Hot off the presses! May 06 Nature

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Latest Articles Include:

• A plan for the ocean
  - Nature 465(7294):9 (2010)
  Nature | Editorial A plan for the ocean Journal name:NatureVolume:465,Page:9Date published:(06 May 2010)DOI:doi:10.1038/465009aPublished online05 May 2010 Governments have typically regulated their coastal waters as if fishing, shipping and the like were separate entities. A new, integrated approach could change all that — while greatly boosting marine science. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Although the US government's 28 April approval of a controversial wind farm off the coast of Massachusetts had little in common with the 22 April sinking of an oil rig off the Louisiana coast, or the environmentally catastrophic oil spill that followed, both events highlight the increasingly wide range of demands being made on coastal waters around the world. Government regulators are finding it ever more difficult to reconcile those demands, as wind turbines, off-shore aquaculture and a growing roster of other new activities jostle for space with the already long list of existing claimants, including fisheries, shipping lanes and recreational boating. These uses of the ocean are often incompatible not only with one another, but also with the need to protect what remains of fragile marine ecosystems. The difficulty of finding that balance has led some governments to radically rethink their sector-by-sector, statute-by-statute regulatory strategies, replacing them with a more coordinated decision-making process known as coastal and marine spatial planning (CMSP). The idea is to bring together all the stakeholders, from energy companies and government agencies to environmentalists and fishermen, to sort through the interdependencies and their long-term implications, and then to map out the uses permissible in any particular region. In effect, CMSP is zoning for the oceans. So far, leadership in CMSP has come mainly from Australia, from European countries such as Germany, Norway and the Netherlands, and from a handful of US states — notably Massachusetts, Florida and Oregon. The US federal government has lagged far behind, with different agencies regulating fisheries, energy, water quality and the like as if none of these activities had anything to do with the others. That could soon change. Within the next couple of months, US President Barack Obama is expected to announce a national ocean policy that would implement CMSP throughout the country. The policy has been under development by an interagency task force since June 2009, and a draft (see http://go.nature.com/zyx8Go) has been publicly circulating since December. The final policy will undoubtedly be tweaked to address public comments. But in broad outline it will call for US coastal waters to be divided into nine areas, each with a regional ocean council that will draw up a CMSP programme addressing local issues and priorities. A National Ocean Council would review each regional plan to ensure that it is compatible with the others and with national policy. As welcome as Obama's announcement will be, it is just the first step. Getting any necessary legislation passed, setting up the national and regional councils, reaching agreement on the roles of the states, Native American tribes and other stakeholders could take years. But both Congress and the Obama administration should pursue this goal as rapidly as possible. Meanwhile, they should also be pursuing the research required to ensure that CMSP is based on the best scientific information. One early priority, for example, will be to chart the biologically and ecologically important areas — not just on the sea floor, but throughout the water column, and not just once but over time, as populations move and habitats shift from season to season. Such maps are lacking in many US regions, but could prove invaluable for basic ocean science as well as for CMSP. Another goal will be to identify potential indicators for evaluating the effectiveness of the various plans. Are fishery closures helping to revive fish populations? Are marine protected areas working? And are the observed effects really due to the management plan, or to exogenous forces such as climate change? None of this research will come cheap. But Obama has already made a good start with his 2011 budget request for the National Oceanic and Atmospheric Administration, which asks for US$20 million to fund grants for regional CMSP work, and has a separate budget item for sea-floor mapping and charting. His request also includes $4 million for CMSP work by the US Geological Survey. Even if fully implemented, Obama's national ocean policy will not prevent every controversy or eliminate the danger of oil spills. But it would be a much-needed step in the right direction, and would move the United States to the forefront of efforts to make rational use of a finite and fragile resource. Additional data
• Up in the air
  - Nature 465(7294):9 (2010)
  Nature | Editorial Up in the air Journal name:NatureVolume:465,Pages:9–10Date published:(06 May 2010)DOI:doi:10.1038/465009bPublished online05 May 2010 Ways to obtain more accurate data can and should be put in place to police greenhouse-gas emissions. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg It is hardly surprising that climate discussions tend to gloss over uncertainties in data on greenhouse-gas emissions. Governments are struggling towards an international agreement to reduce those emissions, and their focus is necessarily on coming up with specific, enforceable targets. But the fact is that scientists' ability to measure emissions and verify that countries are following through on their commitments is far from adequate. And that is unlikely to change without the full engagement of governments and scientists. There are a number of reasons to be sceptical about current emissions data (see page 18). Some are a matter of human frailty: it is often in the best interests of both companies and governments to underestimate emissions, and thus to overstate the effectiveness of a given technology or policy in reducing them. That temptation will only increase as countries ramp up climate commitments. Other reasons, however, hinge on the uncertainties inherent in even the best emissions statistics. In the energy sector, for example, the statistics rely on imperfect estimates of, say, the amount of fuel moving through a pipe or leaking out of a valve. Emissions also vary from one chunk of coal to another, according to their origins, as well