverse health and safety effects it will take the specific circumstances into account — a transient feeling of vertigo may be dangerous only if the worker is standing and at risk of falling. It also plans to consider safety calculations from agencies other than the ICNIRP, such as the international Institute of Electrical and Electronics Engineers (IEEE) and Germany's Federal Ministry of Labour and Social Affairs (BMAS), which some researchers say are more strongly grounded in science. It suggests grading the disputed sub-100 kHz frequency range into three categories on the basis of a risk assessment that acknowledges the higher safety limits recommended by the IEEE and BMAS, banning access only when exposure is high. MRI would be exempt from these binding exposure limits. Instead, a Europe-wide agreement on safe working practices would be developed and workers would be given appropriate training. This, Keevil says, will avoid the problem of impeding research or medicine, but "will achieve the same aim of keeping people safe". There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• US biotech firms line up for tax credits
  - Nature (London) 465(7300):854 (2010)
  Application process begins for cash to beat the downturn. Slow growth: the US biotech industry has suffered in the recession.T. Horowitz/Corbis Tucked away on page 759 of the voluminous health-care law signed by President Barack Obama in March is a provision to aid small companies doing research and development (R&D) in biotechnology. Starting on 21 June, many of those companies will be racing to take advantage of a tax credit worth up to $5 million per company and totalling $1 billion. Called the Therapeutic Discovery Project Program, the initiative aims to lift an industry that has struggled during the recent economic crisis. When anxious investors shifted money to low-risk investments, high-risk biopharmaceutical companies, particularly young firms with no products on the market, were left scrambling for cash (see graph). The pressure has taken its toll. According to the Biotechnology Industry Organization (BIO), there were at least 394 public US biotech firms in January 2008. By January 2010, 285 remained. Most of those lost were early-stage firms. "We were seeing literally a generation of biotech companies being shelved," says Alan Eisenberg, BIO's vice-president for emerging companies and business development. The tax credit is targeted at vulnerable young businesses — only those with fewer than 250 employees are eligible — and covers up to half of the R&D expense for qualifying projects. Because most biotech companies don't earn a profit in their early years, and therefore owe no taxes, they wouldn't benefit from a tax credit. So the programme allows those firms to convert the credits into grants. In fact, the programme is largely a grants programme disguised as a tax credit, says Barry Bozeman, a professor of public policy at the University of Georgia in Athens, who notes that tax credits tend to be more politically palatable. Source: BIO To be eligible, a project must demonstrate the potential to produce new therapies, reduce the cost of health care or contribute to the goal of curing cancer within 30 years. GlycoMimetics of Gaithersburg, Maryland, is one potential candidate for the credit. Rachel King, the company's chief executive, hopes the money could be used to expand clinical trials for its drug to treat sickle-cell anaemia. XOMA, a firm in Berkeley, California, will probably submit multiple applications, each for a different project, says its chief financial officer, Fred Kurland. One project XOMA is likely to put forward is its lead therapeutic — an antibody that reduces inflammation. Syndax of Waltham, Massachusetts, a company that focuses on cancer, is still mapping out its strategy to maximize its chances of getting the credit, says its financial controller, John Pallies. "We could do one application per drug, or per type of cancer, or per patient population," he says. "There's not a good sense of how these projects are going to be evaluated." Under the programme there is no limit to the number of projects that can be funded at a single company, and the $1 billion total will be distributed among all qualifying projects. Eisenberg estimates that about 600 of BIO's members will apply for funds, plus about 600 companies that are not part of the organization. This deluge of applications could lead to smaller awards per proposal. "In all likelihood, with so many applications, no project is going to get more than a million dollars," says Kurland. Eisenberg points out that 85% of BIO's members with fewer than 350 employees have R&D budgets of less than $30 million. The grants are clearly tiny compared with the billions often required to fully develop a new drug, but they are enough to stimulate early-stage research, says Eisenberg. "Will it mean that you don't have to go out and do other fundraising?" says Kurland. "No. But maybe it gets you over the hump, or maybe it encourages others to invest in your company." ADVERTISEMENT The credit should help address concerns that US biotechnology is falling behind in the face of increasingly vigorous international competition. "The United States was the first to have a tax credit for R&D back in 1981," says Gregory Tassey, a senior economist at the National Institute of Standards and Technology in Gaithersburg. "Since then, other countries have come up with their own. Now we're down around seventeenth in terms of actual financial impact of our R&D credit." For now, the credit is only mandated to cover costs incurred in 2009 and 2010, but it's a safe bet that the industry will lobby for the programme's renewal. Even so, the credit is unlikely to solve the real challenge facing the sector: how to sustain a high-risk industry that often takes a decade or longer to generate a viable product. "This is not going to solve any long-term problem," says William Caldwell, chief executive of Advanced Cell Technology, headquartered in Santa Monica, California. "It's just going to be part of the funds that a company can access just to stay alive." There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Mr Smits goes to Brussels
  - Nature (London) 465(7300):857 (2010)
  Enthusiastic welcome for new European research chief. Robert-Jan Smits.G. Bolstad, Research Council of Norway He doesn't own a car, preferring on principle to walk whenever possible. And he buys his own sandwiches. But Robert-Jan Smits, Europe's down-to-earth new research chief, is utterly at home in the rarefied world of European Union (EU) bureaucracy. Smits, who will become director general for research on 1 July — in time to oversee the gestation and birth, in 2014, of the European Commission's multibillion-euro Eighth Framework Programme for research — ascended to the post in record time. And he arrives with considerable goodwill among the researchers whose lives will be affected by his decisions. The research director general is responsible for drafting all research funding initiatives for approval by the European Parliament and Council, the EU's legislative bodies. He is also charged with ensuring the smooth running of all elements of the EU Framework programmes — from postdoctoral fellowships to the huge international fusion-energy project ITER. Commission staff and scientists who deal with the commission are openly thrilled. "We are all so enthusiastic about this appointment," says Helga Nowotny, president of the European Research Council (ERC), the basic-research granting agency. Nowotny is normally critical of the commission and its frustrating bureaucracy. But, she says, Smits "has a good track record, and he understands research issues extremely well". "The appointment is terrific news," adds materials scientist John Wood, principal of Imperial College London and chair of the European Research Area Board, which promotes the unification of European research efforts. "He may be a bit bureaucratic at times, but he is a listener, and is always trying to find solutions to problems." Such unaccustomed praise for a top European bureaucrat also reflects widespread relief at the departure of the unpopular incumbent, José Manuel Silva Rodríguez, who becomes an adviser to commission president José Manuel Barroso. Silva Rodríguez arrived in 2005 from the commission's agriculture directorate, and critics say he rigidly applied its strict accounting culture to research without understanding scientists' need for flexibility. Researchers complain that they are being crushed by the detailed accounting expected of them (see Nature 465, 666; 2010). By contrast, Smits, a natural consensus-seeker, understands how researchers can best be served, even within the restrictive commission rules, say his supporters. Much is at stake in his success, because the commission's Framework programmes are not only financially significant, they influence much of the research agenda in Europe. Yet they work badly, and scientists find the procedures for participating in them discouragingly complex. Smits, at 52, is considered young for this high position. Trained in international law in his native Netherlands, then in Switzerland and the United States, he has become steeped in the research culture since joining the commission in 1992. He has been in charge of issues as diverse as research infrastructures, such as biobanks, and the relations between the commission and facilities such as CERN, the particle-physics laboratory near Geneva, Switzerland. In April, he became deputy director general of the Joint Research Centre, which conducts research for EU policy-makers, a position he will now relinquish. ADVERTISEMENT Smits has a pronounced pro-industry spin, colleagues say. This has not unnerved scientists who have watched him enthusiastically assist the 2007 birth of the popular ERC. And it actively endeared him to EU commissioner Máire Geoghegan-Quinn, who took office in February (see Nature 463, 722–723; 2010). Insiders say Geoghegan-Quinn quickly spotted him as someone who would deliver on her two key missions: to bring research closer to the innovation pipeline and to simplify procedures to make them more attractive to scientists. The commissioner, who prides herself on being 'a doer', surprised everyone by getting Smits into his post so quickly. Silva Rodríguez could not have stayed beyond the end of this year (the director general cannot hold the post for more than 5 years), but Geoghegan-Quinn exercised her prerogative to make the change early. As the person responsible for achieving the top-level research objectives set by Geoghegan-Quinn, Smits's relationship with her will be key to his success, says Silva Rodríguez's predecessor, Achilleas Mitsos. "If you have a good trusting relationship with your commissioner, you can get things done," he says. That seems likely to be the case for Smits and Geoghegan-Quinn, he adds. "They share a similar philosophy." There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Russia woos lost scientists
  - Nature (London) 465(7300):858 (2010)
  Minister of education and science discusses plans for rebuilding the country's research base. Once a scientific powerhouse, Russia is still struggling to rebuild a research system shattered by the demise of the Soviet Union in 1991 and the decade of economic hardship that followed. To speed up the recovery, the Russian government recently announced a 90-billion-rouble (US$2.8 billion) programme aimed at strengthening universities and getting high-profile expatriate researchers to return to Russia (see Nature 464, 1257; 2010). And a conference next week in St Petersburg will gather representatives of Russia's scientific diaspora to discuss how émigrés can help to restore Russian science to its former glory. In an exclusive interview, Nature spoke to the minister of education and science of the Russian Federation, about how he hopes to bring the diaspora back home and boost the international standing of Russian science. Andrei Fursenko, the minister of education and science of the Russian Federation.ITAR-TASS/PHOTOSHOT The revolutionary changes that occurred in the 1990s created many problems for science, such as a dramatic decrease in funding, the decline of the scientist's social status, and a low demand for research from the economy. We think that over the past decade we have been gradually overcoming these difficulties and restoring the traditions of the Russian schools of science. Science has once again become interesting and attractive for talented young people and Russian businesses. Russian scientists are actively collaborating with their foreign colleagues. But there are still many obstacles. They include the archaic system for organizing Russian science, in which scientific research is often artificially separated from education. Russian science has long been isolated from global science, and as a result our scientific priorities and their support system are obsolete. Science is notorious for its paternalistic nature generally, and in our case it has been further exacerbated by its Soviet upbringing. All these obstacles are ultimately surmountable. Furthermore, I have reason to believe that the current situation is fundamentally different from what it was five or seven years ago. It would be premature to speak about a breakthrough, but positive changes are obvious. We hope we will be able to gradually create a network of world-class research universities in our country. The nature of modern science is global, and it would be wrong and detrimental to impede the international mobility of scientists. For a number of reasons, however, this mobility has proven to be a one-way street for Russia. It is estimated that up to 35,000 scientists emigrated from Russia in the 1990s. Approximately the same number are still officially assigned to their respective institutions in Russia, but are in fact permanently working abroad. As a result, in many disciplines our old professors have been left without apprentices, and our young scientists have no one to learn from. These gaps should be filled not by restricting the mobility of scientists but by expanding it, and not only by encouraging our scientists to return, but also by attracting leading foreign specialists to Russia. Last year, the government launched a federal programme, 'Scientific and pedagogical labour force for an innovative Russia', to encourage our scientists working abroad to return, take leadership of scientific teams and implement research projects in Russia. The projects were selected for federal funding on the basis of competitions, and generated a great deal of interest. The winners include our compatriots living and working in 22 foreign countries. Among them are scientists, university professors and the heads of laboratories of some leading universities and research centres in the United States, Germany and Great Britain. The money will come from the federal budget over the next three years, and will be used to fund university research. It will be made available in the form of competitive grants of up to 150 million roubles each, which will support scientific research projects in 2010–12, with the possibility of extending the projects for another year or two. This is not a redistribution of previously allocated science and education funding; these are new, additional funds. Both Russian and foreign scientists are eligible for the grants. They will be awarded to universities, which will then agree with the recipients — principal investigators (PIs) of international repute — the terms and conditions of the research. Applications will have to pass through peer review according to international practice. To encourage mobility, Russian PIs will be required to relocate to a university they have not worked at before, and to set up a research team involving local scientists. Each research-project team must include young scientists, as well as graduate and undergraduate university students. A maximum of 60% of the grant money can be used for salaries. ADVERTISEMENT The scientific research areas will be determined, and the grant decisions made, by the Russian Federation's grant board, which consists of internationally renowned Russian scholars. I have been asked to head the board. An official request for proposals will be published on 25 June. A lot depends on the personal initiative, energy and entrepreneurship of the scientist or research group. Universities in Moscow and St Petersburg tend to take a more active part in international cooperation than most of the regional universities, although those in Tomsk and Novosibirsk are increasingly showing results that are on a par with them. Our goal is to provide the entire Russian scientific community with equal opportunities to expand international links and to create partnerships that are not limited to a handful of demonstration projects at elite universities. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• UN body will assess ecosystems and biodiversity
  - Nature (London) 465(7300):859 (2010)
  Nations agree on way to keep watch on Earth's health. The United Nations is setting up a body to monitor global ecology modelled on its influential climate panel. Last week, representatives from 85 countries gathered in Busan, South Korea, to approve the formation of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES), which will operate much like the Intergovernmental Panel on Climate Change. According to the document hammered out on 11 June, the IPBES will conduct periodic assessments of Earth's biodiversity and 'ecosystem services' — ecosystems outputs, such as fresh water, fish, game, timber and a stable climate, that benefit humankind. These assessments, based on reviews of the scientific literature, will answer questions about how much biodiversity is declining and what the implications of extinctions and ecosystem change might be for humanity. Assessments will take place from global to sub-regional scales. "Governments wanted to be reassured that it would be lean and mean and streamlined." The IPBES will help to train environmental scientists in the developing world, both with a budget of its own and by alerting funders to gaps in global expertise. The organization will also identify gaps in research and highlight tools — such as models — for policy-makers looking to apply a scientific approach to decisions on issues such as land management. Negotiations in Busan stretched late into the night as delegates debated the scope of the IPBES and how it would be funded. A key concern among developed countries was that the body should "not become a huge bureaucracy", says Nick Nuttall, a spokesman for the United Nations Environment Programme. "Governments wanted to be reassured that it would be lean and mean and streamlined." ADVERTISEMENT Among the governments that assented to the IPBES's creation were the European Union, the United States and Brazil. This autumn the plan will come before the general assembly of the United Nations for official approval, which those involved say is a virtual certainty. Anne Larigauderie, executive director of Paris-based Diversitas, a facilitator for biodiversity science, says that the IPBES could turn the "fragmented" field of biodiversity research into a more coordinated "common enterprise" that will lead to better models of future biodiversity changes. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Correction
  - Nature (London) 465(7300):859 (2010)
  The Editorial 'Mouse megascience' (Nature 465, 526; 2010) wrongly stated that the estimated cost of phenotyping 4,000 mouse genes is $900 million; that is actually the estimated cost for phenotyping all 20,000 mouse genes. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Metrics: Do metrics matter?