as among different kinds of crude oil. Outside the energy sector, the challenges are even more complex. Agricultural emissions vary from crop to crop and from farm to farm, and there is no single equation for estimating carbon uptake by forests. The further one digs down into the data, the more uncertainties one encounters. So what should be done? The US National Research Council tackled this question in a report issued in March, laying out a roadmap that could — and should — be implemented relatively cheaply over the next few years. The first task is to improve emissions inventories. At present, industrialized nations are required to report their annual emissions data to the United Nations each year, but these data need to be broken down by time, region and, as far as possible, by facility. Major developing countries would then need to be phased into this same system. These inventories are calculated using government and industry data. However, given the high economic stakes, even the most thorough such reporting will not suffice as evidence about which nations are and are not living up to their commitments. These emissions numbers will need to be independently verified with an expanded network of atmospheric measurements. To accomplish this, governments should extend and improve their verification efforts by increased monitoring of major facilities, cities and agricultural areas, as well as by supporting a global monitoring capability from space. Europe is making progress in this direction with a planned ground-based Integrated Carbon Observation System that could be rolled out within a few years, but efforts are needed around the world. Where satellites are concerned, the outlook is encouraging, although frustratingly slow. Japan is collecting initial data from GOSAT, its satellite for observing greenhouse gases; NASA, meanwhile, is pushing forward with a second Orbiting Carbon Observatory after losing the first during launch last year. All of these efforts need to be continued, strengthened and expanded. The specifics of who pays and how the data-gathering is managed will doubtless be hammered out over time, and may well have to be included in whatever international climate treaty finally emerges. But regardless of how the details play out, it's clear that those policing any such treaty will need a much more sophisticated monitoring system than the ad-hoc version in use today. Additional data
• Open to all
  - Nature 465(7294):10 (2010)
  Nature | Editorial Open to all Journal name:NatureVolume:465,Page:10Date published:(06 May 2010)DOI:doi:10.1038/465010aPublished online05 May 2010 A new approach to technology assessment would supplement expert opinion with input from society. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Ever since 1995, when a then-new Republican majority voted to close the US Congress Office of Technology Assessment (OTA) on the grounds that it wasn't necessary, calls have been made for its revival. Many say that the closure was short-sighted. Congress, like legislatures and executives in other nations, sorely needs a way to assess the complex scientific and technical issues involved in subjects such as climate change or genetically modified organisms. But anything that replaces the OTA will need to confront some marked changes to the political environment that prevailed two decades ago. Then, the OTA's stock in trade was expertise, with about 150 professional staff members marshalling the best available technical information to produce authoritative reports. Today, by contrast, the public and politicians alike are considerably less willing to accept the consensus of 'experts', even when it comes to technically grounded policy questions. The dominant strain in American domestic politics, as manifested in President Barack Obama's marshalling of grass-roots activists during his 2008 election campaign, and in the more recent 'Tea Party' movement against 'big' government, is a hunger for direct participation. Reinventing Technology Assessment, a 2010 report from the Woodrow Wilson International Center for Scholars in Washington DC that lays out a new vision for US technology assessment, points to recent international experience, particularly in Europe, and calls for a broader, 'participatory technology assessment' (pTA) model that would supplement expert opinion with early input from all corners of society. Such a model might have helped the US government to avoid spending 30 years and US$9 billion to develop the Yucca Mountain nuclear waste repository in Nevada, only for Obama to abandon the project last year in deference to local opposition. As National Academy of Sciences studies of risk assessment have inferred, it would have been wiser and cheaper to interact with the public at the beginning of the project, rather than at its end. Whatever the virtues of the pTA approach, however, it is likely to be tricky to implement. If the process is to be credible to the public, for example, it will have to be open and transparent. Yet the doors cannot be thrown open to anyone who shows up at a meeting; that would make the process vulnerable to manipulation by special-interest groups, which have become adept at drumming up phony 'astroturf' grass-roots movements and spreading misinformation to inflame public opinion. Instead, the pTA organizers would have to do a careful job of recruiting representative samples of citizens, and motivating them to participate — presumably by paying them. For decision-makers to listen, a pTA approach would have to be integrated with existing advisory mechanisms. One possibility would be to assign pTA responsibilities to well-established organizations such as Congress's Government Accountability Office, or the independent National Academies. Another possibility, advocated by the Wilson Center report, would be to create a non-governmental Expert and Citizen Assessment of Science and Technology network, which would include organizations with experience in public outreach such as non-partisan policy research institutions, universities and science museums. Whatever its institutional form, however, the pTA approach needs to be attempted. It is exactly what Congress needs as it grapples with complex technical issues, and is squarely in line with the stated objective of Democrat and Republican politicians to build wider public participation in decision-making. All that's required is for Congress itself to agree, on a bipartisan basis, to set it up. Additional data
• Ecology: Not-so-lonesome lizards
  - Nature 465(7294):12 (2010)
  
• Neuroscience: What makes masculinity?
  - Nature 465(7294):12 (2010)
  
• Oceanography: Deep-sea biomass boom
  - Nature 465(7294):12 (2010)
  
• Atmospheric science: Ozone high and low
  - Nature 465(7294):12 (2010)
  
• Microscopy: See through tissue
  - Nature 465(7294):12 (2010)
  
• Genomics: Rat sequencing redux
  - Nature 465(7294):12 (2010)
  
• Drug development: Virus knockdown
  - Nature 465(7294):13 (2010)
  
• Optical devices: Organic light
  - Nature 465(7294):13 (2010)
  
• Microbiology: Bacterial break up
  - Nature 465(7294):13 (2010)
  
• Cognitive neuroscience: Attention please!
  - Nature 465(7294):13 (2010)
  
• Journal club
  - Nature 465(7294):13 (2010)
  
• News briefing: 6 May 2010
  - Nature 465(7294):14 (2010)
  The week in science. This article is best viewed as a PDF. Policy|Business|Business watch|Events|Research|The week ahead|News maker|Number crunch Two of the most popular lines of human embryonic stem cells, H9 and H7, are now eligible for use by US-government-funded researchers. The lines were approved under the George W. Bush administration, but have spent months waiting for the green light (see Nature 464, 967; 2010) under a liberalized policy announced by President Barack Obama in March 2009. The National Institutes of Health in Bethesda, Maryland, added them, along with 11 other newcomers, to its registry of federally fundable stem-cell lines on 27 April. The State Council of China has announced that it will no longer bar people with HIV from entering the country. In a statement on 27 April, it said that the ban had a very limited effect in controlling diseases, and was inconvenient for those visiting major events. China joins South Korea and the United States in repealing HIV entry bans this year. The United Nations lists 51 countries, territories and areas with restrictions on the travel of HIV-positive individuals. The InterAcademy Council has picked the 12-member committee that will conduct an independent review of the procedures and processes of the Intergovernmental Panel on Climate Change. The council — an international organization based in Amsterdam that represents national science academies worldwide — chose economist Harold Shapiro, a former president of Princeton University and the University of Michigan to head the team (see go.nature.com/d9wy6A), which also includes ozone chemist and Nobel laureate Mario Molina. Its first meeting will be on 14–15 May, and it plans to deliver a peer-reviewed report to the United Nations, who requested the review, by 30 August. International efforts to significantly reduce the rate of biodiversity loss by 2010 have failed, a comprehensive study published on 29 April confirmed (Science doi:10.1126/science.1187512). The Convention on Biological Diversity set the target in 2002. The study tracked 31 indicators of ecosystem health, such as population trends and habitat conditions, from 1970 to the present; most showed no notable decreases in the rate of biodiversity loss. Britain's Royal Institution has settled its legal dispute with former director Susan Greenfield, who claimed sexual discrimination after she was sacked in January (see Nature 463, 140; 2010). A statement on 28 April said that the institution had reached full agreement on the terms of Greenfield's departure; neither the institution nor Greenfield would comment on those terms. Greenfield's supporters recently failed in an attempt to oust the council of the institution, which is facing severe financial difficulties. New council members are due for election at the institution's annual general meeting on 17 May. India's government introduced a bill to its parliament on 3 May that would enable foreign universities to set up campuses in the country, in an effort to raise the quality of higher education. Overseas institutions would have to guarantee and maintain a fund of 500 million rupees (US$11 million), and plough all profits back into their Indian branch. The legislation is thought to be unlikely to pass until the next parliamentary session of India's lower house starts at the end of July. The United States' first offshore wind farm was finally approved by Ken Salazar, Secretary of the Interior, on 28 April. The controversial US$1-billion project has been mired in regulatory review for nine years. Cape Wind Associates, headquartered in Boston, Massachusetts, plans to install 130 turbines off the coast of Cape Cod in Massachusetts, which will generate a maximum capacity of 468 megawatts. Opponents are vowing to fight the project in the courts. A treatment for prostate cancer has become the first therapeutic cancer vaccine to receive regulatory approval in the United States. On 29 April, the US Food and Drug Administration (FDA) approved Provenge (sipuleucel-T) to treat advanced hormone-resistant prostate cancer. Stock in Dendreon, the vaccine's Seattle, Washington-based manufacturer, rose 27% on the announcement. Provenge seemed on the cusp of approval three years ago, but the FDA demanded additional clinical trial data (see Nature 464, 1110–1111; 2010). The vaccine is tailor-made from a patient's own immune cells, and will cost about $93,000 per patient, the company said. The US Patent and Trademark Office last week ruled that a contested patent for growing embyronic stem cells, held by the Wisconsin Alumni Research Foundation (WARF), is invalid. The patent covers work done by stem-cell researcher James Thomson at the University