  - Nature (London) 465(7300):860 (2010)
  Many researchers believe that quantitative metrics determine who gets hired and who gets promoted at their institutions. With an exclusive poll and interviews, Nature probes to what extent metrics are really used that way. Download a PDF of this story No scientist's career can be summarized by a number. He or she spends countless hours troubleshooting experiments, guiding students and postdocs, writing or reviewing grants and papers, teaching, preparing for and organizing meetings, participating in collaborations, advising colleagues, serving on editorial boards and more — none of which is easily quantified. But when that scientist is seeking a job, promotion or even tenure, which of those duties will be rewarded? Many scientists are concerned that decision-makers put too much weight on the handful of things that can be measured easily — the number of papers they have published, for example, the impact factor of the journals they have published in, how often their papers have been cited, the amount of grant money they have earned, or measures of published output such as the h-index. Last month, 150 readers responded to a Nature poll designed to gauge how researchers believe such metrics are being used at their institutions, and whether they approve of the practice. Nature also contacted provosts, department heads and other administrators at nearly 30 research institutions around the world to see what metrics are being used, and how heavily they are relied on. The results suggest that there may be a disconnect between the way researchers and administrators see the value of metrics. Three-quarters of those polled believe that metrics are being used in hiring decisions and promotion, and almost 70% believe that they are being used in tenure decisions and performance review (see 'Metrics perceptions'). When asked to rate how much they thought administrators were relying on specific criteria for evaluation, poll respondents indicated that the most important measures were grants and income, number of publications, publication in high impact journals and citations of published research. And a majority (63%) are unhappy about the way in which some of these measures are used (see 'No satisfaction'). "Too much emphasis is paid to these flawed, seemingly objective measures to assess productivity," wrote a biologist from the United States. Respondents doubted that traditional, qualitative review counts for much. From a field of 34 criteria, "Review of your work by peers outside your department or institution" and "Letters of recommendation from people in your fie! ld" were tenth and twelfth, respectively — with 20–30% of the respondents stating that their institutions placed no emphasis on these factors at all. Yet in Nature 's interviews, most administrators insisted that metrics don't matter nearly as much for hiring, promotion and tenure as the poll respondents seem to think. Some administrators said that they ignore citation-based metrics altogether when making such decisions, and instead rely largely on letters of recommendation solicited from outside experts in a candidate's field. "Outside letters basically trump everything," says Robert Simoni, chairman of the biology department at Stanford University in California. That sentiment was echoed by academic administrators worldwide. "Metrics are not used a great deal," says Alex Halliday, head of the Mathematical, Physical and Life Sciences Division at the University of Oxford, UK. "The most important things are the letters, the interview and the CV, and our opinions of the papers published," he says. "I don't look at impact factors" of the journals a candidate publishes in, says Kenichi Yoshikawa, dean of the Graduate School of Science at Japan's Kyoto University. "These usually highlight trendy papers, boom fields and recently highlighted topics. We at Kyoto don't want to follow boom." Metrics are not wholly excluded, of course. Those 'qualitative' letters of recommendation sometimes bring in quantitative metrics by the back door. "We do not look at publication records or tell the reviewers to," says Yigong Shi, dean of the School of Life Sciences at Tsinghua University in Beijing. "But in reality, they do have an impact, because the reviewers will look at them." Mixed messages Administrators may also send mixed signals: metrics don't matter, except that they do. "Each year we collect the average performances of people across various different things: student evaluations of lectures, teaching loads, research income, paper output, h-indices," says Tom Welton, head of the chemistry department at Imperial College London. Welton insists that this information is reported back to researchers as a guideline, "not a hurdle that has to be leapt over to get a promotion". Nevertheless, the fact that such measures are being made could give the impression that they are being relied on heavily. At the Massachusetts Institute of Technology in Cambridge, Claude Canizares, vice-president for research and associate provost, says that "we pay very little attention, almost zero, to citation indices and counting numbers of publications". But, he says, "if someone has multiple publications in a higher-impact journal, it's like getting another set of letters — the peers that reviewed that paper gave it high marks". A separate reason for the disparity is that the use of metrics can vary markedly between countries (see 'Around the world with metrics') — or even between disciplines. Poll respondents and administrators agree that metrics have potential pitfalls. For example, 71% of respondents said that they were concerned that individuals at their institutions could manipulate the metrics, for example by publishing several papers on the same basic work. Most deans and provosts seemed less concerned about that possibility, arguing that such practices were unlikely to slip past reviewers. But they were wary of the more insidious effects of using metrics. "If you decide that publishing a large number of papers is important, then you've decided that's what quality is," says Gregory Taylor, dean of the Science Faculty at the University of Alberta in Edmonton, Canada. "That's always a very dangerous route to go down, because then you get people working to achieve by the formulae, which isn't a very good way to encourage people to use their imagination." Indeed, half the poll respondents said that they shaped their research behaviours on the basis of the metrics being used at their university. Although many of the altered behaviours given were fairly innocuous — for example, "work harder" — some had the potential to compromise scientific ideals. "It discourages me from doing important research work that may be of null association," said one respondent, a US postdoctoral fellow. Breaking the old-boys' networks Despite general dissatisfaction with the way in which metrics are being used, some poll respondents welcome them. Many said that they appreciated the transparency and objectivity that quantitative metrics could provide. "I prefer this to qualitative metrics," wrote one, a department head in chemistry and engineering from Europe. Others who were dissatisfied with the use of metrics at their institution said they felt that the metrics weren't being used enough or weren't being used consistently. "The metrics can be nullified at the college or provost level," complained a US professor of neuroscience. If nothing else, says Welton, the use of quantitative measures can reassure young researchers that the institution is not perpetuating an old-boys' network, in which personal connections are valued over actual achievement. Administrators who say that they do consider metrics in the decision-making process stress that they recognize the limitations of such measures in defining the ! career of an individual. Researchers in different fields and different specialities publish and cite at different rates. An intimate understanding of the fields — and more importantly the individuals being assessed — is crucial, they say. This ultimately makes the use of metrics more subjective by necessity. ADVERTISEMENT Surprisingly, if poll respondents desire change, it's not necessarily away from quantitative metrics. When Nature gave respondents a list and asked them to choose the five criteria that they thought should be used to evaluate researchers, the most frequently chosen was "Publication in high-impact journals", followed by "Grants earned", "Training and mentoring students" and "Number of citations on published research". In other words, what respondents think they are being measured on roughly matches what they want to be measured on. The challenge for administrators, it seems, is not to reduce their reliance on metrics, but to apply them with more clarity, consistency and transparency. "The citation index is one of those things that is interesting to look at, but if you use it to make hiring decisions or use it as a sole or main criterion, you're simply abrogating a responsibility to some arbitrary assessment," says Jack Dixon, vice-president and chief scientific officer of the Howard Hughes Medical Institute in Chevy Chase, Maryland. While he says that the institute eschews such metrics, he recognizes that they will continue to be used. "All decisions are based on various criteria. The thing you hope for is that the decisions are fair, and are based upon criteria that the reviewers know and understand." There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Metrics: A profusion of measures
  - Nature (London) 465(7300):864 (2010)
  Scientific performance indicators are proliferating — leading researchers to ask afresh what they are measuring and why. Richard Van Noorden surveys the rapidly evolving ecosystem. Download a PDF of this story. Scientists have been sizing up their colleagues since science began. But it was American psychologist James McKeen Cattell who first popularized the idea that systematically ranking scientists by 'performance' could provide benefits beyond scratching the itch of professional envy. In the 1910 second edition to his 1906 work, American Men of Science: A Biographical Directory, he argued that tracking performance over time could assist the progress of research. "It is surely time for scientific men to apply scientific method to determine the circumstances that promote or hinder the advancement of science," he wrote. That rationale for systematic evaluation hasn't changed much in 100 years, but the evaluation techniques have evolved dramatically. Where Cattell simply asked experts to rank the star performers in a field by merit — "Expert judgment is the best, and in the last resort the only, criterion of performance," he wrote — a host of objective indicators, or metrics, are now used to quantify nebulous notions of scientific quality, impact or prestige. Within the past decade, the development of ever more sophisticated measures has accelerated rapidly, fuelled by the ready availability of online databases such as the Web of Science from Thomson Reuters, Scopus from Elsevier and Google Scholar. "Right now we're going through a Cambrian explosion of metrics." "Right now we're going through a Cambrian explosion of metrics," says Johan Bollen, an informatics scientist at Indiana University in Bloomington. It has become all but impossible even to count today's metrics. Bibliometricians have invented a wide variety of algorithms, many of them unknown to the everyday scientist, some mistakenly applied to evaluate individuals, and each surrounded by a cloud of variants designed to help them apply across different scientific fields or different career stages (see 'Metrics explosion'). Here, Nature categorizes metrics old and new, lays out their strengths and weaknesses — and examines a growing feeling among researchers that it is time to slow down and discuss what these measures are actually for. The era of quantitative, computer-tabulated science metrics dates back to the 1950s, when linguist Eugene Garfield began indexing the scientific literature using punch cards. A company in Philadelphia, Pennsylvania, that Garfield founded in 1955 was renamed the Institute for Scientific Information (ISI) in 1960, the same year it began to publish the Science Citation Index. This was a systematic effort to track citations — the footnotes by which journal authors acknowledge their intellectual debts. (ISI is now owned by the publishing firm Thomson Reuters.) In 1965, Garfield and his colleagues used ISI's databases to show that Nobel laureates published five times the average number of papers, and that their work was cited 30 to 50 times the average — a finding that for decades established citations as the pre-eminent quantitative measure of a scientist's influence1. Click for a larger version.THOMSON REUTERS, WEB OF SCIENCE For all that, Garfield's best-known and most widely used citation-based metric, the 'impact factor' (see 'Field guide to metrics'), which he developed in 1963, is of little use in measuring an individual's performance; it applies only to the popularity of the journal. "If there is one thing every bibliometrician agrees, it is that you should never use the journal impact factor to evaluate research performance for an article or for an individual — that is a mortal sin," says Anthony van Raan, director of the Centre for Science and Technology Studies at Leiden University in the Netherlands. Big impact A better metric for assessing an individual by their citations is the h-index, which has been swiftly adopted by major online databases since being introduced in 2005 by physicist Jorge Hirsch of the University of California in San Diego. According to Hirsch's definition, someone who had written, say, 50 papers that had each been cited at least 50 times would have an h-index of 50. An author's h-index has the virtue of measuring his or her article productivity and citation-based impact simultaneously. But it does have flaws, including the fact that an author's h-index can reflect longevity as much as quality — and can never go down with age, even if a researcher drops out of science altogether. "You should never use the journal impact factor to evaluate research performance for an article or for an individual — that is a mortal sin." To combat this, "there have probably been more than a dozen variants of the h-index suggested since 2005, and even scholars in the field of bibliometrics have still not established which are the best ones to use," says Anne-Wil Harzing, a professor of international management at the University of Melbourne in Australia. For that reason, she adds, most scientists stick to the original h-index, whatever its limitations. A third, increasingly popular, class of measure is the 'evaluative informetric', which gives heavier weight to citations from papers that are themselves highly cited. The principle is much the same as the PageRank algorithm that Google uses to order its search results: a link from a popular page is more highly weighted than one from a not-so-popular page. Both Thomson Reuters and Elsevier now offer to compute this kind of metric for journals — the companies refer to the result as the Eigenfactor and the SCImago Journal Rank (SJR), respectively. Unlike the resolutely journal-oriented impact factor, the page-rank concept has been usefully applied to individuals by some researchers. Filippo Radicchi, a researcher in complex networks at the Institute for Scientific Interchange in Turin, Italy, and his colleagues have used weighted citations to derive a network of links between more than 400,000 papers published between 1893 and 2006 in the Physical Review journals. By slicing through the network year by year, the researchers then showed how the influence of each scientist's articles spread through a community over time — which they in turn used to produce a quantitative ranking of physics authors2. For all their popularity, however, citation-based metrics share some fundamental weaknesses when it comes to evaluating individual researchers. One is that research papers commonly have multiple authors — "possibly hundreds of them", says Henk Moed, a senior science adviser at Elsevier in Amsterdam. A number of corrections can be applied to give the various authors fractional credit. But in some research fields, such as high-energy physics, there can be so many co-authors that assigning credit to individuals makes little sense, Moed says: "Here one seems to reach the limits of the bibliometric system." Another weakness is that the scores depend on the database being used. Thomson Reuters's science, social science and arts and humanities databases — accessible through its Web of Knowledge interface — include data from about 11,500 journals. Elsevier's Scopus, introduced in 2004, includes abstracts and references from 16,500 peer-reviewed journals. And the free automatically indexed database Google Scholar, also introduced in 2004, includes details of patents as well as scientific papers, and covers many more journals in engineering, social sciences and the humanities than either of the others. A search in May showed that papers in international management by Harzing had been cited 815 times according to Thomson Reuters, 952 times according to Scopus and 2,226 times according to Google Scholar. Push for normality For bibliometricians, the most daunting problem with citation-based metrics is getting the 'normalization' right: if molecular biologists tend to cite more often than physicists, then molecular biologists will have higher h-indices or citation counts, making it difficult to compare individuals from the two fields. In principle, such variations can be evened out by dividing a researcher's citation rate by the average citation count for his or her field. But in practice, any attempt to do so swiftly gets bogged down in categorization: what constitutes a 'field'? A stem-cell researcher, for example, may bridle at being normalized by the average citation rate of cell biologists in general. "Everyone has made a contribution to their particular granular subject area. If you define the area too broadly, you miss subtleties; too narrowly and you get nothing useful out of it," says Charles Oppenheim, emeritus professor of information science at Loughborough University, UK. One way to get around that problem is to let the citations define the categorization. This is the idea behind various attempts to construct 'maps of science', using networks of interconnecting citations to spot discrete research fields or intellectual environments. The process is hard to standardize, says van Raan. Nonetheless, he says, "for individual scientists, mapping is the most interesting development in bibliometrics today". Bollen agrees: such maps often show how research papers or novel disciplines lie at the centre of particular fields of activity, he says — which could allow a scientist to assert, "my work connected nanotechnology to archaeology", or "if I hadn't published this paper, these domains would never have been connected". Bibliometricians have suggested a host of measures to quantify such statements. These include 'betweenness centrality' — how often a paper in the network lies on the shortest path between any other two papers — and 'closeness centrality': the average number of connections required to get from a paper to any of the other papers. What aspects of scientific impact these measure is not entirely clear, but they probably give an indication of interconnectedness and interdisciplinarity. Cyberstalking Meanwhile, some metrics researchers are looking to make a break from citations. As most scientific articles are now accessed and read online, why not just track the readers' actions in cyberspace through article or journal page views or downloads? Publishers such as the Public Library of Science already offer download statistics for their articles, together with social-bookmarking tools that allow scientists to flag papers that they find particularly useful. (Similar tools are offered by the online services Mendeley and Faculty of 1000.) The disadvantage of this approach is that it apportions the impact of a research paper according to all public views, not just those by scientists. But that can also be seen as an advantage, in that it expands the idea of scientific impact. For example, medical researchers might find that doctors, nurses and public-health policy-makers frequently view articles online, although the researchers never receive a traditional citation from these end-users. One early hurdle for this nascent field is that there are not yet global standards for journals to report data files of user activity. But COUNTER (Counting Online Usage of Networked Electronic Resources), a consortium of librarians and publishers based in Oxford, UK, is working to reach agreement on such a standard by 2012. Bollen's team is exploring whether online-usage data might help funding agencies to pick out fast-moving areas of innovation before citation-based statistics have a chance to catch up. The researchers have obtained a database of 1 billion usage events — records of users accessing scientific articles, newspapers and magazines in the years 2002 to 2007. They can also see in what order a user in any one session clicks through resources, allowing them to track the general flow of activity and produce maps showing which articles are central to which networks of activity. There are now maps that show how work in the social sciences and humanities formed bridges between scientific disciplines3. "In principle you could use these records to track scientific activity in real time, and to follow science taking place on Twitter, blogs, or through online software, none of which can be recorded by citation data," says Bollen. Before this vision of instant influence-tracking can become solid, however, data on the Internet need to be organized and referenced in more consistent ways, and publishers need to agree to release information on usage statistics. Even as they push forward innovative ideas, many researchers in the metrics field say that it is high time for some reflection and consolidation. Little, if any, of the recent buzz has made it past the pages of scholarly journals into regular use on scientists' CVs, and, says Peter Binfield, publisher of PLoS ONE, "it feels like the field is going off in multiple directions". "These people should know better than to think that there is a single measure you can use." More widely, says Bollen, although bibliometricians know that the idea of measuring scientific performance shares a fuzziness with the idea of measuring intelligence, many are too keen to promote their own innovations rather than focus on what they actually measure. "The point should not be to come up with a new metric. It should be to explain what metrics represent, and why we want them," says Bollen. "Can we come back to the scientific community and say 'if this is what you want to measure, then this is a good way to do that'?" Much of the next few years of clearing through the rubble of metrics will involve this kind of process, he says. Similarly, although using a variety of metrics gives the clearest picture of scientific impact, some published research demonstrates that many people still desire a single index. "There is some mind-numbing detail on how 'my version is better than yours'; all these people should know better than to think that there is a single measure you can use," says David Pendlebury, a consultant for Thomson Reuters based in Bend, Oregon. ADVERTISEMENT Many metrics correlate strongly with one another, suggesting that they are capturing much of the same information about the data they describe. Bollen's team last year published a study4 comparing correlations between 39 measures of scientific impact for journals, attempting to tease out what different aspects of scholarly impact they captured. For example, the most important factor seems to be whether a metric measures 'rapid' or 'delayed' impact. Meanwhile, modern metrics are slowly finding users outside the traditional groups: journals hoping to promote their products or research-performance managers who, like Cattell, hope to boost research. Individual researchers are beginning to explore how new tools such as network mapping and online usage data could help them to identify other scientists who are close to their special interests, deliver relevant papers to literature searches more speedily or to pinpoint emerging innovative fields. Soon they could start to claim bibliometrics for themselves — assisting research in ways that Cattell never envisioned. * References * Garfield, E. & Sher, I. H. in Research Program Effectiveness (eds Yovits, M. C., Gilford, D. M., Wilcox, R.H., Staveley, E. & Lemer, H. D.) 135-146 (Gordon and Breach, 1966). * Radicchi, F. , Fortunato, S. , Markines, B. & Vespignani, A.Phys. Rev. E80, 056103 (2009). * Butler, D.Nature458, 135 (2009). * Bollen, J. , Van de Sompel, H. , Hagberg, A. & Chute, R.PLoS ONE4, e6022 (2009). * Nature435, 1003-1004 (2005). There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• World view: Talking the talk
  - Nature (London) 465(7300):867 (2010)
  Without effective public engagement, there will be no synthetic biology in Europe, says Colin Macilwain. It has become fashionable, in some quarters, to decry orchestrated 'dialogues' between scientists and the public as excuses for much talk and little in the way of practical outcomes. But for synthetic biology in Europe, at least, it is dialogue or bust. Unless the public is on board, the field won't develop here, where loss of public trust has halted entire technologies. That's why the engineers and biologists who are interested in synthetic biology have been working to embed social scientists and members of the public firmly in the field. Their involvement will be crucial as it develops, from the early exploration of concepts and tools to the still-remote prospect of plants and microorganisms 'designed' for various uses. Last July, the Leopoldina — Germany's national academy of science — and the DFG, the country's main research agency, issued a joint statement pledging a dialogue with the German public on synthetic biology. This week, two of the British research councils published initial results of an unusually detailed and extensive dialogue between members of the public and scientists on synthetic biology. British research leaders, chastened by the public's rejection of genetically modified (GM) crops a decade ago, have been particularly active in trying to develop more proactive and sophisticated approaches to public consultation. The Synthetic Biology Dialogue report carries a very clear message. Brian Johnson, chairman of the dialogue's steering group and former biotechnology adviser to the conservation group English Nature, says that people want to know "why you are doing this work, who pays for it, and who governs it". Lessons from GM crops Scientists habitually overlooked such claims before previous crises of public confidence. For example, during the public debate that ended in Europe's virtual moratorium on GM foods, plant scientists kept telling anyone who would listen that the technology would be deployed for the public good. At the same time, everyone in the biotechnology industry knew that Monsanto had the best strains, and that its main interest was in doubling the traditionally modest margins that farmers used to pay for seed. This unresolved clash between the true and purported 'motivation' of agricultural biotechnology helps to explain why government-sponsored dialogue in that arena remains so fraught. In the past few weeks, two members of the steering panel for the UK Food Standards Agency's dialogue on GM foods — Helen Wallace of the protest group GeneWatch and Brian Wynne, a sociologist at the University of Lancaster — resigned, alleging that the process was being used as a public-relations exercise by the agency as it moves towards approval of transgenic strains. These resignations could yet destabilize plans to cultivate GM crops in Britain for the first time. The environment secretary in the new British government, Caroline Spelman — a former biotech lobbyist — has branded the dialogue as rigged in industry's favour and seems minded to shut it down. Such a step will make it all the harder for the government to press ahead on GM crops, without unleashing another deluge of press criticism. The newly published synthetic-biology dialogue is on much firmer ground. It was started last November by organizations that can be seen as relatively honest brokers, the Biotechnology and Biological Sciences Research Council (BBSRC) and the Engineering and Physical Sciences Research Council (EPSRC). And it got going at a stage in synthetic biology's development when its potential applications are too remote to attract the direct interest of government ministers or big business. Additionally, the culture of the nascent discipline in Europe is, so far, distinct from that of more business-orientated areas such as genetics or plant biotechnology. Most of those involved are young academics who don't yet see their work primarily in terms of commercial application. Many are more temperamentally attuned to open innovation than to fighting over patent protection, and may therefore be equipped to assuage the fears of one dialogue participant that synthetic biology would be "greed-led". "Regulators across Europe have a poor record of maintaining public confidence." Almost two years before Craig Venter announced his 'synthetic cell', the UK research councils funded seven networks of scientists and engineers to start exploring technical aspects of synthetic biology, ranging from the necessary standards and methods to applications, such as electronics and tissue engineering. They demanded at the outset that social scientists and members of the public be 'embedded' into these networks. "Whatever we do has to be done with society's authority," says Alistair Elfick, a medical engineer at the University of Edinburgh and chair of the network looking at technical standards. The formal dialogue overseen by Johnson's group cost about £350,000 (US$510,000), and involved 160 citizens, at four locations, who were invited to two-and-a-half days of discussions, spread out over weeks so that people had time to think about what was being said. In the longer term, research-council officials want public participation to remain integral to the development of the discipline. This could take many forms including, some senior participants believe, helping to design regulatory mechanisms for synthetic biology that will be publicly credible as well as technically robust. Regulators across Europe have a poor record of maintaining public confidence. These regulators, everywhere in the world, rely primarily on the process of quantitative risk assessment to assess the safety of, for example, a GM organism by comparing it with that of an ancestor. If synthetic biology were to create new organisms without ancestors, this approach would break down. Current regulators are in denial about this impasse. Whether the new UK coalition government will continue the public dialogue on synthetic biology, or act on its findings, remains unknown. Meanwhile the allegations that the dialogue on GM crops was being rigged by the last government present a political opportunity to the coalition led by Prime Minister David Cameron: it could conduct such exercises with a genuine intent that they influence policy. That option is open to every European government that is considering how to ensure that its researchers grasp the opportunity that synthetic biology may represent. Without meaningful public involvement in its development, as well as appropriate regulation, the entire field will live under the threat that events, or scaremongering, could derail it at any moment. Colin Macilwain is based in the United Kingdom. e-mail: cfmworldview@gmail.com There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• New data system to galvanize Brazil's conservation efforts
  - Nature (London) 465(7300):869 (2010)
  The Global Environment Facility last month endorsed an ambitious project to construct a Brazilian national biodiversity information system. This will be tailored to the needs of key decision-makers in the government and in the private sector (see http://go.nature.com/OYiHOj
• Green development credits to foster global biodiversity
  - Nature (London) 465(7300):869 (2010)
  Innovative financial mechanisms for global biodiversity conservation are a top priority for the tenth meeting of the Conference of the Parties to the Convention on Biological Diversity (CBD) in Japan in October.Frustrated with nearly 20 years of waiting for promised funds, some countries and environmental organizations are pressing for a 'green development' mechanism, analogous to the Kyoto Protocol's Clean Development Mechanism.
• Expand scientific input to address environmental effects
  - Nature (London) 465(7300):869 (2010)
  The proposed Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) (Nature 465, 525; 2010) should be part of a broader complementary system of scientific input.
• Call for cooperation to contain damage by Chile's salmon farms
  - Nature (London) 465(7300):869 (2010)
  The Aysén region in southern Chile — a key habitat for several endangered marine species — is under enormous pressure from the country's powerful salmon industry. Chile should follow the lead of nations such as Italy (see Nature 464, 673; 2010
• How to improve the use of metrics
  - Nature (London) 465(7300):870 (2010)
  Since the invention of the science citation index in the 1960s, quantitative measuring of the performance of researchers has become ever more prevalent, controversial and influential. Six commentators tell Nature what changes might ensure that individuals are assessed more fairly.
• How the boson got Higgs's name
  - Nature (London) 465(7300):873 (2010)
  Frank Close enjoys a journalistic account of the sociology and politics of the search for the elusive particle named after physicist Peter Higgs, but cautions that the idea has deeper roots than its name implies.
• Books in brief
  - Nature (London) 465(7300):874 (2010)
  The Universe is an intangible sea of information, suggests physicist Vlatko Vedral in his book Decoding Reality (Oxford Univ. Press, 2010).
• Earth-shaking images
  - Nature (London) 465(7300):874 (2010)
  Catastrophist ideas have seen a resurgence since the 1980s, when geologist Walter Alvarez associated the dinosaurs' disappearance with an asteroid impact. The sense that cataclysmic events shape the planet has been reinforced by a string of recent natural disasters — the 2004 Indian Ocean earthquake, Hurricane Katrina in 2005 and the 2010 Haiti earthquake.
• Nature trapped in glass
  - Nature (London) 465(7300):875 (2010)
  Works by Danish glass artist Steffen Dam, inspired by animal and plant morphology, will be on show next month in Seattle, Washington. Rows of cylindrical jars seem to imprison jellyfish whose tentacles swirl in slipstreams of frozen air bubbles, while translucent panels appear to house various sections of botanical or zoological specimens.
• Biochemistry: A radically different enzyme
  - Nature (London) 465(7300):877 (2010)
  The enzyme co-substrate S-adenosylmethionine is a potential source of two different free radicals, yet only one seemed to occur in nature. The discovery of an unusual enzyme reveals that both radicals can be formed.
• Solar system: Blink from a remote world
  - Nature (London) 465(7300):878 (2010)
  The use of stellar occultations to disclose unknown aspects of our Solar System is not new. But the latest such event to be reported involves an object that lies beyond the orbit of Neptune — and is a first.