of Wisconsin in the 1990s. The 28 April decision reverses the office's March 2008 ruling to uphold the patent in the face of challenges from the Public Patent Foundation, based in New York (see Nature 452, 265; 2008). Two similar patents upheld in 2008 were not eligible for appeal; all three expire in 2015. WARF says that it will appeal against the decision. See go.nature.com/VdjqmA for more. The drug giant AstraZeneca has agreed to pay US$520 million to settle US government allegations that it illegally promoted the anti-psychotic drug Seroquel (quetiapine fumarate) as a treatment for medical conditions for which it had not received approval — such as Alzheimer's disease, depression and sleeplessness. Under the terms of the agreement, disclosed last year but finalized on 27 April, the company continues to deny the allegations, which were first raised by the whistleblower James Wetta in 2004. AstraZeneca's total sales of Seroquel reached $4.87 billion last year. Click for a larger version.SOURCE: ERNST & YOUNG Biotech companies in the established markets of the United States, Canada, Australia and Europe reacted to a cash-constrained 2009 by cutting research and development costs and increasing efficiencies. The industry's belt-tightening efforts helped to dramatically increase its year-on-year profits (see chart), according to a 27 April review from analysts Ernst and Young. The United States saw an impressive upsurge in profitability despite the acquisition of biotech company Genentech by Roche, thus removing Genentech's billions of dollars of profit from the analysts' statistics. "Much of the cost-cutting in 2009 was precipitated by short-term thinking and the very real need to survive," the report notes. A greater number of public biotech companies survived the year than industry observers had anticipated: 622 existed in established markets as of December 2009 compared with 700 in 2008, and those that remain have built up greater reserves of cash this year. But, the report adds, "in seeking short-term survival, some companies may be hurting their long-term prospects". For example, the industry's research and development expenditures dropped 21%, from US$28.7 billion in 2008 to $22.6 billion in 2009. Meanwhile, biotech prospects in emerging markets such as China and India continued to blossom, although the report did not make quantitative comparisons. NASA/EARTH OBSERVATORY/J. ALLEN US ecologists and coastal residents are preparing for an environmental catastrophe to unfold over the coming months as oil flowing from a ruptured pipeline into the Gulf of Mexico starts to lap at the Louisiana shore. As Nature went to press, an oil slick and oily sheen covering thousands of square kilometres (white swirl pictured) was being blown towards the fragile marshlands of the Mississippi delta, while the oil spewing into the ocean after the explosion and sinking of the Deepwater Horizon oil rig on 20 April showed no signs of abating or being brought under control by frantic engineers, with at least 800,000 litres erupting from the well every day. See go.nature.com/qzXUgX for more. Russia and Italy plan to build an experimental nuclear-fusion reactor, called IGNITOR, according to an intra-governmental memorandum signed on 26 April in Milan. The 1.3-metre radius doughnut-shaped device (a tokamak) would heat and squeeze hydrogen isotopes to a self-sustaining plasma state. IGNITOR would be smaller and its magnetic fields stronger than Iter, the international fusion project under construction in St-Paul-lez-Durance, France, and would be built at the Troitsk Institute of Innovative and Thermonuclear Research near Moscow. See go.nature.com/tCSAwr for more. The James Martin 21st Century School at the University of Oxford, UK, said on 28 April that it had secured US$100 million for new research in just one year. The institute met the challenge of its main benefactor, philanthropist and computer scientist James Martin, to find donors to match his $50-million conditional pledge. The money will be used for 19 research projects into 'global problems facing humanity', such as the future of cities and vaccine design. Martin gave $100 million to establish the institute in 2005. The Vision Sciences Society's 10th annual meeting in Naples, Florida, brings together biologists, neuroscientists, computer scientists and cognitive psychologists to discuss vision and its relation to the brain. → http://www.visionsciences.org London's Royal Society hosts a meeting on research into ageing, and how to prevent ageing-related diseases. → go.nature.com/N6P4RV Large-scale genomic studies and the implications of genome research are on the agenda of The Biology of Genomes meeting in Cold Spring Harbor, New York. → go.nature.com/zMuMD3 Basic research and the clinical applications of stem-cell research are to be discussed at a European Molecular Biology Laboratory conference in Heidelberg, Germany. → go.nature.com/4jMNTl J. BRIERTY/NEWSPIX/NEWS LTD The Nuclear Compton Telescope, a NASA-funded gamma-ray probe, crashed on its 29 April balloon launch in Alice Springs, Australia. See go.nature.com/1x4xJn for more. The number of nuclear warheads maintained in the US stockpile, declared for the first time on the opening day of the United Nations nuclear non-proliferation conference in New York. Source: Financial Times, 3 May 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.
• The code within the code
  - Nature 465(7294):16 (2010)
  Computational biologists grapple with RNA's complexity. One of the most beautiful aspects of the genetic code is its simplicity: three letters of DNA combine in 64 different ways, easily spelled out in a handy table, to encode the 20 standard amino acids that combine to form a protein. RNA: a difficult beast to predict.LAGUNA DESIGN/SPL But between DNA and proteins comes RNA, and an expanding realm of complexity. RNA is a shape-shifter, sometimes carrying genetic messages and sometimes regulating them, adopting a multitude of structures that can affect its function. In a paper published in this issue (see page 53), a team of researchers led by Benjamin Blencowe and Brendan Frey of the University of Toronto in Ontario, Canada, reports the first attempt to define a second genetic code: one that predicts how segments of messenger RNA transcribed from a given gene can be mixed and matched to yield multiple products in different tissues, a process called alternative splicing. This time there is no simple table — in its place are algorithms that combine more than 200 different features of DNA with predictions of RNA structure. The work highlights the rapid progress that computational methods have made in modelling the RNA landscape. In addition to understanding alternative splicing, informatics is helping researchers to predict RNA structures, and to identify the targets of small regulatory snippets of RNA that do not encode protein. "It's an exciting time," says Christopher Burge, a computational biologist at the Massachusetts Institute of Technology in Cambridge. "There's going to be a lot of progress in the next few years." The floodgates were opened by high-throughput technologies that allow researchers to compile comprehensive catalogues of RNA molecules found in various tissues and under different environmental conditions. Such techniques revealed that 95% of the human genome is alternatively spliced, and that changes in this process accompany many diseases. But no one knew how to predict which form of a particular gene would be expressed in a given tissue. "The splicing code is a problem that we've been bashing our heads against for years," says Burge. "Now we finally have the technologies we need." "The splicing code is a problem that we've been bashing our heads against for years." Blencowe and Frey's team used the masses of data generated by these technologies to train a computer algorithm to predict the outcome of alternative splicing in mice. Given the DNA sequence of a particular gene, the algorithm predicts which segments of that DNA sequence will be included in a final messenger RNA molecule in one of four tissue types: the central nervous system, muscle, the digestive system and embryos. The model works well, says Burge, and is an important technological advance. But he hopes that it will be refined to mimic more closely the mechanism that the cellular splicing machinery uses to make its choices. Wiggle and jiggle The sequence of letters in an RNA molecule is not the only determinant of how the molecule will function. Its three-dimensional structure can also affect how it interacts with other molecules, including drugs that are designed to target it. "RNA forms highly flexible structures that wiggle and jiggle just due to thermal motion," says Hashim Al-Hashimi, a biophysicist at the University of Michigan in Ann Arbor. "It is very difficult to define them as a static structure." Structures of the same molecule determined using various techniques sometimes look wildly different, Al-Hashimi adds, because RNA is sensitive to even small variations in its environment. As a result, researchers including Al-Hashimi are eager to develop methods that will predict the three-dimensional structure of RNA on the basis of its sequence. At present, experimental techniques that reveal how an RNA molecule folds back on itself — its secondary structure — are fairly advanced. For example, in 2009, Kevin Weeks, a chemist at the University of North Carolina at Chapel Hill and his colleagues reported the full secondary structure of the HIV-1 genome — a strand of RNA about 9,000 letters long (J. M. Watts et al. Nature 460, 711–716; 2009). Al-Hashimi has developed a method that combines such two-dimensional structures with knowledge of the constraints on RNA flexibility to predict aspects of the three-dimensional structure (M. H. Bailor et al. Science 327, 202–206; 2010). But automated programs for predicting three-dimensional structures are still quite limited in scope and need refining, says Tamar Schlick, a computational chemist at New York University. Much of the enthusiasm for understanding RNA is motivated by the discovery of small RNAs that do not code for protein, yet can regulate gene expression. The hunt is on to catalogue these RNAs and their targets — a quest aided by advances in algorithm design and the accumulation of genome sequences. This allows researchers to search the vast stretches of noncoding DNA between genes: the conservation of sections in many species could suggest that they have important functions. ADVERTISEMENT But enthusiasm for finding functional noncoding RNAs may be getting out of hand, cautions Sean Eddy, a computational biologist at the Howard Hughes Medical Institute's Janelia Farm research campus in Ashburn, Virginia. Teams have reported thousands of such RNAs, but few researchers have followed up to confirm exactly what these RNAs do, or whether the molecules are simply aborted mistakes made by the machinery that converts DNA to RNA. For now, Burge says he is enjoying the ongoing renaissance in RNA informatics. "These new technologies have given me hope." 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.