• Genomics: The tale of our other genome
  - Nature (London) 465(7300):879 (2010)
  The groundwork for analysing the human microbiome — sequencing the collective genome of all our resident microorganisms — is now done. This work is of significance for understanding both human health and disease.
• Condensed-matter physics: Single skyrmions spotted
  - Nature (London) 465(7300):880 (2010)
  Skyrmions are a special type of particle that has long been predicted to exist in many fields of physics. Direct images of these structures have now been made in a magnetic material.
• Conservation biology: When an infection turns lethal
  - Nature (London) 465(7300):881 (2010)
  Losses in biodiversity and the emergence of new infectious diseases are among the greatest threats to life on the planet. The declines in amphibian populations lie at the interface between these issues.
• Structural biology: Immunity takes a heavy Toll
  - Nature (London) 465(7300):882 (2010)
  Toll receptors trigger immune responses through adaptor proteins and kinase enzymes. Structural studies reveal that hierarchical assembly of these proteins into a helical tower initiates downstream signalling events.
• Obituary: Martin Gardner (1914–2010)
  - Nature (London) 465(7300):884 (2010)
  'Mathemagician' who popularized maths and debunked pseudoscience.
• Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling
  - Nature (London) 465(7300):885 (2010)
  Nature | Article Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling * Su-Chang Lin1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yu-Chih Lo1 Search for this author in: * NPG journals * PubMed * Google Scholar * Hao Wu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:885–890Date published:(17 June 2010)DOI:doi:10.1038/nature09121Received16 February 2010Accepted29 April 2010Published online19 May 2010 Abstract * Abstract * Accession codes * Author information * Supplementary information * Comments Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88–IRAK4–IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88–IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual DDs in the complex, which are confirmed by mutagenesis and previously identified signalling mutations. Specificities in Myddosome formation are dictated by both molecular complementarity and correspondence of surface electrostatics. The MyD88–IRAK4–IRAK2 complex provides a template for Toll signalling in Drosophila and an! elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction. View full text Subject terms: * Structural biology * Immunology * Biochemistry * Cell biology Figures at a glance * Figure 1: Structure of the ternary Myddosome complex. , Ribbon diagram of the structure, with the six MyD88 molecules in cold colours, the four IRAK4 molecules in earth-tone colours and the four IRAK2 molecules in warm colours. , Superposition of MyD88 DD (cyan), IRAK4 DD (yellow) and IRAK2 DD (magenta). Helices H1 to H6 and the H1–H2, H2–H3 and H4–H5 loops are labelled. , Surface diagram of the complex with each subunit labelled using the same colour coding as in . M, MyD88; I4, IRAK4; I2, IRAK2. , Planar arrangement of the complex. , The helical symmetry is shown in a helical wheel representation with each ball representing a molecule and looking down the helical axis. Each molecule is labelled as an integer sequentially from M1 to I24. * Figure 2: Composite interactions and specificity in the ternary complex. , Schematic representation of a composite binding site. The nth, (n + 1)th and (n + 3)th molecules provide type IIb, Ib and IIIb surfaces to interact with the type IIa, Ia and IIIa surfaces of a downstream molecule, respectively. , Composite binding site for IRAK4 (yellow) formed from three MyD88 molecules (M3, M4 and M6) through type I, II and III interactions. , Enlargement of the square in . Note that the unique H1–H2 loop of MyD88 is critical for Myddosome assembly. , Composite binding site for IRAK2 (purple) formed from three IRAK4 molecules (I41, I42 and I44) through type I, II and III interactions. , Enlargement of the square in . , Good charge complementarity between IRAK4 and MyD88 and poor charge complementarity between the top and bottom surfaces of MyD88. , Good charge complementarity between IRAK2 and IRAK4 and very poor charge complementarity between the top and bottom surfaces of IRAK2. * Figure 3: Model of sequential assembly in TLR/IL1-R signalling. , On ligand binding, TLR/IL-1Rs, including the cytoplasmic TIR domains, are dimerized or oligomerized. This results in the recruitment of other TIR containing adaptor proteins. In this case, MyD88 is recruited to the receptor complex and the death domain is oligomerized. In the presence of IRAK4, the death domain of IRAK4 (I41) can be recruited to the oligomerized MyD88 DDs through the three interfaces (M3, M4, M6) and quickly forms the binary Myddosome complex. Downstream kinases (IRAK2 in this case, but IRAK1 as well) can then be recruited in a similar fashion and signalling is triggered. , A model of the TLR signalling complex that recruits the MyD88–IRAK4–IRAK2 complex with proteins drawn to scale. TLRs, cyan and green (PDB code 3FXI for the extracellular domain of TLR4 and PDB code 2J67 for the TIR domain of TLR10). MD2, yellow and magenta (PDB code 3FXI in complex TLR4). Orange, MyD88–IRAK4–IRAK2 complex. Red, IRAK4 kinase domain (PDB code 2NRU). Blue, IRAK2 ki! nase domain using that of IRAK4. * Figure 4: Common architecture in Drosophila Toll signalling and DD assembly in general. , Superposition of Tube–Pelle (green and cyan) and IRAK4–IRAK2 (yellow and brick red) complexes. , Model of the dMyD88–Tube–Pelle complex in both ribbon and surface representations. Pelle is coloured in cyan. Tube is coloured in green except that the H2–H3 loop insertion (H2′ and H2′′) is in blue and the H4–H5 loop is in yellow. The model of dMyD88, obtained based on the MyD88 DD structure but without modelling the insertion in the H1–H2 loop, is coloured in magenta except that the H1–H2 loop is in red. , Enlargement of the dMyD88–Tube interface. Residues important for dMyD88–Tube complex formation are shown in sticks. Note that the real H1–H2 loop of dMyD88 is six residues longer than that in the model. , Superposition of the type I, II and III interactions in the MyD88–IRAK4–IRAK2 and the PIDD–RAIDD complexes. The resultant angular differences are labelled. , Planar arrangement of the PIDD–RAIDD complex. R, RAIDD; P, PIDD. Subunits in on! e strand of the double helix are labelled as R and P and those in the other strand are labelled R′ and P′. , The helical symmetry is shown in a helical wheel representation with each ball representing a molecule and looking down the helical axis. Note that two helical strands are present in the complex. , Surface representations of the two helical strands in the PIDD–RAIDD complex. The lower strand is about 5 Å lower than the higher strand, but they can be superimposed well. The lower strand (left) plus the higher strand (middle) equals the PIDD–RAIDD complex (right). Accession codes * Abstract * Accession codes * Author information * Supplementary information * Comments Primary accessions Protein Data Bank * 3FXI * 2J67 * 2NRU * 3MOP * 3FXI * 2J67 * 2NRU * 3MOP Author information * Abstract * Accession codes * Author information * Supplementary information * Comments Affiliations * Department of Biochemistry, Weill Cornell Medical College, New York, New York 10021, USA * Su-Chang Lin, * Yu-Chih Lo & * Hao Wu Contributions H.W. initiated the project idea. S.-C.L. and Y.-C.L. designed and performed the experiments. S.-C.L. and H.W. interpreted the data and wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Hao Wu (haowu@med.cornell.edu) The atomic coordinates and structure factors have been deposited in the Protein Data Bank under accession code 3MOP. Supplementary information * Abstract * Accession codes * Author information * Supplementary information * Comments PDF files * Supplementary Information (10.1M) This file contains Supplementary Tables 1-4, Supplementary Figures 1-11 with legends and Supplementary Discussions 1-2. Additional data
• Diphthamide biosynthesis requires an organic radical generated by an iron–sulphur enzyme
  - Nature (London) 465(7300):891 (2010)
  Nature | Article Diphthamide biosynthesis requires an organic radical generated by an iron–sulphur enzyme * Yang Zhang1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Xuling Zhu1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew T. Torelli1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Lee2 Search for this author in: * NPG journals * PubMed * Google Scholar * Boris Dzikovski1 Search for this author in: * NPG journals * PubMed * Google Scholar * Rachel M. Koralewski1 Search for this author in: * NPG journals * PubMed * Google Scholar * Eileen Wang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jack Freed1 Search for this author in: * NPG journals * PubMed * Google Scholar * Carsten Krebs2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Steven E. Ealick1 Search for this author in: * NPG journals * PubMed * Google Scholar * Hening Lin1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:891–896Date published:(17 June 2010)DOI:doi:10.1038/nature09138Received06 December 2009Accepted30 April 2010 Abstract * Abstract * Accession codes * Author information * Supplementary information * Comments Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Archaeal and eukaryotic translation elongation factor 2 contain a unique post-translationally modified histidine residue called diphthamide, which is the target of diphtheria toxin. The biosynthesis of diphthamide was proposed to involve three steps, with the first being the formation of a C–C bond between the histidine residue and the 3-amino-3-carboxypropyl group of S-adenosyl-l-methionine (SAM). However, further details of the biosynthesis remain unknown. Here we present structural and biochemical evidence showing that the first step of diphthamide biosynthesis in the archaeon Pyrococcus horikoshii uses a novel iron–sulphur-cluster enzyme, Dph2. Dph2 is a homodimer and each of its monomers can bind a [4Fe–4S] cluster. Biochemical data suggest that unlike the enzymes in the radical SAM superfamily, Dph2 does not form the canonical 5′-deoxyadenosyl radical. Instead, it breaks the Cγ,Met–S bond of SAM and generates a 3-amino-3-carboxypropyl radical. Our results su! ggest that P. horikoshii Dph2 represents a previously unknown, SAM-dependent, [4Fe–4S]-containing enzyme that catalyses unprecedented chemistry. View full text Subject terms: * Biochemistry * Chemical biology Figures at a glance * Figure 1: The structure of diphthamide and its proposed biosynthesis pathway. The diphthamide residue is the target of bacterial ADP-ribosyltransferases, diphtheria toxin and Pseudomonas exotoxin A. EF2, translation elongation factor 2. * Figure 2: Structure of the PhDPH2 homodimer. Ribbon diagram of the PhDph2 homodimer with one monomer in dark colours and the other in light colours. Each monomer is also coloured according to secondary structure, with dark and light green for β-strands, dark and light blue for α-helices and violet and pink for 310 helices. The three conserved cysteine residues for each monomer are shown in the stick representation, in orange. * Figure 3: In vitro reconstitution of PhDph2 activity. , Activity assay using carboxy-14C-SAM: the top panel shows the Coomassie-blue-stained gel; the bottom panel shows the autoradiography. Lane 1: protein standard; lane 2: blank lane; lane 3: PhEF2 plus SAM, negative control; lane 4: PhDph2 plus SAM, negative control; lane 5: PhEF2 His600Ala plus PhDph2 plus SAM, negative control; lane 6: PhEF2 plus PhDph2 plus SAM plus dithionite; lane 7: PhEF2 plus PhDph2 plus SAM, no dithionite, negative control. , The matrix-assisted laser desorption/ionization mass spectra of PhEF2 unmodified (top) and modified by PhDph2 in an in vitro reaction (bottom). * Figure 4: Spectroscopic characterization of the [4Fe–4S] cluster in PhDph2. , Ultraviolet–visible absorption spectra of anaerobically isolated and dithionite-reduced PhDph2. , X-band EPR spectra of dithionite-reduced PhDph2 at different temperatures. , 4.2-K/53-mT Mössbauer spectrum of anaerobically isolated, 57Fe-labelled PhDph2 expressed in E. coli. The horizontal axis shows the velocity of the γ-ray source. , Structure of PhDph2 including the [4Fe–4S] cluster. C, green; O, red; N, blue; S, yellow; Fe, orange. Blue mesh represents two-fold NCS-averaged difference density map contoured at 10σ omitting the [4Fe–4S] cluster and the three covalently bonded cysteine sulphur atoms. * Figure 5: Identification of SAM-derived small-molecule products in PhDph2-catalysed reactions. , High-performance liquid chromatography analysis of reaction products suggests that PhDph2 does not form 5′-deoxyadenosine. , 1H NMR spectra showing that ABA and HSA formed in the reaction when PhEF2 was not present, but not in a control reaction in which PhDph2 was not present. The peaks from HSA and ABA are marked by blue and magenta arrows, respectively. f1, chemical shift in the F1 dimension. , Detection of dansylated reaction products by LC–MS. The mass spectroscopy (MS) traces (total ion counts (TIC) and ion counts for specific compounds) are shown for the reaction with PhDph2, the control reaction without PhDph2, and ABA and HSA standards. TIC is indicated by the axis value times the magnification number, either 1,000,000 or 100,000, whereas the specific ion counts are magnified by a factor of ten from their actual values. The m/z value for each specific ion is indicated in the upper left corner, and followed by the magnification number. For example, in the upper! panel, the specific ion for dansyl homoserine, m/z 353 (green), has ion count ~2,000,000 and its actual value is 200,000. * Figure 6: The proposed reaction mechanism for PhDph2. The formation of ABA and HSA can be best explained by an ACP radical intermediate. The radical can be generated by electron transfer from the [4Fe–4S] cluster, similar to the generation of a 5′-deoxyadenosyl radical in other radical SAM enzymes. In the presence of PhEF2, the radical will react with PhEF2 to form the modified PhEF2 product. In the absence of PhEF2, the radical can either abstract a hydrogen atom to form ABA or be quenched by dithionite to give HSA. Ade, adenosine base. Accession codes * Abstract * Accession codes * Author information * Supplementary information * Comments Primary accessions Protein Data Bank * 3LZC * 3LZD * 3LZC * 3LZD Author information * Abstract * Accession codes * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Yang Zhang & * Xuling Zhu Affiliations * Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA * Yang Zhang, * Xuling Zhu, * Andrew T. Torelli, * Boris Dzikovski, * Rachel M. Koralewski, * Eileen Wang, * Jack Freed, * Steven E. Ealick & * Hening Lin * Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA * Michael Lee & * Carsten Krebs * Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA * Carsten Krebs Contributions Y.Z. determined the crystal structure of iron-free PhDph2, X.Z. performed the biochemical studies and prepared protein samples for spectroscopic and structural studies, A.T.T. determined the crystal structure of anaerobically purified PhDph2, M.L. and C.K. performed the Mössbauer spectroscopy, B.D. and J.F. performed the EPR spectroscopy, R.M.K. prepared the initial PhDph2 crystals, E.W. prepared the PhEF2 mutant proteins, S.E.E. supervised the crystallographic studies, H.L. supervised the biochemical studies and H.L., S.E.E. and C.K. prepared the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Hening Lin (hl379@cornell.edu) or * Steven E. Ealick (see3@cornell.edu) Atomic coordinates and structure factors for the crystal structures reported here have been deposited with the Protein Data Bank under accession codes 3LZC for iron-free PhDph2 and 3LZD for reconstituted PhDph2. Supplementary information * Abstract * Accession codes * Author information * Supplementary information * Comments PDF files * Supplementary Information (9.7M) This file contains Supplementary Table 1 and Supplementary Figures 1-9 with legends. Additional data
• Size and albedo of Kuiper belt object 55636 from a stellar occultation
  - Nature (London) 465(7300):897 (2010)
  Nature | Letter Size and albedo of Kuiper belt object 55636 from a stellar occultation * J. L. Elliot1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * M. J. Person1 Search for this author in: * NPG journals * PubMed * Google Scholar * C. A. Zuluaga1 Search for this author in: * NPG journals * PubMed * Google Scholar * A. S. Bosh1 Search for this author in: * NPG journals * PubMed * Google Scholar * E. R. Adams1 Search for this author in: * NPG journals * PubMed * Google Scholar * T. C. Brothers1 Search for this author in: * NPG journals * PubMed * Google Scholar * A. A. S. Gulbis1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * S. E. Levine1, 5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * M. Lockhart1 Search for this author in: * NPG journals * PubMed * Google Scholar * A. M. Zangari1 Search for this author in: * NPG journals * PubMed * Google Scholar * B. A. Babcock7 Search for this author in: * NPG journals * PubMed * Google Scholar * K. DuPré8 Search for this author in: * NPG journals * PubMed * Google Scholar * J. M. Pasachoff8 Search for this author in: * NPG journals * PubMed * Google Scholar * S. P. Souza8 Search for this author in: * NPG journals * PubMed * Google Scholar * W. Rosing9 Search for this author in: * NPG journals * PubMed * Google Scholar * N. Secrest10 Search for this author in: * NPG journals * PubMed * Google Scholar * L. Bright3 Search for this author in: * NPG journals * PubMed * Google Scholar * E. W. Dunham3 Search for this author in: * NPG journals * PubMed * Google Scholar * S. S. Sheppard11 Search for this author in: * NPG journals * PubMed * Google Scholar * M. Kakkala12 Search for this author in: * NPG journals * PubMed * Google Scholar * T. Tilleman5 Search for this author in: * NPG journals * PubMed * Google Scholar * B. Berger13 Search for this author in: * NPG journals * PubMed * Google Scholar * J. W. Briggs13, 14 Search for this author in: * NPG journals * PubMed * Google Scholar * G. Jacobson13 Search for this author in: * NPG journals * PubMed * Google Scholar * P. Valleli13 Search for this author in: * NPG journals * PubMed * Google Scholar * B. Volz13 Search for this author in: * NPG journals * PubMed * Google Scholar * S. Rapoport15 Search for this author in: * NPG journals * PubMed * Google Scholar * R. Hart16 Search for this author in: * NPG journals * PubMed * Google Scholar * M. Brucker17 Search for this author in: * NPG journals * PubMed * Google Scholar * R. Michel18 Search for this author in: * NPG journals * PubMed * Google Scholar * A. Mattingly19 Search for this author in: * NPG journals * PubMed * Google Scholar * L. Zambrano-Marin20 Search for this author in: * NPG journals * PubMed * Google Scholar * A. W. Meyer21 Search for this author in: * NPG journals * PubMed * Google Scholar * J. Wolf22 Search for this author in: * NPG journals * PubMed * Google Scholar * E. V. Ryan23 Search for this author in: * NPG journals * PubMed * Google Scholar * W. H. Ryan23 Search for this author in: * NPG journals * PubMed * Google Scholar * K. Morzinski24 Search for this author in: * NPG journals * PubMed * Google Scholar * B. Grigsby24 Search for this author in: * NPG journals * PubMed * Google Scholar * J. Brimacombe25 Search for this author in: * NPG journals * PubMed * Google Scholar * D. Ragozzine26 Search for this author in: * NPG journals * PubMed * Google Scholar * H. G. Montano27 Search for this author in: * NPG journals * PubMed * Google Scholar * A. Gilmore28 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:897–900Date published:(17 June 2010)DOI:doi:10.1038/nature09109Received02 February 2010Accepted16 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The Kuiper belt is a collection of small bodies (Kuiper belt objects, KBOs) that lie beyond the orbit of Neptune and which are believed to have formed contemporaneously with the planets. Their small size and great distance make them difficult to study. KBO 55636 (2002 TX300) is a member of the water-ice-rich Haumea KBO collisional family1. The Haumea family are among the most highly reflective objects in the Solar System. Dynamical calculations indicate that the collision that created KBO 55636 occurred at least 1 Gyr ago2, 3. Here we report observations of a multi-chord stellar occultation by KBO 55636, which occurred on 9 October 2009 ut. We find that it has a mean radius of 143 ± 5 km (assuming a circular solution). Allowing for possible elliptical shapes, we find a geometric albedo of in the V photometric band, which establishes that KBO 55636 is smaller than previously thought and that, like its parent body, it is highly reflective. The dynamical age implies ei! ther that KBO 55636 has an active resurfacing mechanism, or that fresh water-ice in the outer Solar System can persist for gigayear timescales. View full text Subject terms: * Astronomy * Astrophysics * Planetary sciences Figures at a glance * Figure 1: Light curves for KBO 55636. , The light curve from the Faulkes North 2.0-m telescope at Haleakala, Maui, plotted relative to the mid-time of the event according to the data-computer time at Haleakala (DCT1). An Andor Luca-R camera recorded a series of CCD frames of the field surrounding the occulted star. The sub-frame field was 90 × 90 arcsec (250 × 251 pixels), and no filter was used. Data recording started at 10:23:35.000 (DCT1) and lasted for 17.15 min. The light curve was constructed by computing the ratio of the observed flux from the occultation star to the total signal from three stars in the field. The unfiltered observations had an effective wavelength of ~700 nm. , The light curve from a 0.36-m portable telescope at the Mauna Kea Mid Level, plotted relative to the mid-time of the event according to the data-computer time of the Mauna Kea Mid Level (DCT2). An SBIG ST-2000XM camera (field size: 14 × 10.5 arcmin; 1,600 × 1,200 pixels) was used with an Astrodon Lu! minance near-infrared-blocking filter30 that cuts off wavelengths longer than 700 nm. Data recording started at 10:27:29 (DCT2) and lasted for 13.5 min. The light curve was constructed by computing the ratio of the observed flux from the occultation star to the total signal from five stars in the field. , The light curve from the Leeward Community College 0.50-m telescope and a POETS camera (unfiltered). The field of view was 7 × 7 arcmin. The recording started at 10:17:40 ut (12 min before the predicted mid-time6) and lasted 24 min. The light curve was constructed by computing the ratio of the observed flux from the occultation star to the total signal from eight stars in the field. No occultation event is seen in the data. More details of the data recording at these and other stations are contained in Table 1 and Supplementary Table 2. * Figure 2: Occultation chords and the radius of KBO 55636. , The two solid lines represent the two observed occultation chords, plotted in the shadow plane and