• Nurse wants elite UK science focus
  - Nature 465(7294):16 (2010)
  Incoming head of Royal Society sets out his agenda. Paul Nurse has been nominated to be the next president of Britain's Royal Society.J. Hill/The Times/N.I. Syndication Less than 24 hours after being nominated as the new president of the Royal Society — Britain's national academy of science — Paul Nurse had already kicked off a controversy. In an interview published on 27 April in the British newspaper The Times, he argued for a more elitist approach to the funding of science. "You need a combination of special systems that attract and support those who are excellent," he said, "and rigorous reviews so that when they cease to be excellent, as many often are, they don't just hang on to those resources." The interview (conducted before his nomination) riled many scientists in Britain, who are suspicious of concentrating limited resources on a few leading lights at the expense of the many. Nurse now says that his comments were not meant as an attack on the system as a whole. "The words didn't come out quite right," he says, before adding: "I do think there's a need to think about how one supports the very best science, which might need to be dealt with a little bit differently from the rest." Speaking frankly is nothing new for the 61-year-old Nobel prizewinner. "Paul's quite opinionated," says Antony Carr, a biochemist at the University of Sussex, in Brighton, UK, who was a graduate student with Nurse in the mid-1980s. "Our lab meetings were fun but also a bit daunting at times," Carr recalls. "You were just waiting for him to tell you how it really was." "He can be kind of intense sometimes," adds Emily Nurse, one of his two daughters and a high-energy physicist at University College London. In earlier years, she says, she and her sister received many lectures on topics ranging from science to history. "I've never known anyone to be so interested in things," she says. Born into a working-class family, Nurse's straight talking and sharp scientific skills eventually won him the chair at the University of Oxford's department of microbiology in 1988. He took charge of the Imperial Cancer Research Fund in London in 1996, steering the fund through its 2002 merger with another charity, the Cancer Research Campaign, into Cancer Research UK. Nurse was convinced that the charities would work better together than as competitors, and persuaded nervous scientists in both that the merger would be a success. In 2001, he shared the Nobel Prize for Physiology or Medicine for his work on the genetics of cell division in yeast and humans. Two years later he was made president of the Rockefeller University in New York. While at Rockefeller, Nurse kept a toe on the other side of the pond. He heads the scientific advisory panel for the UK Centre for Medical Research and Innovation, a £520 million (US$780 million) biomedical research centre planned for the heart of London. Many of his peers say that a move to the top job at the Royal Society is a natural step. "He was, I think it's fair to say, the obvious choice," says Robert May, a zoologist at the University of Oxford, UK, and a former president of the society. Nurse has the perfect blend of academic credentials and political clout for the job, May says. "He just ticks all the boxes." Nurse's appointment will have to be confirmed by the fellows of the Royal Society on 8 July and he would not assume the post until 30 November. He says he is not yet ready to discuss his plans as president, but campaigning for greater support for the very best scientists in Britain is squarely on his agenda. The idea comes from his experience as a trustee of the Howard Hughes Medical Institute in Chevy Chase, Maryland, which gives top scientists long-term support to set up labs in their most productive years, rather than doling out money for specific research projects. In November 2009, the Wellcome Trust, Britain's largest non-governmental funder of biomedical research, unveiled a similar plan (see Nature 462, 145; 2009). Nurse says he would like to see something like this applied to government funding. He suggests that 100–150 leading researchers across all disciplines would receive enough money to fully fund their research, allowing them to hire staff and buy equipment. Their grants would be regularly reviewed to ensure that they were still producing work worthy of the support. Such a programme would cost only around £100 million to £200 million per year, he says, amounting to a few per cent of the UK government's science budget. ADVERTISEMENT Despite the disquiet over Nurse's interview in The Times, Carr says that most researchers will be willing to at least hear Nurse out on this and other ideas. "People are a little nervous," says Carr, "but if you didn't have someone with opinions, then things wouldn't get done." Nurse will certainly have plenty to do as president of the Royal Society, which the government consults on policy and funding issues. Cash will be a key issue following a general election on 6 May, when the incoming government looks set to cut public spending, including science funding. In April, Nurse signed a letter attacking the opposition Conservative Party's science policy and supporting the incumbent Labour government. But he insists that "there will be no problem with me working with whoever ends up in power. I would argue for science." 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.