centred on KBO 55636. Alignment of the chords requires that 32.95 s be subtracted from the data-computer time (DCT2) at the Mauna Kea Mid Level, but whether we would subtract the time shift from DCT2 or add it to DCT1 does not affect the results of the analysis. The arrow illustrates the derived radius for KBO 55636 of 143 ± 5 km under the assumption of a circular figure in the sky plane (see text and Supplementary Information section 5B for a discussion of elliptical figures). The ±5 km error (1 s.d.) in the radius arises solely from the errors in the model fit for the duration of the Mauna Kea Mid Level light curve (Table 1) and corresponds to the size of the points plotted at the ends of the chords. , The three solid lines represent the southern edge, centre line and northern edge of KBO 55636's occultation shadow, assuming a circular body. The positions of! our observing stations at Leeward Community College, Haleakala, and the Mauna Kea (MK) Mid Level are indicated. Although the sky was clear and data were recorded, no occultation was seen at Leeward Community College. Author information * Author information * Supplementary information * Comments Affiliations * Department of Earth, Atmospheric, and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA * J. L. Elliot, * M. J. Person, * C. A. Zuluaga, * A. S. Bosh, * E. R. Adams, * T. C. Brothers, * A. A. S. Gulbis, * S. E. Levine, * M. Lockhart & * A. M. Zangari * Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA * J. L. Elliot * Lowell Observatory, Flagstaff, Arizona 86001, USA * J. L. Elliot, * L. Bright & * E. W. Dunham * Southern Africa Large Telescope and South African Astronomical Observatory, PO Box 9, 8935, Cape Town, South Africa * A. A. S. Gulbis * United States Naval Observatory (USNO), Flagstaff, Arizona 86001, USA * S. E. Levine & * T. Tilleman * American Association of Variable Star Observers, Cambridge, Massachusetts 02138, USA * S. E. Levine * Physics Department, Williams College, Williamstown, Massachusetts 01267, USA * B. A. Babcock * Astronomy Department, Williams College, Williamstown, Massachusetts 01267, USA * K. DuPré, * J. M. Pasachoff & * S. P. Souza * Las Cumbres Observatory Global Telescope Network, Santa Barbara, California 93117, USA * W. Rosing * University of Hawai'i, Hilo, Hawai'i 96720-4091, USA * N. Secrest * Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington DC 20015, USA * S. S. Sheppard * Department of Geology, University of Hawai'i, Leeward Community College, Pearl City, Hawai'i 96782, USA * M. Kakkala * Amateur Telescope Makers of Boston, Westford, Massachusetts 01886, USA * B. Berger, * J. W. Briggs, * G. Jacobson, * P. Valleli & * B. Volz * Dexter-Southfield Schools, Brookline, Massachusetts 02145, USA * J. W. Briggs * Research School of Astronomy and Astrophysics, Mt Stromlo Observatory, Weston Creek, Australian Capital Territory 2611, Australia * S. Rapoport * Mt Kent Observatory, University of Southern Queensland, Toowoomba, Queensland 4350, Australia * R. Hart * Department of Physics & Astronomy, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, USA * M. Brucker * Instituto de Astronomía, Universidad Nacional Autónoma de México, Apartado Postal 877, 22800 Ensenada, Baja California, Mexico * R. Michel * IBM, St Leonards, New South Wales 2065, Australia * A. Mattingly * Nompuewenu Observatory, University of Texas Brownsville/Texas Southmost College, Brownsville, Texas 78520, USA * L. Zambrano-Marin * SOFIA, Universities Space Research Association, NASA Ames, Moffett Field, California 94035, USA * A. W. Meyer * SOFIA, Deutsches SOFIA Institute, NASA Ames, Moffett Field, California 94035, USA * J. Wolf * Magdalena Ridge Observatory, New Mexico Tech, Socorro, New Mexico 87801, USA * E. V. Ryan & * W. H. Ryan * Department of Astronomy and Astrophysics, University of California, Santa Cruz, California 95064, USA * K. Morzinski & * B. Grigsby * James Cook University, Cairns, Queensland 4870, Australia * J. Brimacombe * Harvard-Smithsonian Center for Astrophysics, Cambridge, Massachusetts 02138, USA * D. Ragozzine * Observatorio Astronómico, Universidad Nacional Autónoma de Nicaragua, Managua, Nicaragua * H. G. Montano * Mt John University Observatory, Lake Tekapo 7945, New Zealand * A. Gilmore Contributions J.L.E. helped plan the observations, consulted on the occultation prediction, analysed the data, and wrote the paper. M.J.P. organized the observers, performed observations from Brownsville, Texas, and consulted on the prediction, data reduction, text and figures. C.A.Z. analysed the data for the stellar occultation prediction and constructed the light curves. A.S.B. directed the data analysis for the occultation prediction. E.R.A. wrote the light-curve generation software. S.E.L. made astrometric observations and performed observations of the occultation from the USNO in Flagstaff. M.L. designed and built 12 PICO camera systems and attempted observations from Cairns. J.M.P. arranged for observations at several sites and helped to plan the observations. S.P.S. consulted on the design of the PICO. L.B., E.W.D., S.S.S. and T.T. supplied astrometric data for the occultation prediction. D.R. provided information used to derive the geometric albedo of KBO 55636. Authors identifie! d in Supplementary Table 2 were responsible for the observations. All authors were given the opportunity to review the results and comment on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * J. L. Elliot (jle@mit.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (1.2M) This file contains Supplementary Information and Data, Supplementary Tables 1-5, Supplementary Figures 1-3 with legends and References. Additional data
• Real-space observation of a two-dimensional skyrmion crystal
  - Nature (London) 465(7300):901 (2010)
  Nature | Letter Real-space observation of a two-dimensional skyrmion crystal * X. Z. Yu1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Y. Onose2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * N. Kanazawa3 Search for this author in: * NPG journals * PubMed * Google Scholar * J. H. Park4 Search for this author in: * NPG journals * PubMed * Google Scholar * J. H. Han4 Search for this author in: * NPG journals * PubMed * Google Scholar * Y. Matsui1 Search for this author in: * NPG journals * PubMed * Google Scholar * N. Nagaosa3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Y. Tokura2, 3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:901–904Date published:(17 June 2010)DOI:doi:10.1038/nature09124Received27 January 2010Accepted23 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Crystal order is not restricted to the periodic atomic array, but can also be found in electronic systems such as the Wigner crystal1 or in the form of orbital order2, stripe order3 and magnetic order. In the case of magnetic order, spins align parallel to each other in ferromagnets and antiparallel in antiferromagnets. In other, less conventional, cases, spins can sometimes form highly nontrivial structures called spin textures4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23. Among them is the unusual, topologically stable skyrmion spin texture, in which the spins point in all the directions wrapping a sphere4, 5, 6, 7. The skyrmion configuration in a magnetic solid is anticipated to produce unconventional spin–electronic phenomena such as the topological Hall effect24, 25, 26. The crystallization of skyrmions as driven by thermal fluctuations has recently been confirmed in a narrow region of the temperature/magnetic field (T–B) phase diagram in ! neutron scattering studies of the three-dimensional helical magnets MnSi (ref. 17) and Fe1−xCoxSi (ref. 22). Here we report real-space imaging of a two-dimensional skyrmion lattice in a thin film of Fe0.5Co0.5Si using Lorentz transmission electron microscopy. With a magnetic field of 50–70 mT applied normal to the film, we observe skyrmions in the form of a hexagonal arrangement of swirling spin textures, with a lattice spacing of 90 nm. The related T–B phase diagram is found to be in good agreement with Monte Carlo simulations. In this two-dimensional case, the skyrmion crystal seems very stable and appears over a wide range of the phase diagram, including near zero temperature. Such a controlled nanometre-scale spin topology in a thin film may be useful in observing unconventional magneto-transport effects. View full text Subject terms: * Materials science * Applied physics * Methods * Materials * Engineering Figures at a glance * Figure 1: Topological spin textures in the helical magnet Fe0.5Co0.5Si. , , Helical () and skyrmion () structures predicted by Monte Carlo simulation. , Schematic of the spin configuration in a skyrmion. –, The experimentally observed real-space images of the spin texture, represented by the lateral magnetization distribution as obtained by TIE analysis of the Lorentz TEM data: helical structure at zero magnetic field (), the skyrmion crystal (SkX) structure for a weak magnetic field (50 mT) applied normal to the thin plate () and a magnified view of (). The colour map and white arrows represent the magnetization direction at each point. * Figure 2: Variations of spin texture with magnetic field and temperature in Fe0.5Co0.5Si. –, Magnetic-field dependence of the spin texture, in real-space Lorentz TEM (overfocus) images. –, FFT patterns corresponding to –. –, Temperature profiles of the distribution map of the lateral magnetization for a magnetic field of 50 mT. Magnetic fields were applied normal to the (001) thin film. The colour wheel represents the magnetization direction at every point. * Figure 3: Phase diagrams of magnetic structure and spin textures in a thin film of Fe0.5Co0.5Si. –, Spin textures observed using Lorentz TEM obtained by Monte Carlo simulation. –, Spin textures after TEM. H, helical structure; SkX, skyrmion crystal structure; FM, ferromagnetic structure. , , Observed () and calculated () phase diagrams in the B–T plane. The magnetic field was applied perpendicular to the image plane. In , B and T are normalized using the arbitrary constants BC and TC. The colour bars in the phase diagrams indicate the skyrmion density per 10−12 m2 () and per d2 (), d being the helical spin wavelength. Dashed lines show the phase boundaries between the SkX, H and FM phases. Stars in and indicate (T, B) conditions for the images shown in – and –, respectively. Author information * Author information * Supplementary information * Comments Affiliations * Advanced Electron Microscopy Group and High Voltage Electron Microscopy Station, National Institute for Materials Science, Tsukuba 305-0044, Japan * X. Z. Yu & * Y. Matsui * Multiferroics Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Tokyo 113-8656, Japan * X. Z. Yu, * Y. Onose & * Y. Tokura * Department of Applied Physics, University of Tokyo, Tokyo 113-8656, Japan * Y. Onose, * N. Kanazawa, * N. Nagaosa & * Y. Tokura * Department of Physics, Sung Kyun Kwan University, Suwon 440-746, Korea * J. H. Park & * J. H. Han * Cross-Correlated Materials Research Group and Correlated Electron Research Group, RIKEN-ASI, Wako 351-0198, Japan * N. Nagaosa & * Y. Tokura Contributions Y.T. contributed to the planning of the study and the writing of the paper. X.Z.Y. and Y.M. performed the Lorentz TEM observations and wrote the experimental section of the paper. Y.O. and N.K. grew the sample crystal and contributed to the assignment of the Lorentz TEM images. J.H.P., J.H.H. and N.N. did the calculations and wrote a significant part of the discussion. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * X. Z. Yu (yu.xiuzhen@nims.go.jp) or * Y. Tokura (tokura@ap.t.u-tokyo.ac.jp) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary information (1.1M) This file contains Supplementary Methods, Supplementary Data, References and Supplementary Figures 1-4 with legends. Additional data
• Visualizing and controlling vibrational wave packets of single molecules
  - Nature (London) 465(7300):905 (2010)
  Nature | Letter Visualizing and controlling vibrational wave packets of single molecules * Daan Brinks1 Search for this author in: * NPG journals * PubMed * Google Scholar * Fernando D. Stefani1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Florian Kulzer1 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard Hildner1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tim H. Taminiau1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yuri Avlasevich2 Search for this author in: * NPG journals * PubMed * Google Scholar * Klaus Müllen2 Search for this author in: * NPG journals * PubMed * Google Scholar * Niek F. van Hulst1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:905–908Date published:(17 June 2010)DOI:doi:10.1038/nature09110Received24 November 2009Accepted20 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The active steering of the pathways taken by chemical reactions and the optimization of energy conversion processes1, 2, 3 provide striking examples of the coherent control of quantum interference through the use of shaped laser pulses. Experimentally, coherence is usually established by synchronizing a subset of molecules in an ensemble4, 5, 6, 7 with ultra-short laser pulses8. But in complex systems where even chemically identical molecules exist with different conformations and in diverse environments, the synchronized subset will have an intrinsic inhomogeneity that limits the degree of coherent control that can be achieved. A natural—and, indeed, the ultimate—solution to overcoming intrinsic inhomogeneities is the investigation of the behaviour of one molecule at a time. The single-molecule approach9, 10 has provided useful insights into phenomena as diverse as biomolecular interactions11, 12, 13, cellular processes14 and the dynamics of supercooled liquids15 and co! njugated polymers16. Coherent state preparation of single molecules has so far been restricted to cryogenic conditions17, whereas at room temperature only incoherent vibrational relaxation pathways have been probed18. Here we report the observation and manipulation of vibrational wave-packet interference in individual molecules at ambient conditions. We show that adapting the time and phase distribution of the optical excitation field to the dynamics of each molecule results in a high degree of control, and expect that the approach can be extended to achieve single-molecule coherent control in other complex inhomogeneous systems. View full text Subject terms: * Applied physics * Engineering * Methods * Materials Figures at a glance * Figure 1: Ultrafast coherent excitation of single molecules. , Spectra of the fluorophore (DNQDI29; dissolved in toluene) and broad-band excitation laser used (see Methods). , Single fluorescent molecules were imaged and investigated in an epi-confocal microscope. Each individual molecule was excited with tailored sequences of 15-fs (full-width at half-maximum) pulses defined by the inter-pulse time delay Δt and phase shift φ. Both Δt and φ were controlled with a double-pass 4f pulse shaper based on a spatial light modulator. , The fluorescence intensity of the single molecules was recorded for different combinations of Δt and φ (for example, (Δti, φi), (Δtk, φk), and so on), which were applied sequentially, separated by periods of no illumination and repeated until the molecule photobleached. * Figure 2: Single-molecule wave-packet interference. , Fluorescence images of single molecules excited with two mutually delayed (Δt), phase-locked laser pulses. , Integrated intensity as a function of Δt for the fluorescence emission of the three molecules marked in . A typical background trace is shown for reference. The traces are normalized to their respective average in order to visualize fluctuations in the intensity. Error bars, ±1 s.d. , Averaged response of 52 molecules compared to the theoretical prediction based on the bulk absorption spectrum. , Result of the Fourier analysis of 52 single-molecule traces. Distributions and scatter plot of the main frequency component (f) and its corresponding phase (θ). Marker size and bin width include the experimental errors. * Figure 3: Phase control of single-molecule wave packets. Single-molecule fluorescence intensity as a function of the time delay between two in-phase (φ = 0) and in-antiphase (φ = π) excitation pulses. The excitation intensity was constant for all (Δt, φ) combinations except for the (excluded) points near zero delay with φ = π. , The fits to the (φ = 0) and (φ = π) traces are based on the bulk absorption spectrum. Fourier analysis of the fits shows that f = 31 THz in both traces and the difference in θ is π. , Some molecules present fluctuations even for time delays Δt as long as 120 fs and with more than one frequency component. Error bars, ±1 s.d. * Figure 4: Single-molecule time-phase coherent excitation maps. –, Time-phase fluorescence excitation maps of four different molecules excited with a four-pulse sequence. Δt and φ are the time delay and phase shift between each consecutive pulse in the sequence. The fluorescence intensity (colour scale) is normalized to the average. The maximum/minimum ratio, that is, the contrast achievable through control of coherent excitation, is shown in the upper right corner of each plot. Author information * Author information * Comments Affiliations * ICFO—Institut de Ciencies Fotoniques, Mediterranean Technology Park, 08860 Castelldefels (Barcelona), Spain * Daan Brinks, * Fernando D. Stefani, * Florian Kulzer, * Richard Hildner, * Tim H. Taminiau & * Niek F. van Hulst * Max Planck Institute for Polymer Research, Ackermannweg 10, D-55128 Mainz, Germany * Yuri Avlasevich & * Klaus Müllen * ICREA—Institució Catalana de Recerca i Estudis Avançats, 08015 Barcelona, Spain * Niek F. van Hulst * Present address: Departamento de Física & Instituto de Física de Buenos Aires (IFIBA, CONICET), Universidad de Buenos Aires, Pab. I Ciudad Universitaria, 1428 Buenos Aires, Argentina. * Fernando D. Stefani Contributions D.B., F.D.S. and N.F.v.H. conceived and designed the experiments. D.B., F.K. and R.H. constructed the experimental set-up. D.B. and F.D.S. carried out the measurements and analysis. D.B., F.D.S. and T.H.T. performed control experiments. Y.A. and K.M. provided the fluorescent molecules. F.D.S., D.B. and N.F.v.H. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Fernando D. Stefani (Fernando.Stefani@df.uba.ar) or * Niek F. van Hulst (Niek.vanHulst@ICFO.es) Additional data
• Massive volcanic SO2 oxidation and sulphate aerosol deposition in Cenozoic North America
  - Nature (London) 465(7300):909 (2010)
  Nature | Letter Massive volcanic SO2 oxidation and sulphate aerosol deposition in Cenozoic North America * Huiming Bao1 Search for this author in: * NPG journals * PubMed * Google Scholar * Shaocai Yu2 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel Q. Tong3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:909–912Date published:(17 June 2010)DOI:doi:10.1038/nature09100Received06 May 2009Accepted13 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Volcanic eruptions release a large amount of sulphur dioxide (SO2) into the atmosphere1, 2. SO2 is oxidized to sulphate and can subsequently form sulphate aerosol3, which can affect the Earth's radiation balance, biologic productivity and high-altitude ozone concentrations, as is evident from recent volcanic eruptions4. SO2 oxidation can occur via several different pathways that depend on its flux and the atmospheric conditions3. An investigation into how SO2 is oxidized to sulphate—the oxidation product preserved in the rock record—can therefore shed light on past volcanic eruptions and atmospheric conditions. Here we use sulphur and triple oxygen isotope measurements of atmospheric sulphate extracted from tuffaceous deposits to investigate the specific oxidation pathways from which the sulphate was formed. We find that seven eruption-related sulphate aerosol deposition events have occurred during the mid-Cenozoic era (34 to 7 million years ago) in the northern High Pla! ins, North America. Two extensively sampled ash beds display a similar sulphate mixing pattern that has two distinct atmospheric secondary sulphates. A three-dimensional atmospheric sulphur chemistry and transport model study reveals that the observed, isotopically discrete sulphates in sediments can be produced only in initially alkaline cloudwater that favours an ozone-dominated SO2 oxidation pathway in the troposphere. Our finding suggests that, in contrast to the weakly acidic conditions today5, cloudwater in the northern High Plains may frequently have been alkaline during the mid-Cenozoic era. We propose that atmospheric secondary sulphate preserved in continental deposits represents an unexploited geological archive for atmospheric SO2 oxidation chemistry linked to volcanism and atmospheric conditions in the past. View full text Subject terms: * Earth sciences * Geology * Geophysics * Environmental science * Climate science Figures at a glance * Figure 1: Geological context of the samples. Location of the northern High Plains, North America and a composite Eocene–Oligocene–Miocene stratigraphy with seven 17O-anomalous (Δ17O > +1.4‰) sulphate deposition events recorded in tuffaceous beds. Solid bars indicate the relative positions of these ash beds. See the Supplementary Information for sources of the assigned numerical ages. Fm, Formation; CPF, Chamberlain Pass Formation; PPM, Peanut Peak Member; BCCM, Big Cottonwood Creek Member; MC-H Fm, Monroe Creek-Harrison Formation. The two events in bold black, at 28 and 34 Myr ago, are the focus of this study. * Figure 2: Three sulphate endmember mixings. Relationships between three sulphate stable isotope parameters—Δ17O and δ18O (both in ‰ VSMOW) and δ34S (in ‰ VCDT)—for sulphates extracted from the mid-Gering ash bed in the Wildcat Ridge area, Nebraska (–) and the J ash bed at Pete Smith Hill, Nebraska (–). (In each of panels –, there is also one datum point from Alcova, Wyoming.) There are two sets of sulphates: small blue diamonds for water extraction and large red squares for HCl extraction. Error bars (s.d.) are equal to or smaller than symbols. Superimposed triangles represent the endmember sulphate positions E1, E2 and E3 for the two ash beds, respectively (Supplementary Table 4). VSMOW, Vienna Standard Mean Ocean Water; VCDT, Vienna Canyon Diablo Troilite. * Figure 3: Modelling results on sulphate fluxes and Δ17O values. Total column (0 to 2 km above the surface) sulphate flux (solid black) and Δ17O value (dashed red) over time in western Nebraska, obtained from a three-dimensional atmospheric sulphur chemical-transport model, assuming a constant SO2 emission rate of 5 million tons a day from an eruption in north-central Colorado, background cloudwater of pH = 6 (upper), 7 (middle), and 8 (lower), and [Fe2+] and [Mn2+] = 10−5 μg m−3. Author information * Author information * Supplementary information * Comments Affiliations * Department of Geology and Geophysics, Louisiana State University, Baton Rouge, Louisiana 70803-4101, USA * Huiming Bao * Atmospheric Modeling and Analysis Division (E243-03), National Exposure Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA * Shaocai Yu * Air Resources Laboratory, National Oceanic and Atmospheric Administration, Silver Springs, Maryland 20910, USA * Daniel Q. Tong Contributions H.B. designed the research, and did field and laboratory studies. S.Y. and D.Q.T. did the three-dimensional sulphur oxidation and transport modelling study. H.B. wrote the manuscript. All authors contributed to manuscript revisions. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Huiming Bao (bao@lsu.edu) or * Shaocai Yu (yu.shaocai@epa.gov) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (593K) This file contains Supplementary Tables S1-S5, Supplementary Methods, Supplementary Figures S1-S8 with legends and References. Additional data