• Greenhouse-gas numbers up in the air
  - Nature 465(7294):18 (2010)
  To control emissions, countries must first account accurately for their carbon. That will take considerable effort, reports Jeff Tollefson. The state of California is about to become a giant playground for more than 200 atmospheric scientists. Beginning this week and extending into July, aircraft will criss-cross the skies, measuring an array of greenhouse gases, aerosols and other atmospheric properties as they fly over cities, industrial facilities and agricultural areas. Dozens of scientists will man two ground stations, while a ship monitors the air off the coast and two electric vehicles zip about collecting samples upwind and downwind of selected sites. One of three NOAA aircraft that will measure greenhouse gases above California.J. EDDS/CORBIS Organized by the California Air Resources Board and the National Oceanic and Atmospheric Administration (NOAA) in Boulder, Colorado, the 'CalNex' campaign is designed to take a detailed snapshot of the air above California. Scientists plan to study a host of issues relating to air quality and global warming, but one of the primary goals will be to plug holes and reduce nagging uncertainties in the state's two-year-old inventory of greenhouse-gas emissions. Much depends on the veracity of those numbers, including the state's commitment to reduce such emissions to 80% below 1990 levels by mid-century. And the challenge is not unique to California. Developed countries that are party to the United Nations Framework Convention on Climate Change (UNFCCC) are required to report inventories of their yearly greenhouse-gas emissions. Yet those numbers are riddled with uncertainties, and independent estimates suggest that the total reported emissions for some gases may be off by more than 50%. If a future global-warming treaty is to have any credibility, scientists and governments need to develop a reliable system for verifying greenhouse-gas emissions around the globe. "Countries have a tendency to always report a little bit less because it looks good, and nobody can prove that they are wrong unless we go to the atmosphere," says Ingeborg Levin, an atmospheric physicist at the University of Heidelberg in Germany. "Countries have a tendency to always report a little bit less because it looks good." Levin is one of many scientists developing air-sampling networks, computer models and satellites to assess the origin and amount of greenhouse-gas emissions. She sees the California programme as a model and says that governments need to begin working with scientists to reduce uncertainties in their emissions inventories. "It is extremely difficult to do this accurately," she says. "It must be a concerted effort between the people who do the inventories and the people who do the measurements." In March, the US National Research Council (NRC) weighed in, calling for more detailed inventories from industrialized countries and an expansion and improvement of greenhouse-gas monitoring networks everywhere. The NRC estimated that it would cost just US$11 million over five years to improve greenhouse-gas reporting systems among the 10 largest developing countries, which are not currently required to report their annual emissions to the United Nations climate framework. In principle, these countries agreed to additional reporting requirements as part of the Copenhagen climate accord signed in December, but developing and developed nations are still negotiating how to structure a verification system. Finding all the carbon Much of the current focus is on emissions from fossil fuels, which account for more than half of the global greenhouse gases pumped into the atmosphere annually, and are the easiest to quantify. Essentially all of the carbon in fossil fuels winds up in the atmosphere as carbon dioxide after combustion, and so carbon dioxide emissions can be calculated directly from a country's fuel consumption. Emission inventories from industrialized northern countries with reliable energy statistics have relatively small uncertainties, but there is still more guesswork than many care to acknowledge. In developing countries, where data remain sparse and emissions are rising, the numbers are even less reliable. "We're making silk purses from sows' ears," says Gregg Marland, a scientist with the Energy Department's Carbon Dioxide Information Analysis Center (CDIAC) in Oak Ridge, Tennessee. Even discrepancies of 5–10% can be significant, as many countries are trying to reduce their emissions by similar magnitudes in the next few years. One of the best estimates for global carbon emissions comes from CDIAC, which collects information from the United Nations, agencies within various countries and industrial organizations to build its own independent inventory. The centre analyses those data to provide more specific information about where and when greenhouse gases were emitted. CDIAC estimated global carbon dioxide emissions at 30.2 billion tonnes in 2006, not including changes in land use. But Marland says that figure comes with an uncertainty of 6–10%. And the picture gets fuzzier with other gases. The NRC report gave uncertainties ranging from below 25% to more than 100% for reported emissions of other greenhouse gases, as well as carbon dioxide from agriculture and other land uses. In a quest to improve emissions estimates, scientists are pushing governments to expand their monitoring networks. NOAA currently heads a network of some 150 greenhouse-gas monitoring stations around the world, but these stations were originally sited to avoid major pollution sources because scientists at the time were more interested in large-scale trends, rather than in monitoring particular pollution emitters. The agency is now moving in the opposite direction, seeking to expand the network to cover cities, agricultural areas and major industrial sources. In Europe, scientists are pushing forward with the Integrated Carbon Observation System (ICOS), which aims by 2014 to convert a series of about 50 independent monitoring stations into a single network with uniform monitoring capabilities; it would also add 20 stations to provide finer resolution in key areas. In all, ICOS would cost €150 million to €200 million ($200 million to $266 million) up front, with operating costs of €25 million annually. In California, as part of CalNex, NOAA plans to use aircraft to sample pollution plumes downwind of cities, refineries, power plants and agricultural fields. One target in the Los Angeles area is methane. The state built its inventory for that gas using standard calculations recommended by the Intergovernmental Panel on Climate Change, but a