• The importance of rift history for volcanic margin formation
  - Nature (London) 465(7300):913 (2010)
  Nature | Letter The importance of rift history for volcanic margin formation * John J. Armitage1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jenny S. Collier1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tim A. Minshull2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:913–917Date published:(17 June 2010)DOI:doi:10.1038/nature09063Received20 November 2009Accepted26 March 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Rifting and magmatism are fundamental geological processes that shape the surface of our planet. A relationship between the two is widely acknowledged but its precise nature has eluded geoscientists and remained controversial. Largely on the basis of detailed observations from the North Atlantic Ocean, mantle temperature was identified as the primary factor controlling magmatic production1, with most authors seeking to explain observed variations in volcanic activity at rifted margins in terms of the mantle temperature at the time of break-up2, 3. However, as more detailed observations have been made at other rifted margins worldwide, the validity of this interpretation and the importance of other factors in controlling break-up style have been much debated4, 5, 6, 7. One such observation is from the northwest Indian Ocean, where, despite an unequivocal link between an onshore flood basalt province, continental break-up and a hot-spot track leading to an active ocean island ! volcano, the associated continental margins show little magmatism5, 8. Here we reconcile these observations by applying a numerical model that accounts explicitly for the effects of earlier episodes of extension. Our approach allows us to directly compare break-up magmatism generated at different locations and so isolate the key controlling factors. We show that the volume of rift-related magmatism generated, both in the northwest Indian Ocean and at the better-known North Atlantic margins, depends not only on the mantle temperature but, to a similar degree, on the rift history. The inherited extensional history can either suppress or enhance melt generation, which can explain previously enigmatic observations. View full text Subject terms: * Earth sciences Figures at a glance * Figure 1: Geological setting and model results for the northwest Indian Ocean. , Gravity anomaly map showing the location of the conjugate Seychelles and Laxmi Ridge margin profiles. The black region marks the flood basalts of the Deccan Traps. 1 mGal = 10−3 cm s−2. , Temperature and mantle depletion (trace element X, Methods) with melt fraction at the centre of extension before break-up of the Seychelles/Laxmi ridge margin (64.6 Myr ago), from our preferred two-rift model. The location of the Gop rift is marked by the white triangle and that of the Seychelles/Laxmi ridge break-up is marked by the black triangle. In the lower plot, we show the extent of the melt region (dotted line) and the 1% and 2% melt fraction contours (dashed and solid lines, respectively). , , Predicted igneous crustal thickness () and predicted average lower-crustal seismic velocity () over time, assuming that the lithosphere was initially underlain by a 50-km-thick thermal anomaly at 200 °C. The blue curve is for a model in which there is a single rift event 64.5!  Myr ago (half-spreading rate, 60 mm yr−1) and the red curve is for a model with two rift events, one 71 Myr ago (half-spreading rate, 80 mm yr−1) and the other 64.5 Myr ago20. In the double-rift model, the Gop rift taps the thermal anomaly and the subsequent melting in the Seychelles/Laxmi ridge margin is of a slightly depleted mantle8. Open circles, filled circles and open triangles respectively mark the observed igneous crustal thickness () or the average lower-crustal seismic velocity () from the Gop rift, the Laxmi ridge and the Seychelles margins5, 8. Uncertainties in the observations are representative values taken from ref. 8. * Figure 2: Geological setting and model results for the North Atlantic Ocean. , Gravity anomaly map showing the location of the conjugate southeast Greenland and Hatton Bank margin profiles24, 25. The black regions mark the North Atlantic igneous province: the flood basalts of the East Greenland Traps and the British Tertiary volcanic province (BTVP). , Temperature and mantle depletion with melt fraction, contoured as in Fig. 1, at the centre of extension before break-up (59.3 Myr ago), from our preferred model that considers the Hatton Basin opening. The location of the Hatton Basin is marked by the white triangle and that of the southeast Greenland/Hatton Bank break-up is marked by the black triangle. In the model there is a 50-km-thick thermal anomaly at 200 °C beneath the lithosphere. , , Predicted igneous crustal thickness () and predicted average lower-crustal seismic velocity () over time. Uncertainties in the observations are representative values taken from ref. 25. In each panel, the top plot assumes that the lithosphere is of uniform, ! 125-km thickness at the start of rifting between the Hatton Bank and southeast Greenland, and the bottom plot includes previous extension of the Hatton Basin that ceases 80 Myr ago. To account for competing models for the observed spreading rates, we show two alternative scenarios with half-spreading rates between Hatton Bank and Greenland that are 20 mm yr−1 (blue) and 40 mm yr−1 (red) for the first 4 Myr and then decrease to 10 mm yr−1 (refs 18, 25). Open and filled circles respectively mark the observed igneous crustal thickness () and the average lower-crustal seismic velocity () from the Sigma III (southeast Greenland) and iSIMM (Hatton Bank) surveys24, 25. * Figure 3: Rift history controls magmatism at a rifted margin. , Northwest Indian Ocean. The first episode of extension tapped the thermal anomaly, which is associated with the Deccan Traps. This formed the Gop rift and exhausted the thermal anomaly beneath the region of extension. The second episode of extension that led to break-up was above melt-depleted mantle and led to the amagmatic Seychelles/Laxmi ridge margin. , North Atlantic. The first episode of extension formed the Hatton Bank. During the inter-rift period, the thermal anomaly ponded beneath the lithosphere, such that during the second episode of extension this thermal anomaly was tapped, leading to the high volumes of melt generated during the break-up of southeast Greenland from the Hatton Bank. * Figure 4: The influence of rift history on melt generation during continental break-up. , Peak igneous crustal thickness for extension at different half-spreading rates. In all model runs, break-up is achieved by a single, continuous extensional event. The four curves show cases for the arrival of a 50-km-thick thermal anomaly at 200 °C at different times after the initiation of extension. , Peak break-up igneous thickness for a two-phase rift event. Extension is at the same half-spreading rate for both phases of rifting and the first extensional phase lasts for 5 Myr. There is a lateral migration of 100 km before the onset of the second extensional phase, which follows either immediately or after a time lag. The curves are labelled according to the arrival time of the hot layer (measured from the start of each model run), with the thermal anomaly arriving either at the start of phase one (dashed line) or the start of phase two (solid lines: 5 Myr, no time lag; 15 Myr, time lag = 10 Myr; 25 Myr, time lag = 20 Myr). Author information * Author information * Supplementary information * Comments Affiliations * Department of Earth Science & Engineering, Imperial College London, London SW7 2AZ, UK * John J. Armitage & * Jenny S. Collier * National Oceanography Centre, Southampton, University of Southampton, Southampton SO14 3ZH, UK * Tim A. Minshull Contributions J.J.A. designed and performed the numerical experiments. J.J.A., J.S.C. and T.A.M. analysed the geophysical and numerical results, and contributed equally to the writing of the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * John J. Armitage (j.armitage@imperial.ac.uk) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (249K) This file contains Supplementary Data, Supplementary Figures S1-S2 with legends, Supplementary Table S1and References Additional data
• Ecological interactions are evolutionarily conserved across the entire tree of life
  Gómez JM Verdú M Perfectti F - Nature (London) 465(7300):918 (2010)
  Nature | Letter Ecological interactions are evolutionarily conserved across the entire tree of life * José M. Gómez1 Search for this author in: * NPG journals * PubMed * Google Scholar * Miguel Verdú2 Search for this author in: * NPG journals * PubMed * Google Scholar * Francisco Perfectti3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:918–921Date published:(17 June 2010)DOI:doi:10.1038/nature09113Received02 February 2010Accepted22 April 2010Published online02 June 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Ecological interactions are crucial to understanding both the ecology and the evolution of organisms1, 2. Because the phenotypic traits regulating species interactions are largely a legacy of their ancestors, it is widely assumed that ecological interactions are phylogenetically conserved, with closely related species interacting with similar partners2. However, the existing empirical evidence is inadequate to appropriately evaluate the hypothesis of phylogenetic conservatism in ecological interactions, because it is both ecologically and taxonomically biased. In fact, most studies on the evolution of ecological interactions have focused on specialized organisms, such as some parasites or insect herbivores3, 4, 5, 6, 7, belonging to a limited subset of the overall tree of life. Here we study the evolution of host use in a large and diverse group of interactions comprising both specialist and generalist acellular, unicellular and multicellular organisms. We show that, as prev! iously found for specialized interactions, generalized interactions can be evolutionarily conserved. Significant phylogenetic conservatism of interaction patterns was equally likely to occur in symbiotic and non-symbiotic interactions, as well as in mutualistic and antagonistic interactions. Host-use differentiation among species was higher in phylogenetically conserved clades, irrespective of their generalization degree and taxonomic position within the tree of life. Our findings strongly suggest a shared pattern in the organization of biological systems through evolutionary time, mediated by marked conservatism of ecological interactions among taxa. View full text Subject terms: * Evolution Figures at a glance * Figure 1: How to study the evolution of both specialized and generalized interactions. , In specialized clades, each species (numbered tips in the phylogeny) interacts with a single host. Species are grouped according to the host used. Phylogenetic conservatism is determined by mapping such groups onto the phylogeny. , In contrast, grouping species according to host use is more complex in generalized clades. Network analysis allows the detection of modules, which are groups of species sharing more hosts among themselves than they do with species in other modules. Phylogenetic conservatism of host use is determined by mapping such modules onto the phylogeny. Consequently, this method allows the exploration of the evolutionary conservatism of ecological interactions in all types of system, irrespective of their degree of generalization or host specificity. * Figure 2: Differences between phylogenetically conserved and non-conserved clades in average host range per clade and modularity. , The occurrence of phylogenetic conservatism was not related to host range, indicating that, irrespective of the type of organism or interaction, the degree of generalization (quantitatively estimated as host range) was independent of the phylogenetic conservatism of the interactions. , In contrast, the modularity index was consistently higher in phylogenetically conserved interactions, indicating that in these systems there was a decrease in the sharing of hosts among modules, irrespective of the type of organism. (average ± s.e.m., n = 110, *P < 0.01; NS, not significant). * Figure 3: Ecological interactions are evolutionarily conserved across the entire tree of life. The phylogenetic tree shows the evolutionary relationships between the studied genera and the phylogenetic conservatism of the ecological interactions mapped onto the tips. Red names represent genera with conserved ecological interactions (that is, with a significant phylogenetic signal) and blue names represent genera with non-conserved ecological interactions (that is, with a nonsignificant phylogenetic signal). Black names represent genera in which the phylogenetic signal could not be tested because modularity was not significant or an accurate phylogeny was not available. Viruses were excluded because they are polyphyletic and cannot be accurately located within the tree. Author information * Author information * Supplementary information * Comments Affiliations * Departamento de Ecología, Universidad de Granada, E-18071 Granada, Spain * José M. Gómez * Centro de Investigaciones sobre Desertificación, Consejo Superior de Investigaciones Científicas-Universidad de Valencia-Generalitat Valenciana, E-46470 Valencia, Spain * Miguel Verdú * Departamento de Genética, Universidad de Granada, E-18071 Granada, Spain * Francisco Perfectti Contributions J.M.G., M.V. and F. P. designed the study, J.M.G. compiled the data set and performed the analysis of host use, M.V. performed the phylogenetic analyses, J.M.G. wrote a first version of the manuscript and all authors contributed to the final draft. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * José M. Gómez (jmgreyes@ugr.es) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (897K) This file contains Supplementary Tables 1-6, Supplementary Figure 1 with legend, Supplementary Data 1and Supplementary Notes 1-116 with References. Additional data
• Sequence space and the ongoing expansion of the protein universe
  Povolotskaya IS Kondrashov FA - Nature (London) 465(7300):922 (2010)
  Nature | Letter Sequence space and the ongoing expansion of the protein universe * Inna S. Povolotskaya1 Search for this author in: * NPG journals * PubMed * Google Scholar * Fyodor A. Kondrashov1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:922–926Date published:(17 June 2010)DOI:doi:10.1038/nature09105Received23 November 2009Accepted19 April 2010Published online19 May 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The need to maintain the structural and functional integrity of an evolving protein severely restricts the repertoire of acceptable amino-acid substitutions1, 2, 3, 4. However, it is not known whether these restrictions impose a global limit on how far homologous protein sequences can diverge from each other. Here we explore the limits of protein evolution using sequence divergence data. We formulate a computational approach to study the rate of divergence of distant protein sequences and measure this rate for ancient proteins, those that were present in the last universal common ancestor. We show that ancient proteins are still diverging from each other, indicating an ongoing expansion of the protein sequence universe. The slow rate of this divergence is imposed by the sparseness of functional protein sequences in sequence space and the ruggedness of the protein fitness landscape: ~98 per cent of sites cannot accept an amino-acid substitution at any given moment but a vast ! majority of all sites may eventually be permitted to evolve when other, compensatory, changes occur. Thus, ~3.5 × 109 yr has not been enough to reach the limit of divergent evolution of proteins, and for most proteins the limit of sequence similarity imposed by common function may not exceed that of random sequences. View full text Subject terms: * Evolution * Genetics * Genomics * Molecular biology Figures at a glance * Figure 1: Expansion of the physical and the protein universes. Physical space continues to expand after the Big Bang, whereas sequence space is a pre-defined abstract entity a limited subspace of which corresponds to sequences with a specific function. In both cases, the correlation between distance from one point of observation (green) to reference points in space (blue) and the relative rates of divergence (blue arrows) reveals whether or not these objects (proteins or galaxies) recede from a common point of origin (middle diagram) or have reached the limit of their divergence (shown only for proteins in the bottom-right diagram). * Figure 2: Measuring the rate of divergence of distant protein sequences. We infer the directionality of a substitution by the use of closely related outgroups (solid lines) and then relate them to an arbitrarily distant reference sequence (broken line). , A substitution leads 'away' from the reference sequence (red) when the ancestral amino acid is identical to that at the orthologous site of the reference sequence, and leads 'towards' the reference sequence (blue) when the derived amino acid is identical to the amino acid in the reference sequence. , Use of amino-acid similarity to infer the directionality of substitutions where neither the derived nor the ancestral amino acid is identical to the reference amino acid. The substitution shown in purple leads the evolving sequence away from the reference sequence (His–Asp and Glu–Asp BLOSUM62 similarity scores are -1 and 2, respectively), whereas the orange one leads the evolving sequence towards the reference sequence (Trp–Tyr score, 2; Gly–Tyr score, -3). Directionality cannot be ! determined when the BLOSUM62 scores of the ancestral and the derived amino acids are equal to the score of the reference amino acid (brown). , Divergent sites (red brackets) and convergent sites (blue brackets). * Figure 3: The rate of expansion of the protein sequence universe. Nt/Na values for sites where the derived or the ancestral amino acid was identical to the reference amino acid (blue) and for all type-1 and type-2 sites (green), including those where the directionality of the substitution was determined from the BLOSUM62 matrix. The Nt/Na ratio for fourfold-synonymous sites is shown in orange. Least-squares regression with correlation coefficient R is shown for the Nt/Na values calculated without the BLOSUM62 correction (blue). Error bars, s.e.m. * Figure 4: Sequence space of two nucleotide sites. Fitness landscapes as modified from fig. 1 of ref. 9 as graphs in which vertices correspond to unique sequences and edges correspond to mutational steps. , When all sequences confer high fitness (green vertices), there are two shortest paths (purple arrows), two steps long, that connect two arbitrary points in sequence space (AT and GC). , When half of all sequences confer low fitness (black vertices), the number of evolutionarily accessible paths is reduced and their lengths are increased. , When alleles G and A in the second site are deleterious independently of the alleles in the first site, the fitness landscape is a simple subset of the total sequence space and the availability of short paths between vertices of high fitness is unaffected. The numbers of vertices conferring high fitness are the same in the fitness landscapes shown in and ; however, represents a highly rugged fitness ridge whereas shows a fitness ridge without any epistatic interactions. * Figure 5: Divergent and convergent evolution. The relative rates of divergent evolution, Kd/K4 (blue), and of convergent evolution, Kc/K4 (red), at divergent and convergent sites, respectively. Error bars, s.e.m. Author information * Author information * Supplementary information * Comments Affiliations * Bioinformatics and Genomics Programme, Centre for Genomic Regulation, Calle Dr Aiguader 88, Barcelona Biomedical Research Park Building, 08003 Barcelona, Spain * Inna S. Povolotskaya & * Fyodor A. Kondrashov Contributions I.S.P. performed all analyses and obtained all of the data. F.A.K. conceived the study and drafted the manuscript. Both authors participated in the design of the analyses and the interpretation of the results. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Fyodor A. Kondrashov (fyodor.kondrashov@crg.es) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (515K) This file contains Supplementary Information comprising: Rationale for avoiding deep ancestral state reconstructions and Deconstructing the Nt and Na measurements, References and Supplementary Figures 1-8 with legends. * Supplementary Table 1 (302K) This table contains genomes that have not been used as quadruplets but were assigned to COGs that were present in LUCA. Additional data
• Fine-tuning of pre-balanced excitation and inhibition during auditory cortical development
  - Nature (London) 465(7300):927 (2010)
  Nature | Letter Fine-tuning of pre-balanced excitation and inhibition during auditory cortical development * Yujiao J. Sun1 Search for this author in: * NPG journals * PubMed * Google Scholar * Guangying K. Wu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Bao-hua Liu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Pingyang Li1 Search for this author in: * NPG journals * PubMed * Google Scholar * Mu Zhou1 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhongju Xiao4 Search for this author in: * NPG journals * PubMed * Google Scholar * Huizhong W. Tao1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Li I. Zhang1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:927–931Date published:(17 June 2010)DOI:doi:10.1038/nature09079Received04 November 2009Accepted13 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Functional receptive fields of neurons in sensory cortices undergo progressive refinement during development1, 2, 3, 4. Such refinement may be attributed to the pruning of non-optimal excitatory inputs, reshaping of the excitatory tuning profile through modifying the strengths of individual inputs, or strengthening of cortical inhibition. These models have not been directly tested because of the technical difficulties in assaying the spatiotemporal patterns of functional synaptic inputs during development. Here we apply in vivo whole-cell voltage-clamp recordings to the recipient layer 4 neurons in the rat primary auditory cortex (A1) to determine the developmental changes in the frequency–intensity tonal receptive fields (TRFs) of their excitatory and inhibitory inputs. Surprisingly, we observe co-tuned excitation and inhibition immediately after the onset of hearing, suggesting that a tripartite thalamocortical circuit with relatively strong feedforward inhibition is for! med independently of auditory experience. The frequency ranges of tone-driven excitatory and inhibitory inputs first expand within a few days of the onset of hearing and then persist into adulthood. The latter phase is accompanied by a sharpening of the excitatory but not inhibitory frequency tuning profile, which results in relatively broader inhibitory tuning in adult A1 neurons. Thus the development of cortical synaptic TRFs after the onset of hearing is marked by a slight breakdown of previously formed excitation–inhibition balance. Our results suggest that functional refinement of cortical TRFs does not require a selective pruning of inputs, but may depend more on a fine adjustment of excitatory input strengths. View full text Subject terms: * Neuroscience Figures at a glance * Figure 1: The synaptic TRFs shortly after the onset of hearing. , Three synaptic models for the functional refinement of sensory spike receptive fields (reduction in the size of receptive fields). Curves represent tuning profiles of excitation (black) and inhibition (red) along a sensory space. A pair of dotted vertical lines indicate the total response range of excitatory inputs. I, pruning of peripheral excitatory inputs (that is, reduced total response range). II, adjustment of input strengths without pruning of inputs. III, broadening and strengthening of cortical inhibition. , Current–voltage curves for a recorded A1 neuron. Inset, average traces of synaptic currents (five repeats) of the neuron evoked by a noise stimulus. Average amplitude was measured within the 1–2 ms (red) and 21–22 ms (black) windows after the onset of the average synaptic response recorded at −80 mV. Correlation coefficient (r) is shown. , TRFs of excitatory and inhibitory inputs for an example P13 neuron. Arrays of traces depict the excitatory (! −80 mV) and inhibitory (0 mV) currents evoked by individual tone stimuli at various frequencies and intensities. Red arrow marks the intensity threshold. Colour map depicts the peak amplitudes of tone-evoked synaptic currents within the TRF. The example excitatory (black) and inhibitory (red) responses evoked by the same tone (indicated by red dots) were enlarged. Dotted vertical lines mark the 75-ms window for plotting individual small traces in the array. , Frequency tuning curves of excitatory (E) and inhibitory (I) inputs to the same cell as in at two intensities: the threshold (70 dB) and 20 dB above the threshold (90 dB). The starting and ending frequencies for the inhibitory tuning were marked. Right, the tuning curves are normalized and superimposed (E, black, reversed in polarity). Blue line indicates the half-peak level. , Mismatch indices at threshold intensity (grey) and an intensity of 20 dB above threshold (white). For two P12–P14 cells exhibit! ing an intensity threshold of 80 dB sound pressure level, MM! I was derived at 10 dB above the threshold. *P < 0.005, paired t-test (n = 8, 6 for P12–14 and adult, respectively). Error bar, s.d. * Figure 2: Synaptic TRFs at later developmental stages. –, Synaptic TRFs of example neurons at P16 (), P20 () and P80 (), respectively. , Frequency tuning curves of excitatory and inhibitory inputs at the intensity of 20 dB above threshold for cells shown in –. Presentation is the same as in Fig. 1. * Figure 3: Developmental changes in spectral and temporal patterns of excitatory and inhibitory inputs. , Average intensity threshold of excitatory, inhibitory and spike TRFs. *Significantly higher (P < 0.001), ANOVA with post-hoc test (n = 10, 10, 10, 10 for excitatory TRFs; n = 8, 8, 5, 6 for inhibitory TRFs; and n = 7, 11, 6, 14 for spike TRFs examined by cell-attached recordings). , TFRR of excitatory and inhibitory inputs at 10 dB above intensity threshold. Data were from the same recordings as in . Solid symbols are average values and are connected with dashed lines for easier comparisons between neighbouring groups (the same for , and ). *Significantly lower (P < 0.05), ANOVA with post-hoc test. , Half-peak bandwidths (BW50%) of the tuning curves in . *Different in excitation; #different in inhibition; P < 0.001, ANOVA with post-hoc test. , Mismatch indices at threshold intensity (grey) and 20 dB above threshold (white) at different stages (n = 8, 8, 5, 6). For 20 dB above threshold, ST2 is significantly lower than ST3 and ST4 (P < 0.05, ANOVA with! post-hoc test). For each stage, MMI at threshold is significantly higher than at 20 dB above threshold (P < 0.005, paired t-test). , Average peak amplitudes of evoked inhibitory and excitatory currents from the same recordings as in . The peak amplitude was determined by averaging five responses around the best frequency at the highest intensity tested. The I/E ratio was first calculated for individual cells with both excitatory and inhibitory TRFs recorded, and then averaged (circle, n = 8, 8, 5, 6, respectively). , Onset latencies of synaptic responses, and the relative delay of inhibition. All error bars, s.d. * Figure 4: Synaptic mechanisms underlying the developmental refinement of spike TRFs in A1. , An example cell with cell-attached recording followed by whole-cell recording. Top panels, the excitatory (−80 mV) and inhibitory (0 mV) TRFs of the cell. Scale, 50 pA and 100 ms. Bottom left, the recorded spike TRF. Bottom right, the TRF of derived membrane potential and spike responses. Colour maps represent the peak amplitudes of synaptic inputs (top) and number of spikes evoked (bottom). , Bandwidths of spike TRFs derived and recorded from cells at different stages. Bandwidth was measured at 10 dB above threshold. The value at ST2 is significantly higher (P = 0.1, 0.024, 0.014 between pairs of ST2–ST1, ST2–ST3 and ST2–ST4, respectively, for recorded TRFs (n = 7, 11, 6, 14); P = 0.004, 0.016, 0.015 for derived TRFs (n = 8, 8, 5, 6); ANOVA with post-hoc test). Error bars, s.d. , A developmental model. The excitatory tuning profile is developmentally sharpened whereas the inhibitory tuning remains relatively stable. Vertical lines mark the total range of! inputs. Author information * Author information * Supplementary information * Comments Affiliations * Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA * Yujiao J. Sun, * Guangying K. Wu, * Bao-hua Liu, * Pingyang Li, * Mu Zhou, * Huizhong W. Tao & * Li I. Zhang * Department of Biophysics and Physiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA * Li I. Zhang * Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA * Huizhong W. Tao * Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China * Zhongju Xiao Contributions Y.J.S., G.K.W., P.L. and M.Z. performed the experiments. Y.J.S. and B.-h.L. analysed the data. Z.X., H.W.T. and L.I.Z. designed the experiments and analysis. H.W.T. and L.I.Z. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Li I. Zhang (liizhang@usc.edu) or * Huizhong W. Tao (htao@usc.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Figures (137K) This file contains Supplementary Figures 1-3 with legends. Additional data
• Developmental sensory experience balances cortical excitation and inhibition
  - Nature (London) 465(7300):932 (2010)
  Nature | Letter Developmental sensory experience balances cortical excitation and inhibition * Anja L. Dorrn1, 2, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Kexin Yuan2, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Alison J. Barker2 Search for this author in: * NPG journals * PubMed * Google Scholar * Christoph E. Schreiner2 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert C. Froemke2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:932–936Date published:(17 June 2010)DOI:doi:10.1038/nature09119Received27 October 2009Accepted22 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Early in life, neural circuits are highly susceptible to outside influences. The organization of the primary auditory cortex (A1) in particular is governed by acoustic experience during the critical period, an epoch near the beginning of postnatal development throughout which cortical synapses and networks are especially plastic1, 2, 3, 4, 5, 6, 7, 8. This neonatal sensitivity to the pattern of sensory inputs is believed to be essential for constructing stable and adequately adapted representations of the auditory world and for the acquisition of language skills by children5, 9, 10. One important principle of synaptic organization in mature brains is the balance between excitation and inhibition, which controls receptive field structure and spatiotemporal flow of neural activity11, 12, 13, 14, 15, but it is unknown how and when this excitatory–inhibitory balance is initially established and calibrated. Here we use whole-cell recording to determine the processes underlying ! the development of synaptic receptive fields in rat A1. We find that, immediately after the onset of hearing, sensory-evoked excitatory and inhibitory responses are equally strong, although inhibition is less stimulus-selective and mismatched with excitation. However, during the third week of postnatal development, excitation and inhibition become highly correlated. Patterned sensory stimulation drives coordinated synaptic changes across receptive fields, rapidly improves excitatory–inhibitory coupling and prevents further exposure-induced modifications. Thus, the pace of cortical synaptic receptive field development is set by progressive, experience-dependent refinement of intracortical inhibition. View full text Subject terms: * Neuroscience * Developmental biology Figures at a glance * Figure 1: Refinement of excitatory–inhibitory balance during the A1 critical period. , Imbalanced synaptic frequency tuning at P14. Top, frequency tuning of excitation ('Exc.', filled circles) and inhibition ('Inh.', open circles). Bottom, excitation and inhibition were uncorrelated (linear correlation coefficient r = −0.01, P > 0.8). , Balanced tone-evoked excitation and inhibition in adults. Top, frequency tuning. Bottom, excitation and inhibition were correlated (r = 0.87, P < 0.001). , Increase of excitatory–inhibitory balance during the A1 critical period. Circles, individual recordings; squares, averages. , Summary of developmental changes to excitatory–inhibitory balance. Top, excitatory–inhibitory (E:I) correlation in young and adults (P12–P21, r = 0.37 ± 0.06, n = 43; adults, r = 0.71 ± 0.05, n = 31, P < 10−4 compared with P12–P21, Student's two-tailed t-test). **P < 0.01. Bottom, difference in excitatory and inhibitory best frequencies in young and adults (P12–P21, best frequency difference: 1.4�! �± 0.2 octaves, n = 43; adults, 0.2 ± 0.1 octaves, n = 25, P < 10−6). Error bars, s.e.m. * Figure 2: Delayed maturation of inhibitory frequency tuning. , Excitatory frequency (σExc) tuning was sharper than inhibitory tuning (σInh) at P14. Lines, Gaussian fits (σExc = 4.0, σInh = 9.6). Same recording as in Fig. 1a. , Excitatory and inhibitory tuning were both sharp in adulthood (σExc = 2.7, σInh = 2.5). Same recording as in Fig. 1b. , Excitatory frequency tuning sharpened before inhibition (P12–P15, σExc = 5.4 ± 1.0, σInh = 9.4 ± 1.6, n = 15, P < 0.02). Circles, excitation (filled) and inhibition (open) for each cell; squares, averages. , Summary of developmental changes to tuning. Top, tuning sharpness in young (P12–P21, σExc = 4.9 ± 0.4, σInh = 7.7 ± 0.8, n = 43, P < 0.0004) and adults (σExc = 4.4 ± 0.4, σInh = 4.5 ± 0.6, n = 31, P > 0.8). Bottom, excitation to inhibition ratio was unchanged during A1 critical period. Excitation to inhibition ratios were similar between young (P12–P21, ratio = 1.3 ± 0.2, n = 43) and adults (ratio = 1.2 ± 0.2, n = 31, P�! �> 0.6). Error bars, s.e.m. * Figure 3: Patterned stimulation rapidly enhanced excitation and inhibition during P12–P21. , Long-term synaptic enhancement at P19. Before patterned 2-kHz stimulation ('Pre-exc.'), excitation and inhibition were moderately correlated (rpre = 0.57); after stimulation ('Post-exc.'), correlation increased (rpost = 0.86). Top, excitation at 2 kHz increased after patterned stimulation (enhancement of 75.2%, P < 0.05). Insets, conductances evoked by 2 kHz before (grey) and after (black) repetitive stimulation. Arrow, frequency chosen for patterned stimulation. Scale bars, 1 nS, 40 ms. Bottom, inhibition at 2 kHz increased after repetitive stimulation (enhancement of 138.5%, P < 0.05). , Patterned stimulation did not affect adult A1. Top, excitation was unaltered after 8-kHz patterned stimulation (enhancement of 7.4%, P > 0.3). Scale bars, 0.5 nS, 40 ms. Bottom, inhibition at 8 kHz remained unchanged (enhancement of 1.8%, P > 0.3). Excitatory–inhibitory correlation was unaffected (rpre = 0.68, rpost = 0.74). , Critical period for! synaptic modifications induced by patterned stimulation. Circles, changes to excitation (filled) or inhibition (open) for each recording. , Time course of synaptic modifications to tone presented during patterned stimulation. Top, P12–P21 (excitation: 63.1 ± 11.3%, n = 12, P < 0.0002; inhibition: 52.9 ± 14.1%, P < 0.004). Horizontal bar, patterned stimulation. Bottom, adults (excitation: 5.2 ± 5.3%, n = 11, P > 0.3; inhibition: 0.2 ± 5.1%, P > 0. 9). Error bars, s.e.m. * Figure 4: Patterned stimulation improved excitatory–inhibitory coupling by coordinated synaptic modifications across multiple inputs. , Synaptic modifications at the presented tone frequency spread to other inputs within one octave (excitation one octave from presented frequency: 21.6 ± 6.7%, n = 12, P < 0.01; inhibition: 36.0 ± 12.5%, P < 0.02), but not two or more octaves away (P > 0.3). **P < 0.01; *P < 0.05. , After patterned stimulation, responses at original best frequency were reduced (excitation: −34.8 ± 6.4%, n = 12, P < 0.0003; inhibition: −22.7 ± 6.1%, P < 0.004). , Patterned stimulation increased excitatory–inhibitory correlation in young (Δr = 0.31 ± 0.08, n = 12, P < 0.004) but not adults (Δr = −0.03 ± 0.09, n = 11, P > 0.7). , Non-specific modifications across multiple inputs were predominant for balancing excitation and inhibition. Considered separately, synaptic modifications only at the presented frequency were less effective ('Presented only', Δr = 0.12 ± 0.09, P > 0.2) than changes to all other inp! uts ('Unpresented only', Δr = 0.32 ± 0.09, P < 0.004). Error bars, s.e.m. * Figure 5: Patterned stimulation prevented additional synaptic modifications. , Synaptic tuning before first episode of patterned stimulation. Initially, excitatory–inhibitory correlation was low (rpre = 0.27). , Same cell as in , but after the first period of 4-kHz patterned stimulation. Excitation and inhibition at 4 kHz were enhanced and excitatory–inhibitory correlation increased (excitation: 108.7%, P < 0.03; inhibition: 44.4%, P < 0.05; rpost1 = 0.77). , Same cell as in , but after second period of 4-kHz repetitive stimulation. Excitatory–inhibitory strength and balance were unaffected (excitation: 2.1%, P > 0.4; inhibition: 6.2%, P > 0.3; rpost2 = 0.82). , Summary. Top, conductance changes at presented tone frequency after first (excitation: 61.4 ± 16.7%, n = 5, P < 0.03; inhibition: 84.8 ± 26.5%, P < 0.04) and second (excitation: 6.2 ± 11.4%, n = 5, P > 0.6; inhibition: −6.2 ± 18.0%, P > 0.7) stimulation periods. Bottom, change in excitatory–inhibitory correlation after first (Δr! = 0.48 ± 0.10, P < 0.01) and second (Δr = 0.02 ± 0.09, P > 0.8) stimulation periods. Error bars, s.e.m. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Anja L. Dorrn & * Kexin Yuan Affiliations * Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, and NeuroCure Neuroscience Research Center (NWFZ), Berlin 13125, Germany * Anja L. Dorrn * Coleman Memorial Laboratory and W.M. Keck Foundation Center for Integrative Neuroscience, Neuroscience Graduate Program, Department of Otolaryngology, University of California, San Francisco, California 94143, USA * Anja L. Dorrn, * Kexin Yuan, * Alison J. Barker, * Christoph E. Schreiner & * Robert C. Froemke * Molecular Neurobiology Program, The Helen and Martin Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, Departments of Otolaryngology, Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, USA * Robert C. Froemke Contributions A.L.D., K.Y., A.J.B. and R.C.F. performed the experiments and analyses. All authors discussed the experiments and contributed to the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Robert C. Froemke (robert.froemke@med.nyu.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Figures (795K) This file contains Supplementary Figures 1-9 with legends. Additional data
• TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus
  - Nature (London) 465(7300):937 (2010)
  Nature | Letter TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus * Cristiana Guiducci1 Search for this author in: * NPG journals * PubMed * Google Scholar * Mei Gong1 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhaohui Xu2 Search for this author in: * NPG journals * PubMed * Google Scholar * Michelle Gill2, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Damien Chaussabel2 Search for this author in: * NPG journals * PubMed * Google Scholar * Thea Meeker1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean H. Chan1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tracey Wright3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Marilynn Punaro3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Silvia Bolland5 Search for this author in: * NPG journals * PubMed * Google Scholar * Vassili Soumelis6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacques Banchereau2 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert L. Coffman1 Search for this author in: * NPG journals * PubMed * Google Scholar * Virginia Pascual2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Franck J. Barrat1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:937–941Date published:(17 June 2010)DOI:doi:10.1038/nature09102Received20 November 2009Accepted21 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Glucocorticoids are widely used to treat patients with autoimmune diseases such as systemic lupus erythematosus (SLE)1, 2. However, regimens used to treat many such conditions cannot maintain disease control in the majority of SLE patients and more aggressive approaches such as high-dose methylprednisolone pulse therapy are used to provide transient reductions in disease activity3, 4. The primary anti-inflammatory mechanism of glucocorticoids is thought to be NF-κB inhibition5. Recognition of self nucleic acids by toll-like receptors TLR7 and TLR9 on B cells and plasmacytoid dendritic cells (PDCs) is an important step in the pathogenesis of SLE6, promoting anti-nuclear antibodies and the production of type I interferon (IFN), both correlated with the severity of disease1, 7. Following their activation by self-nucleic acid-associated immune complexes, PDCs migrate to the tissues8, 9. We demonstrate, in vitro and in vivo, that stimulation of PDCs through TLR7 and 9 can accoun! t for the reduced activity of glucocorticoids to inhibit the IFN pathway in SLE patients and in two lupus-prone mouse strains. The triggering of PDCs through TLR7 and 9 by nucleic acid-containing immune complexes or by synthetic ligands activates the NF-κB pathway essential for PDC survival. Glucocorticoids do not affect NF-κB activation in PDCs, preventing glucocorticoid induction of PDC death and the consequent reduction of systemic IFN-α levels. These findings unveil a new role for self nucleic acid recognition by TLRs and indicate that inhibitors of TLR7 and 9 signalling could prove to be effective corticosteroid-sparing drugs. View full text Subject terms: * Medical research * Cell biology * Immunology Figures at a glance * Figure 1: Level of expression of the PDC-induced IFN signature in glucocorticoid-treated SLE patients strictly correlates with circulating blood PDCs. , Module level analysis from whole blood from 29 SLE patients with (n = 18) or without (n = 11) oral glucocorticoid (GC) treatment as described10. Disease activity index (SLEDAI) and therapy used are indicated at the bottom. HCQ, hydroxychloroquine; MMF, mycophenolate mofetil. , Purified PDCs were grown alone or with Flu or purified anti-RNP-IC either alone or with glucocorticoids (10−5 M) or IRS and assayed for IFN-α secretion at 3 h. , Top panel: interferon module expression levels (average from transcripts within the IFN module displayed in ) in SLE patients untreated (n = 30), on 5–10 mg (n = 29) or on 20–30 mg (n = 6) daily oral Prednisone and on intravenous (i.v.) methylprednisolone pulse (three consecutive doses, n = 6). Middle and lower panels: blood PDC and monocyte numbers in SLE patients untreated (n = 13), on 5–10 mg daily oral glucocorticoids (n = 27), oral daily glucocorticoids 20–30 mg (n = 16) and the day after intravenous pulse (n = 6)! . NS, not significant. , Representative flow cytometry analysis of PDCs before and 1 and 6 days after intravenous pulse. , Top: quantification of the average interferon module level expression (Nanostring, see Supplementary Fig. 1) in healthy controls (n = 9), SLE patients before intravenous pulse (n = 26) and at day 1 (n = 1) and day 8 after the pulse (n = 2). Bottom: PDCs frequency in the CD11c population patients before intravenous pulse (D0, n = 10) and at day 1 (n = 9) and day 6 after pulse (n = 2). Data are plotted as mean ± s.e.m. * Figure 2: Glucocorticoids do not affect viability of TLR7- and TLR9-activated PDCs because of its lack of activity on TLR-induced NF-κB activation. –, Purified PDCs were grown in medium (Med) or as indicated and viability was assessed after 24 h. , Average of 6–12 independent donors is shown ± s.e.m. ** P ≤ 0.01. TLRL (TLR ligand) alone versus grown with IRS. , PDCs were grown with glucocorticoids (10−5 M) either alone or as indicated. Average of 5–8 independent donors ± s.e.m. , , PDCs were grown with CpG-C either alone or with inhibitors of p38 MAPK (SB, SB203580), PI-3 kinase (LY, LY294002)or NF-κB (IKK-2 IV, p50 or NEMO inhibitory peptides). Average of 6–8 independent donors ± s.e.m. is shown. –, Nuclear extracts from purified PDCs (, ) or monocytes () were prepared following cultures as indicated and the transcriptional activity of NF-κB was assessed. IKK-2 was used at 0.5 μM. Data are shown as OD values based on absorbance at 450 nm (mean ± s.e.m.) of at least four independent experiments. * Figure 3: TLR9 activation in vivo renders PDCs more resistant to glucocorticoid treatment. , , 129 mice had no treatment (No Tx) or were injected with graded doses of dexamethasone and cells prepared from blood () or spleens () after 18 h. In blood (), data are expressed as number of cells per ml of blood and as total number of cells in spleens (). n = 6 mice per group. , , 129 mice were either left untreated or treated with 1 mg dexamethasone alone or in the presence of either CpG-C ISS (50 μg per mouse) or with CpG-C ISS plus IRS (100 μg per mouse). Number of cells per ml in blood is shown in () and total number of cells in spleen is shown in (). Cumulative data of two independent experiments; n = 8 mice per group is shown. Plotted data represent averages ± s.e.m. ** P ≤ 0.01, *** P ≤ 0.001. * Figure 4: PDCs from lupus-prone mice have intrinsic resistance to glucocorticoid-induced cell death compared to normal mice because of TLR7 and 9 activation by self-nucleic acid. , , Normal (closed symbols) and lupus-prone (open symbols) animals were either left untreated or treated with dexamethasone (GC). Cell numbers in blood (, fold change to pre-bleed) and spleens (, fold change to untreated) was assessed 18 h later. Cumulative data of at least three independent experiments is shown. *** P ≤ 0.001 indicate differences between both lupus strains from either normal strains. 129 and B6, normal mice; TLR7 and NZB, lupus-prone mice. , , (NZBxNZW)F1 and TLR7.Tg.6 mice ( and , respectively) were left untreated or treated with glucocorticoids alone or in the presence of IRS or control (CTRL) ODN (100 μg per mouse sub-cutaneously) given every 3 days for 10 days before the glucocorticoid treatment. Viability was assessed in the spleen 18 h after DEX. Cumulative data of two independent experiments is shown. Author information * Author information * Supplementary information * Comments Affiliations * Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA * Cristiana Guiducci, * Mei Gong, * Thea Meeker, * Jean H. Chan, * Robert L. Coffman & * Franck J. Barrat * Baylor Institute for Immunology Research, Dallas, Texas 75204, USA * Zhaohui Xu, * Michelle Gill, * Damien Chaussabel, * Jacques Banchereau & * Virginia Pascual * Texas Scottish Rite Hospital, Dallas, Texas 75219, USA * Tracey Wright, * Marilynn Punaro & * Virginia Pascual * University of Texas, Southwestern Medical Center and Children's Medical Center, Dallas, Texas 75235, USA * Tracey Wright & * Marilynn Punaro * Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA * Silvia Bolland * Institut Curie, Department of Immunology, 26 rue d'Ulm, 75005 Paris, France * Vassili Soumelis * †Present address: University of Texas, Southwestern Medical Center, Dallas, Texas 75235, USA. * Michelle Gill Contributions C.G. and F.J.B. designed the study; C.G., M.Go., Z.X., M.Gi., T.M. and J.H.C. performed experiments; D.C., V.P., C.G. and F.J.B. collected and analysed data; S.B. provided the mice; T.W. and M.P. followed the cohort of patients and provided clinical samples; C.G., Z.X., R.L.C., V.P. and F.J.B wrote the manuscript; V.S., J.B. and R.L.C. gave conceptual advice. Competing financial interests C.G., M.Go., T.M., J.H.C., R.L.C. and F.J.B. are full-time employees of Dynavax Technologies. Corresponding author Correspondence to: * Franck J. Barrat (fbarrat@dynavax.com) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (349K) This file contains Supplementary Figures 1-7 with legends and Supplementary Tables 1-2. Additional data
• Termination of autophagy and reformation of lysosomes regulated by mTOR
  Yu L McPhee CK Zheng L Mardones GA Rong Y Peng J Mi N Zhao Y Liu Z Wan F Hailey DW Oorschot V Klumperman J Baehrecke EH Lenardo MJ - Nature (London) 465(7300):942 (2010)
  Nature | Letter Termination of autophagy and reformation of lysosomes regulated by mTOR * Li Yu1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Christina K. McPhee4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Lixin Zheng1 Search for this author in: * NPG journals * PubMed * Google Scholar * Gonzalo A. Mardones6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Yueguang Rong2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Junya Peng2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Na Mi2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ying Zhao8 Search for this author in: * NPG journals * PubMed * Google Scholar * Zhihua Liu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Fengyi Wan1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dale W. Hailey6 Search for this author in: * NPG journals * PubMed * Google Scholar * Viola Oorschot9 Search for this author in: * NPG journals * PubMed * Google Scholar * Judith Klumperman9 Search for this author in: * NPG journals * PubMed * Google Scholar * Eric H. Baehrecke4 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael J. Lenardo1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:942–946Date published:(17 June 2010)DOI:doi:10.1038/nature09076Received27 July 2009Accepted01 April 2010Published online06 June 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Autophagy is an evolutionarily conserved process by which cytoplasmic proteins and organelles are catabolized1, 2. During starvation, the protein TOR (target of rapamycin), a nutrient-responsive kinase, is inhibited, and this induces autophagy. In autophagy, double-membrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes, which degrade their contents to regenerate nutrients. Current models of autophagy terminate with the degradation of the autophagosome cargo in autolysosomes3, 4, 5, but the regulation of autophagy in response to nutrients and the subsequent fate of the autolysosome are poorly understood. Here we show that mTOR signalling in rat kidney cells is inhibited during initiation of autophagy, but reactivated by prolonged starvation. Reactivation of mTOR is autophagy-dependent and requires the degradation of autolysosomal products. Increased mTOR activity attenuates autophagy and generates proto-lysoso! mal tubules and vesicles that extrude from autolysosomes and ultimately mature into functional lysosomes, thereby restoring the full complement of lysosomes in the cell—a process we identify in multiple animal species. Thus, an evolutionarily conserved cycle in autophagy governs nutrient sensing and lysosome homeostasis during starvation. View full text Subject terms: * Cell biology * Biochemistry * Molecular biology Figures at a glance * Figure 1: Lysosome homeostasis during starvation. , LAMP1+ lysosome size and quantity in NRK cells (dotted outline) starved for hours (h). Error bars show s.e.m. (n = 3). , Starved NRK cells expressing LAMP1–YFP show tubules (arrows). Box is expanded on the right. , Immuno-TEM (gold marks LAMP1) of starved NRK cells. Continuity (arrow) illustrated between autolysosome (red star) and tubule. , LAMP1–YFP expressing NRK-LC3 cells as in . Arrows show reformation tubules. , Three-dimensional reconstruction of a cell from . , Time-lapse images (seconds) of starved LAMP1–YFP-expressing NRK cells. , Time-lapse images (minutes) of starved LAMP1–PAGFP or LAMP1–RFP-expressing NRK cells after photo-activation. Scale bars, 5 µm. * Figure 2: Proto-lysosome formation and maturation. –, Starved LAMP1–YFP NRK cells stained with Lysotracker or DQ-BSA. , Right, TEM of purified lysosomes. , Magnification (4×) of images shown in . Arrows indicate reformation tubules and arrowhead indicates autolysosome. , , Immunofluorescence () and immuno-EM () using LAMP1 antibody of cells shown in . , Density gradient fractions of NRK cells starved for times shown and blotted for LAMP2 or Cathepsin D. Middle panel shows 8-h fractions 7 and 9 analysed by TEM. Fraction 10 is the gradient top. , Starved LAMP1–PAGFP NRK cells were photo-activated (4 h) and imaged at 12 h with Lysotracker (upper) or DQ-BSA (lower). Boxes show enlargements. R(r) = Pearson's coefficient. Scale bars, 5 µm. * Figure 3: Reactivation of mTOR inhibits autophagy and initiates lysosome reformation. , TEM (bottom; scale bar, 5 µm) and fluorescence (top; scale bar, 10 µm) of NRK-LC3 cells starved for times shown with enlargements (boxes). , , Immunoblots of cells shown in with indicated antibodies (, after transfection with non-specific (NS) or atg5 RNAi). , Autophagy (black lines show independent experiments) and phospho-S6K percentage (densitometry of data shown in , red line). –, LAMP1–YFP NRK-LC3 cells starved for 2 h and then treated with 100 nM rapamycin for another 4 h (total, 6 h) or 6 h (total, 8 h) analysed by blotting () as in or microscopy (; scale bar, 5 µm) with quantification (). Error bars, s.e.m.; n = 3. * Figure 4: Autophagic lysosome reformation. , LAMP1/LC3 NRK cells were starved for 4 h and treated with GTPγS for 6 h of further starvation. , Rab7Q67L–GFP-transfected LC3–CFP/Lamp1–RFP NRK cells starved for 10 h. , Rab7–CFP NRK cells starved for 2 h and treated with 100 nM rapamycin for 8 h of further starvation. , LAMP1–YFP NRK-LC3 cells starved for times shown with 1 µg ml–1 leupeptin and blotted with indicated antibodies. , Cells in imaged.. , Fibroblast cells from patients with Scheie syndrome (GM01256) or healthy controls starved and blotted with indicated antibodies. , Cells in imaged. Lysosome size classified by Image-ProPlus (IPP) software. , Provisional model of the autophagic lysosome reformation (ALR) cycle. Scale bars, 5 µm. Author information * Author information * Supplementary information * Comments Affiliations * Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA * Li Yu, * Lixin Zheng, * Zhihua Liu, * Fengyi Wan & * Michael J. Lenardo * School of Life Science, Tsinghua University, Beijing 100084, China * Li Yu, * Yueguang Rong, * Junya Peng & * Na Mi * State Key Laboratory of Biomembrane and Membrane Biotechnology, Beijing, 100084, China * Li Yu, * Yueguang Rong, * Junya Peng & * Na Mi * Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA * Christina K. McPhee & * Eric H. Baehrecke * Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA * Christina K. McPhee * Cell Biology and Metabolism Program, National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA * Gonzalo A. Mardones & * Dale W. Hailey * Department of Physiology, Universidad Austral de Chile, Valdivia 509-9200, Chile * Gonzalo A. Mardones * Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China * Ying Zhao * Department of Cell Biology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands * Viola Oorschot & * Judith Klumperman Contributions L.Y. first observed lysosome reformation at the end of autophagy, autophagy dependent mTOR reactivation and performed the original characterization of the phenomenon. G.A.M. and D.W.H. made critical DNA constructs and designed the live imaging experiments. L.Z. performed the density gradient analyses. C.K.M. performed Drosophila experiments. V.O. performed immuno-TEM analyses. M.J.L. and L.Y. wrote the manuscript and J.P., Y.R., N.M., Y.Z., Z.L. and F.W. helped in the manuscript revision experiments. Most of the experiments were performed by L.Y. and were conceived by L.Y., E.H.B. and M.J.L. J.K. conceived and executed certain E.M. experiments. All authors wrote, discussed and revised the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Michael J. Lenardo (lenardo@nih.gov) Supplementary information * Author information * Supplementary information * Comments Movies * Supplementary Movie 1 (5.3M) This movie shows that multiple lysosomes fuse with GFP-LC3-labeled autophagic vesicle (see legend S1 in Supplementary Information file). * Supplementary Movie 2 (2.6M) This movie shows tubules extending from autolysosomal membranes (arrow) and small Lamp1-positive vesicles pinching off from the tips of tubules (see legend S8 in Supplementary Information file). * Supplementary Movie 3 (3.6M) This movie shows tubules breaking away from autolysosomes and condensing into Lamp1-positive vesicles (see legend S9 in Supplementary Information file). PDF files * Supplementary Information (5.2M) This file contains legends S1, S8 and S9 for Supplementary Movies 1-3 (see separate movie files) and Supplementary Figures S2-S7 and S10-S22 with legends. Additional data
• Principles of stop-codon reading on the ribosome
  Sund J Andér M Aqvist J - Nature (London) 465(7300):947 (2010)
  Nature | Letter Principles of stop-codon reading on the ribosome * Johan Sund1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Andér1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Johan Åqvist1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:947–950Date published:(17 June 2010)DOI:doi:10.1038/nature09082Received03 February 2010Accepted15 April 2010Published online30 May 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg In termination of protein synthesis, the bacterial release factors RF1 and RF2 bind to the ribosome through specific recognition of messenger RNA stop codons and trigger hydrolysis of the bond between the nascent polypeptide and the transfer RNA at the peptidyl-tRNA site, thereby releasing the newly synthesized protein. The release factors are highly specific for a U in the first stop-codon position1 and recognize different combinations of purines in the second and third positions, with RF1 reading UAA and UAG and RF2 reading UAA and UGA. With recently determined crystal structures of termination complexes2, 3, 4, it has become possible to decipher the energetics of stop-codon reading by computational analysis and to clarify the origin of the high release-factor binding accuracy. Here we report molecular dynamics free-energy calculations on different cognate and non-cognate termination complexes. The simulations quantitatively explain the basic principles of decoding in all ! three codon positions and reveal the key elements responsible for specificity of the release factors. The overall reading mechanism involves hitherto unidentified interactions and recognition switches that cannot be described in terms of a tripeptide anticodon model. Further simulations of complexes with tRNATrp, the tRNA recognizing the triplet codon for Trp, explain the observation of a 'leaky' stop codon5 and highlight the fundamentally different third position reading by RF2, which leads to a high stop-codon specificity with strong discrimination against the Trp codon. The simulations clearly illustrate the versatility of codon reading by protein, which goes far beyond tRNA mimicry. View full text Subject terms: * Biochemistry * Biophysics * Structural biology Figures at a glance * Figure 1: Stop-codon specificity of RF1 and RF2 in termination. , Schematic view of the binding of RF1, RF2 and tRNATrp to the ribosomal aminoacyl-tRNA site (A site), with their cognate codons indicated. E, exit site; P, peptidyl-tRNA site. , Interactions of the characteristic PXT (RF1, yellow) and SPF (RF2, cyan) release-factor tripeptide motifs with the UAA stop codon2, 4 (mRNA, green carbons), where the polar Thr and Ser side chains are explicitly shown. Red, oxygen; blue, nitrogen; orange, phosphorus. , Calculated changes in binding free energy, ΔΔG, for RF1, RF2 and tRNATrp caused by different base alterations in the stop codons. Error bars, 1 s.e.m. * Figure 2: First-position reading. Recognition of U and discrimination against C observed from the average molecular dynamics structures of termination complexes of RF1 (top, yellow carbons) and RF2 (bottom, cyan carbons) with the UAA () and CAA () codons (green). Dashed lines indicate hydrogen bonds. Also shown are the average interaction energies between release-factor residues and the base at the first codon position, where key side chain (sc) and backbone (bb) contributions are indicated. The discrimination against C is reflected by the more positive interaction energies in than in , an effect that is somewhat more pronounced for RF1 than for RF2. Error bars, 1 s.e.m. * Figure 3: Second-position reading. Average molecular dynamics structures of termination complexes with the UAA () and UGA () codons (colour coding as in Fig. 2). RF1 (top) discriminates against a G2, and the dual specificity of RF2 (bottom) arises from a recognition switch involving Glu 128, as reflected by the more favourable interactions with G in RF2 than in RF1 in the plot of average interaction energies in . The more negative absolute interaction energies for G than for A with Glu 119/128 are a consequence of the higher polarity of G, which also has stronger interactions with water in the absence of bound release factors. Error bars, 1 s.e.m. * Figure 4: Third-position reading. Average molecular dynamics structures of termination complexes with the UAA () and UAG () codons (colour coding as in Fig. 2; rRNA G530, light blue). RF1 (top) reads both A and G in the third position with a recognition switch involving Thr 194, Gln 181 and a water molecule bridging to the rRNA backbone, but this is prevented in RF2 by the Gln 181/Val 190 and Ile 192/Arg 201 mutations, as is also evident from the plots of average interaction energies. The side-chain rotamer of Gln 181 that is essential for the recognition switch is dictated by a hydrogen-bond network involving several nearby groups and differs from that proposed in ref. 2. Error bars, 1 s.e.m. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Johan Sund & * Martin Andér Affiliations * Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden * Johan Sund, * Martin Andér & * Johan Åqvist Contributions J.S. and M.A. performed the simulations. All authors analysed the data and prepared the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Johan Åqvist (aqvist@xray.bmc.uu.se) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (551K) This file contains Supplementary Table 1 and Supplementary Figures 1-4 with legends. Additional data
• Ubiquitin-dependent DNA damage bypass is separable from genome replication
  - Nature (London) 465(7300):951 (2010)
  Nature | Letter Ubiquitin-dependent DNA damage bypass is separable from genome replication * Yasukazu Daigaku1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Adelina A. Davies1 Search for this author in: * NPG journals * PubMed * Google Scholar * Helle D. Ulrich1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:951–955Date published:(17 June 2010)DOI:doi:10.1038/nature09097Received27 October 2009Accepted20 April 2010Published online09 May 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Post-replication repair (PRR) is a pathway that allows cells to bypass or overcome lesions during DNA replication1. In eukaryotes, damage bypass is activated by ubiquitylation of the replication clamp PCNA through components of the RAD6 pathway2. Whereas monoubiquitylation of PCNA allows mutagenic translesion synthesis by damage-tolerant DNA polymerases3, 4, 5, polyubiquitylation is required for an error-free pathway that probably involves a template switch to the undamaged sister chromatid6. Both the timing of PRR events during the cell cycle and their location relative to replication forks, as well as the factors required downstream of PCNA ubiquitylation, have remained poorly characterized. Here we demonstrate that the RAD6 pathway normally operates during S phase. However, using an inducible system of DNA damage bypass in budding yeast (Saccharomyces cerevisiae), we show that the process is separable in time and space from genome replication, thus allowing direct visuali! zation and quantification of productive PRR tracts. We found that both during and after S phase ultraviolet-radiation-induced lesions are bypassed predominantly via translesion synthesis, whereas the error-free pathway functions as a backup system. Our approach has revealed the distribution of PRR tracts in a synchronized cell population. It will allow an in-depth mechanistic analysis of how cells manage the processing of lesions to their genomes during and after replication. View full text Subject terms: * Molecular biology * Genetics * Genomics Figures at a glance * Figure 1: Ubiquitin-dependent DNA damage bypass can be delayed until after genome replication. , Cell cycle profiles of synchronized GAL-RAD18 cultures either unirradiated (left) or treated with 10 J m-2 ultraviolet (UV) radiation (middle, right). RAD18 expression was induced by galactose (Gal, right). , Time course of Rad53 phosphorylation in rad18Δ and GAL-RAD18, treated as above. , Experimental scheme for GAL-RAD18 induction during and after S phase. αF, α-factor. –, Survival of the indicated GAL-RAD18 strains (ultraviolet dose: 10 J m-2 except for rad14Δ, which was 2 J m-2). Error bars represent standard deviations from three experiments. , POL30; , pol30(K164R); , rad52Δ; , rad14Δ. , Cell cycle profiles at the time of RAD18 induction. * Figure 2: PRR normally operates during S phase, but chromatin-bound PCNA can be ubiquitylated in G2/M. , Ubiquitylation of His6-PCNA in wild-type cells after release from G1 arrest (ultraviolet dose: 20 J m-2). , Cell cycle profile of the above culture. , Time course of Rad53 phosphorylation in wild-type and rad18Δ cells treated as above. , Cell cycle profiles of the above cultures. , His6-PCNA ubiquitylation in GALS-RAD18 cells treated as described in Fig. 1c. , Distribution of PCNA and Mcm2 in whole-cell extracts (W), soluble (S) and chromatin-associated (C) fractions prepared from G1-irradiated cultures (with or without 20 J m-2) at the indicated times after release. Pgk1 and Orc6 served as controls for soluble and chromatin-bound proteins, respectively. , Quantification of PCNA and Mcm2 in the chromatin fractions. , Cell cycle profiles of the above cultures. Because irradiation slows down cell cycle progression, different timescales were used for damaged versus undamaged cells in – to relate comparable cell cycle stages to each other. * Figure 3: Ultraviolet-induced lesions are bypassed predominantly by TLS. , Experimental scheme for Tet-RAD18 induction during and after S phase (ultraviolet dose: 10 J m-2). Dox, doxycycline. , , Survival of the indicated strains, relative to unirradiated controls. Standard deviations were derived from four experiments. , Cell cycle profiles of the indicated strains at the time of plating. * Figure 4: Quantification and visualization of PRR tracts in G2/M-arrested cells. , Experimental scheme for labelling of PRR tracts in Tet-RAD18 cells (ultraviolet dose: 20 J m-2). , Dot blot for detection of BrdU incorporation. , Quantification of BrdU signals with s.d. from a minimum of three independent experiments. , Dot blot for detection of BrdU incorporation in single TLS polymerase mutants. , Quantification of the signals in . , Fluorescence microscopy images of DNA fibres (green) labelled with BrdU (red) in hydroxyurea-treated S phase cells. , Fluorescence microscopy images of DNA fibres labelled post-replicatively with BrdU in Tet-RAD18 cells. , Density distribution of BrdU patches. , Dose dependence of BrdU patch densities. Horizontal bars indicate median values. Author information * Author information * Supplementary information * Comments Affiliations * Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms EN6 3LD, UK * Yasukazu Daigaku, * Adelina A. Davies & * Helle D. Ulrich * Present address: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK. * Yasukazu Daigaku Contributions Y.D. and A.A.D. performed the experiments; Y.D. and H.D.U. designed the study; H.D.U. wrote the manuscript. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Helle D. Ulrich (helle.ulrich@cancer.org.uk) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (2.5M) This file contains Supplementary Figures S1-S9 with legends, References and Supplementary Table S1. Additional data
• TFIIA and the transactivator Rap1 cooperate to commit TFIID for transcription initiation
  - Nature (London) 465(7300):956 (2010)
  Nature | Letter TFIIA and the transactivator Rap1 cooperate to commit TFIID for transcription initiation * Gabor Papai1, 2, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Manish K. Tripathi5 Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Ruhlmann1, 2, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Justin H. Layer5 Search for this author in: * NPG journals * PubMed * Google Scholar * P. Anthony Weil5 Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick Schultz1, 2, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:956–960Date published:(17 June 2010)DOI:doi:10.1038/nature09080Received04 September 2009Accepted13 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Transcription of eukaryotic messenger RNA (mRNA) encoding genes by RNA polymerase II (Pol II) is triggered by the binding of transactivating proteins to enhancer DNA, which stimulates the recruitment of general transcription factors (TFIIA, B, D, E, F, H) and Pol II on the cis-linked promoter, leading to pre-initiation complex formation and transcription1. In TFIID-dependent activation pathways, this general transcription factor containing TATA-box-binding protein is first recruited on the promoter through interaction with activators1, 2, 3 and cooperates with TFIIA to form a committed pre-initiation complex4. However, neither the mechanisms by which activation signals are communicated between these factors nor the structural organization of the activated pre-initiation complex are known. Here we used cryo-electron microscopy to determine the architecture of nucleoprotein complexes composed of TFIID, TFIIA, the transcriptional activator Rap1 and yeast enhancer–promoter DNA! . These structures revealed the mode of binding of Rap1 and TFIIA to TFIID, as well as a reorganization of TFIIA induced by its interaction with Rap1. We propose that this change in position increases the exposure of TATA-box-binding protein within TFIID, consequently enhancing its ability to interact with the promoter. A large Rap1-dependent DNA loop forms between the activator-binding site and the proximal promoter region. This loop is topologically locked by a TFIIA–Rap1 protein bridge that folds over the DNA. These results highlight the role of TFIIA in transcriptional activation, define a molecular mechanism for enhancer–promoter communication and provide structural insights into the pathways of intramolecular communication that convey transcription activation signals through the TFIID complex. View full text Subject terms: * Structural biology * Molecular biology Figures at a glance * Figure 1: Location of critical components of the initiation process within various TFIID complexes. , Cryo-electron microscopy structure of the yeast holo-TFIID complex. The five major lobes (A, B, C1, C2 and D)5, 7 are depicted with the location of TBP and Taf4, -5 and -12. Taf5 and the histone-fold Tafs, including Taf4 and Taf12, are present in two copies in yeast TFIID8, 15, forming a crescent-shaped complex with twofold symmetry5. , Negatively stained structure of the TFIID–Rap1 complex. The additional density corresponding to Rap1 is coloured in red according to difference maps shown in Supplementary Fig. 5a. , Cryo-electron microscopy model of the unstained TFIID–TFIIA–DNA complex formed between TFIID, TFIIA and the Ad2 MLP. Additional densities present in the TFIID–TFIIA–DNA complex are coloured. The mass corresponding to TFIIA is represented in blue whereas the density arising in the D lobe ascribed to DNA is represented in green. Original density difference maps are found in Supplementary Fig. 5b. Scale bar, 5 nm. * Figure 2: Structure of the initial TFIID–activator–promoter recruitment complex. , Two different surface views of the cryo-electron microscopy map of complex I formed upon incubating TFIID, TFIIA, Rap1 and the UASRAP1–PGK1 enhancer–promoter DNA. TFIIA is not detected in complex I. Densities originating from Rap1 are detected on both sides of lobe B and are coloured red. Densities attributed to DNA are coloured green in lobes D and C2. Scale bar, 5 nm. , Enlargement of the area boxed in and fitting of the atomic model of DNA-bound Rap1 DBD into the additional Rap1 density contacting the inner face of lobe B. The rod of additional density protruding towards lobe C2 superimposes to the expected position of Rap1-bound DNA. * Figure 3: Structure of the committed complex. , Two different surface views of the cryo-electron microscopy map of complex II formed upon incubating TFIID, TFIIA, Rap1 and UASRAP1–PGK1 enhancer–promoter DNA. The additional densities revealed in complex II are coloured as follows: DNA, TFIIA and Rap1 are depicted in green, violet and red, respectively. Scale bar, 5 nm. , Enlargement with slight tilting of the area boxed in and fitting of the crystal structure of the TBP–TFIIA and the Rap1–DBD–DNA complexes identifies the bridging density between lobes C1 and B. Note that part of TFIIA is missing in the crystal structure and may affect the fitting. , Comparison of the position of TFIIA between the TFIID–TFIIA–DNA complex (blue) and complex II (violet) reveals that the position of TFIIA is rotated by 130°. , Platinum shadowing of spread TFIID–TFIIA–Rap1–DNA complexes showing the formation of a DNA loop in the presence of Rap1. * Figure 4: Model depicting the formation of the activated TFIID complex. , Binding of Rap1 (red circles) to its specific DNA recognition elements. , Recruitment of TFIID (yellow) through an interaction with Rap1 and Taf2 (black dot). , Formation of a DNA loop. , Recruitment of TFIIA (blue trapezoid), which induces the formation of a protein bridge between lobes B and C1 that locks the DNA loop. , Model showing the different position of TFIIA in the TFIID–TFIIA–Ad2 MLP DNA complex, which naturally lacks Rap1. The red shape corresponds to TBP whereas the green triangle represents Taf1–TAND autoinhibition. Author information * Author information * Supplementary information * Comments Affiliations * Department of Structural Biology and Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, BP10142, 67404 Illkirch, France * Gabor Papai, * Christine Ruhlmann & * Patrick Schultz * U964, Inserm, Illkirch, F-67400 France * Gabor Papai, * Christine Ruhlmann & * Patrick Schultz * UMR7104, CNRS, Illkirch, F-67400 France * Gabor Papai, * Christine Ruhlmann & * Patrick Schultz * Université de Strasbourg, Strasbourg, F-67000, France * Gabor Papai, * Christine Ruhlmann & * Patrick Schultz * Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA * Manish K. Tripathi, * Justin H. Layer & * P. Anthony Weil Contributions P.S. and P.A.W. initiated the study. M.K.T. purified the complexes and performed the biochemical tests. J.H.L. and M.K.T. participated in the design and production of mutant proteins. C.R. and G.P. performed the looping experiments. P.S. and G.P. prepared the samples for microscopy and recorded the images. G.P. performed the image analysis. The manuscript was prepared and commented on by P.S., P.A.W., M.K.T., J.H.L. and G.P. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Patrick Schultz (patrick.schultz@igbmc.fr) or * P. Anthony Weil (tony.weil@vanderbilt.edu) The electron density maps of the hydrated TFIID, the TFIID–TFIIA–DNA complex and the TFIID–TFIIA–Rap1–DNA complex I and complex II are deposited in the EM Database under accession numbers EM–5175, EM–5178, EM–5176 and EM–5177, respectively. Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (3.9M) This file contains Supplementary Table 1, Supplementary Figures 1-12 with legends and References. Additional data
• Structure of the bifunctional isocitrate dehydrogenase kinase/phosphatase
  Zheng J Jia Z - Nature (London) 465(7300):961 (2010)
  Nature | Letter Structure of the bifunctional isocitrate dehydrogenase kinase/phosphatase * Jimin Zheng1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Zongchao Jia1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:961–965Date published:(17 June 2010)DOI:doi:10.1038/nature09088Received02 February 2010Accepted15 April 2010Published online26 May 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The Escherichia coli isocitrate dehydrogenase kinase/phosphatase (AceK) is a unique bifunctional enzyme that phosphorylates or dephosphorylates isocitrate dehydrogenase (ICDH) in response to environmental changes, resulting in the inactivation or, respectively, activation of ICDH1. ICDH inactivation short-circuits the Krebs cycle by enabling the glyoxlate bypass2, 3. It was the discovery of AceK and ICDH that established the existence of protein phosphorylation regulation in prokaryotes1, 4. As a 65-kDa protein, AceK is significantly larger than typical eukaryotic protein kinases. Apart from the ATP-binding motif, AceK does not share sequence homology with any eukaryotic protein kinase or phosphatase5, 6. Most intriguingly, AceK possesses the two opposing activities of protein kinase and phosphatase within one protein, and specifically recognizes only intact ICDH7, 8. Additionally, AceK has strong ATPase activity9. It has been shown that AceK kinase, phosphatase and ATPase a! ctivities reside at the same site6, 10, although the molecular basis of such multifunctionality and its regulation remains completely unknown. Here we report the structures of AceK and its complex with ICDH. The AceK structure reveals a eukaryotic protein-kinase-like domain containing ATP and a regulatory domain with a novel fold. As an AceK phosphatase activator and kinase inhibitor, AMP is found to bind in an allosteric site between the two AceK domains. An AMP-mediated conformational change exposes and shields ATP, acting as a switch between AceK kinase and phosphatase activities, and ICDH-binding induces further conformational change for AceK activation. The substrate recognition loop of AceK binds to the ICDH dimer, allowing higher-order substrate recognition and interaction, and inducing critical conformational change at the phosphorylation site of ICDH. View full text Subject terms: * Structural biology Figures at a glance * Figure 1: The overall structure of AceK. , AceK contains two domains. The kinase domain on the left (KD, green and blue) resembles eukaryotic protein kinase. The domain on the right is a regulatory domain (RD, pink). The bound AMP molecule (orange) is located between the two domains. The active site of AceK contains an ATP molecule (yellow) that is buried. Also shown is a schematic bar diagram of the AceK domain structures. , Structural comparison of FGFR2 kinase (Protein Data Bank (PDB) ID, 3CLY; brown) and the AceK kinase domain (green and blue). Several loops are highlighted. P-loop; phosphate-binding loop. , Comparison of the AMP-bound (yellow) and AMP-free (marine blue) AceK structures. In the AMP-bound structure, loop-β3αC (yellow) assumes a closed conformation, whereas in the AMP-free AceK the loop (red) moves as much as 16 Å and has an open conformation. * Figure 2: The ATP-binding site and the allosteric AMP-binding site in AceK. , ATP-binding site in the AMP-bound AceK structure. The magnesium ion (purple) is shown. Also highlighted is loop-β3αC. Interactions between ATP and the residues in the binding pocket are shown as dashed lines. , Allosteric AMP (yellow)-binding site in the AMP-bound AceK structure. Residues from the regulatory domain are coloured pink and residues from the kinase domain are coloured green. , Comparison of ATP orientations and interactions between the complex and AMP-bound AceK structures. The complex structure is in blue and AMP-bound AceK is in light grey. ATP′ (light grey) and ATP (green) are from the complex and from AMP-bound AceK, respectively. The movement of γ-phosphate between the two structures is highlighted using a red dashed line. * Figure 3: The AceK–ICDH complex structure. , Overall structure of the AceK–ICDH complex. An ICDH dimer (M1, cyan; M2, gold) and two molecules of AceK (colour-coded as in Fig. 1) are shown. The phosphorylation loop in ICDH is coloured red, along with a space-filling model of Ser 113. The SRL in AceK is coloured blue, along with space-filling models of ATP and AMP. , Structural comparison of the ICDH dimer of the AceK–ICDH complex (M1, cyan; M2, gold) with the open conformation of the ICDH dimer structure (indigo) (PDB ID, 1SJS). The phosphorylation loops of ICDH in the complex structure and in the open ICDH structure are coloured red and pink, respectively. The phosphorylation loop of the closed conformation of ICDH (green) (PDB ID, 5ICD) is included for comparison. Ser 113 and Arg 112 (Ser 113′ and Arg 112′ in the ICDH open conformation, and Ser 113′′ and Arg 112′′ in the ICDH closed conformation) are highlighted and magnified in the inset. Arg 112 moves upwards and rotates more than 1! 00°, from an inner position (green and pink) to an outer position (red), rendering the Ser 113 oxygen atom more outwards-facing. * Figure 4: Higher-order interaction between the AceK SRL and the ICDH dimer, and AceK mutant activity. , Insertion of the AceK SRL (green) into an ICDH pocket, represented by its electrostatic surface. , Detailed interactions between the SRL and the ICDH active cleft. ICDH residues are coloured light blue for M1 and gold for M2; AceK residues are coloured green. Both molecules in the ICDH dimer (M1 and M2) are involved in the interaction with a single AceK molecule. The residue labels indicate whether each residue is from M1, M2 or AceK (a). , Comparison of relative AceK kinase activity among AceK wild type (WT) and the indicated mutants. , Comparison of relative AceK phosphatase activity among AceK wild type and the indicated mutants, in the presence of the kinase inhibitor/phosphatase activator cocktail (5 mM AMP and 5 mM pyruvate). Three independent replicates were performed in every experiment; error bars indicate the standard deviations. Accession codes * Accession codes * Author information * Supplementary information * Comments Primary accessions Protein Data Bank * 3CLY * 1SJS * 5ICD * 3EPS * 3lC6 * 3lCB * 3CLY * 1SJS * 5ICD * 3EPS * 3lC6 * 3lCB Author information * Accession codes * Author information * Supplementary information * Comments Affiliations * Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada * Jimin Zheng & * Zongchao Jia * College of Chemistry, Beijing Normal University, Beijing 100875, China * Jimin Zheng Contributions Experiments were performed by J.Z. Data were analysed by J.Z. and Z.J. The manuscript was prepared by J.Z. and Z.J. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Zongchao Jia (jia@queensu.ca) The atomic coordinates and structure factors for the structures reported here have been deposited in the Protein Data Bank under accession codes 3EPS, 3lC6 and 3lCB. Supplementary information * Accession codes * Author information * Supplementary information * Comments Movies * Supplementary Movie 1 (7.9M) This movie shows the interaction of AceK with ICDH. ICHD dimer is coloured in marine blue. AceK is coloured in green. The phosphorylation site is coloured in gold. PDF files * Supplementary Information (2.1M) This file contains Supplementary Results and Discussion, Supplementary Tables 1-5, Supplementary Figures 1-6 with legends and References. Additional data
• Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
  - Nature (London) 465(7300):966 (2010)
  Nature | Addendum Cancer-associated IDH1 mutations produce 2-hydroxyglutarate * Lenny Dang Search for this author in: * NPG journals * PubMed * Google Scholar * David W. White Search for this author in: * NPG journals * PubMed * Google Scholar * Stefan Gross Search for this author in: * NPG journals * PubMed * Google Scholar * Bryson D. Bennett Search for this author in: * NPG journals * PubMed * Google Scholar * Mark A. Bittinger Search for this author in: * NPG journals * PubMed * Google Scholar * Edward M. Driggers Search for this author in: * NPG journals * PubMed * Google Scholar * Valeria R. Fantin Search for this author in: * NPG journals * PubMed * Google Scholar * Hyun Gyung Jang Search for this author in: * NPG journals * PubMed * Google Scholar * Shengfang Jin Search for this author in: * NPG journals * PubMed * Google Scholar * Marie C. Keenan Search for this author in: * NPG journals * PubMed * Google Scholar * Kevin M. Marks Search for this author in: * NPG journals * PubMed * Google Scholar * Robert M. Prins Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick S. Ward Search for this author in: * NPG journals * PubMed * Google Scholar * Katharine E. Yen Search for this author in: * NPG journals * PubMed * Google Scholar * Linda M. Liau Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua D. Rabinowitz Search for this author in: * NPG journals * PubMed * Google Scholar * Lewis C. Cantley Search for this author in: * NPG journals * PubMed * Google Scholar * Craig B. Thompson Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew G. Vander Heiden Search for this author in: * NPG journals * PubMed * Google Scholar * Shinsan M. Su Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:966Date published:(17 June 2010)DOI:doi:10.1038/nature09132 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nature462, 739–744 (2009) This Article demonstrates that tumour-associated IDH1 somatic mutations result in a gain of enzyme function that causes the accumulation of R(−)-2-hydroxyglutarate (2HG). We proposed that accumulation of 2HG might drive oncogenesis, and referenced work demonstrating 2HG accumulation in patients with 2-hydroxyglutaric aciduria1. As a plausible mechanism of oncogenesis, we proposed that R(−)-2HG induces redox stress owing to impairment of the respiratory chain. This hypothesis suggests that R(−)-2HG may promote cancer mutations, and is consistent with the latency observed in glioma development and the fact that gliomas increase in incidence with age. Nonetheless, we do appreciate that there are other possible mechanisms by which R(−)-2HG may promote tumour formation. Further work has identified that the abnormal production of 2HG is associated with tumours bearing a mutation in either IDH1 or IDH2 and supports a link between 2HG accumulation and cancer. So far, we have! not found any tumour samples containing IDH1 or IDH2 mutations that do not have increased 2HG levels. Determining the mechanistic link between 2HG accumulation and cancer formation, and how each stereoisomer of 2HG may drive malignancy by the same or distinct mechanism is the subject of continuing investigation by our group and others. References * Struys, E. A.et al.Mutations in the d-2-hydroxyglutarate dehydrogenase gene cause d-2-hydroxyglutaric aciduria. Am. J. Hum. Genet.76, 358–360 (2005) * ChemPort * PubMed * Article Download references Additional data
• B-cell-derived lymphotoxin promotes castration-resistant prostate cancer
  - Nature (London) 465(7300):966 (2010)
  Nature | Erratum B-cell-derived lymphotoxin promotes castration-resistant prostate cancer * Massimo Ammirante Search for this author in: * NPG journals * PubMed * Google Scholar * Jun-Li Luo Search for this author in: * NPG journals * PubMed * Google Scholar * Sergei Grivennikov Search for this author in: * NPG journals * PubMed * Google Scholar * Sergei Nedospasov Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Karin Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:966Date published:(17 June 2010)DOI:doi:10.1038/nature09133 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nature464, 302–305 (2010) In Fig. 2a of this Letter, the grey line was inadvertently labelled 'Rag1 + B cells' instead of 'Rag1 + T cells'. Additional data
• Surface hydrophobin prevents immune recognition of airborne fungal spores
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  Nature | Corrigendum Surface hydrophobin prevents immune recognition of airborne fungal spores * Vishukumar Aimanianda Search for this author in: * NPG journals * PubMed * Google Scholar * Jagadeesh Bayry Search for this author in: * NPG journals * PubMed * Google Scholar * Silvia Bozza Search for this author in: * NPG journals * PubMed * Google Scholar * Olaf Kniemeyer Search for this author in: * NPG journals * PubMed * Google Scholar * Katia Perruccio Search for this author in: * NPG journals * PubMed * Google Scholar * Sri Ramulu Elluru Search for this author in: * NPG journals * PubMed * Google Scholar * Cécile Clavaud Search for this author in: * NPG journals * PubMed * Google Scholar * Sophie Paris Search for this author in: * NPG journals * PubMed * Google Scholar * Axel A. Brakhage Search for this author in: * NPG journals * PubMed * Google Scholar * Srini V. Kaveri Search for this author in: * NPG journals * PubMed * Google Scholar * Luigina Romani Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Paul Latgé Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:966Date published:(17 June 2010)DOI:doi:10.1038/nature09134 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nature460, 1117–1121 (2009) In this Article, the data presented in the figures were analysed using the Mann–Whitney test. However, the correct statistical analysis should have been to use an unpaired two-sided t-test. We thank K. Datta for bringing this to our attention. This change in the statistical method, however, does not alter the conclusions of the figures or the article. Additional data
• International network of cancer genome projects
  - Nature (London) 465(7300):966 (2010)
  Nature | Corrigendum International network of cancer genome projects * The International Cancer Genome ConsortiumJournal name:NatureVolume:465,Page:966Date published:(17 June 2010)DOI:doi:10.1038/nature09167 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nature464, 993–998 (2010) In this Perspective, author Heinz Himmelbauer was incorrectly listed as Heinz Himmelbaue, author Brooke B. Gardiner was incorrectly listed as Brooke A. Gardiner, and author Anthony Cros was incorrectly listed as Anthony Cross. Additional data Consortia * The International Cancer Genome Consortium
• Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis
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  Nature | Corrigendum Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis * Masaru Ishii Search for this author in: * NPG journals * PubMed * Google Scholar * Jackson G. Egen Search for this author in: * NPG journals * PubMed * Google Scholar * Frederick Klauschen Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Meier-Schellersheim Search for this author in: * NPG journals * PubMed * Google Scholar * Yukihiko Saeki Search for this author in: * NPG journals * PubMed * Google Scholar * Jean Vacher Search for this author in: * NPG journals * PubMed * Google Scholar * Richard L. Proia Search for this author in: * NPG journals * PubMed * Google Scholar * Ronald N. Germain Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:966Date published:(17 June 2010)DOI:doi:10.1038/nature09193 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nature458, 524–528 (2009) In this Letter, there is a discrepancy in Figures 3d and 4b between the size of the error bars and the reported P values. We have found that in contrast to the other Figures in this paper, the error bars in these two instances represent the standard deviation and not the standard error of the mean. We regret this manuscript preparation error, which does not affect the conclusions or interpretations of the paper. Additional data
• IRC
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  A helping hand.