recent sampling study suggests that actual emissions could be one-third higher than estimated. New tools Click for a larger version.SOURCE: I. LEVIN ET AL. ATMOS. CHEM. PHYS 10, 2655–2662; 2010 Carbon dioxide is also released by plants and animals, so to gain an accurate picture of the contribution of fossil-fuel burning, researchers are developing new tools to differentiate between 'natural' and fossil-fuel carbon in the atmosphere. One technique relies on the radioactive isotope carbon-14, which occurs in trace amounts in atmospheric carbon dioxide. This isotope is taken up and released by plants, but fossil fuels have no carbon-14 because it has a relatively short half-life and they have been buried for millions of years. By taking air samples and measuring their carbon-14 content, researchers can work out how much of the carbon dioxide comes from the biosphere and how much from fossil-fuel emissions. "If you do this on a large scale, it actually sharpens our view of the biosphere," says Pieter Tans, a senior scientist at NOAA's Earth System Research Laboratory in Boulder. Levin has been regularly measuring carbon-14 content in air samples from Germany using a version of a Geiger counter, but Tans and other researchers have recently turned to accelerator mass spectrometry, which is faster and easier to scale up. The NRC committee, which included Tans, recommended ramping up annual carbon-14 measurements to 10,000 worldwide at a cost of $5 million to $10 million. Such detailed monitoring should help scientists calibrate measurements from carbon-monitoring satellites. At present, US and Japanese scientists are busy interpreting initial data from a Japanese satellite, and NASA is planning to launch a second version of the Orbiting Carbon Observatory by 2013 (a rocket failure sent the first one hurtling into the Pacific Ocean in February 2009). The French are currently developing another satellite. "If you want to know if there is a change in emissions from 2010 to 2020, we have to do the measurements now." Many see satellite measurements as a more reliable way to verify greenhouse-gas emissions. "Everybody can look at the emissions of others in a very transparent way," says Philippe Ciais, who doubles as ICOS coordinator and associate director of the Laboratory for Climate Sciences and the Environment in Gif-sur-Yvette, France. Carbon dioxide monitoring and control will be only one part of any future climate treaty; gases such as methane, nitrous oxide and various fluorine-containing compounds have a powerful warming effect and must be monitored as well. The European Commission and the Netherlands Environmental Assessment Agency have teamed up to create an independent inventory for these lesser greenhouse gases. Called the Emissions Database for Global Atmospheric Research (EDGAR), the inventory collects data from international, national and industrial sources to estimate emissions. ADVERTISEMENT At the University of Heidelberg, Levin used EDGAR's assessment as well as direct measurements taken at 14 locations around the globe to calculate emissions of sulphur hexafluoride (SF6), a fireproof insulator used in electrical equipment. A molecule of SF6 has nearly 24,000 times the warming power of a carbon dioxide molecule and remains in the atmosphere for around 3,200 years, which means that essentially all the SF6 ever emitted by humans is still in the atmosphere. Levin's work suggests that SF6 emissions by industrialized countries could be twice as high as those reported to the UNFCCC (see 'Keeping tabs on a greenhouse gas'). Levin says that her finding shows the pitfalls of relying on self-reporting. "If you want to know if there is a change in emissions from 2010 to 2020, we have to do the measurements now, starting in 2010," she says. "I cannot go out today and get air from Heidelberg in September last year. The air is gone." 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.
• Green patents corralled
  - Nature 465(7294):21 (2010)
  Intellectual-property database could ease technology transfer. Driven by efforts to curb fossil-fuel use and concerns about the security of energy supplies, the number of applications for renewable-energy patents is booming. But the patents are scattered across many databases, in different formats that are not readily searchable, leading to a lack of clarity over who owns specific energy-technology patents, and in which regions. This is not only holding up technological progress, it has also become a sticking point in international climate-treaty negotiations. So, in a bid to better inform scientists, businesses and policy-makers, the European Patent Office (EPO) in Munich, Germany, has developed an extensive, free global database of 600,000 clean-energy patents. Click for a larger version. The EPO trawled through 60 million patent documents and re-classified clean-energy patents according to 160 technical categories, such as carbon capture and solar photovoltaics. This should make it much easier to find patent information. The database launches in June through esp@cenet (www.espacenet.com), a gateway to European patent databases. Last year, the EPO received 1,259 renewable-energy patent applications, up 27% from 2008, and the new database will be updated daily to include the growing number of energy patents filed at patent offices worldwide (see 'Going green'). Users will be able to quickly find information about the dozens of components used in wind turbines, for example, and who owns the respective patent rights, says Konstantinos Karachalios, an EPO official who is overseeing the project. That should help to overcome a major hurdle in getting new energy technologies into developing countries (see Nature 462, 555; 2009). "Patents, licensing practices and technology transfer from rich to poor countries are major issues in the fight against climate change," says Ahmed Abdel Latif, the programme manager for intellectual property at the International Centre for Trade and Sustainable Development, a non-governmental advocacy group based in Geneva, Switzerland. As such, he says, this database is "vital". Attempts to revive negotiations on an international climate-change treaty, after a disappointing result at the Copenhagen talks last year, are still being held up by the lack of information about the technologies that developing countries need to tackle global warming, says Wanna Tanunchaiwatana, head of adaptation, technology and science at the United Nations Framework Convention on Climate Change. A clean coal plant, for example, requires a bewildering array of patented processes and devices, but identifying who owns them all can be a major challenge. "Issues around [intellectual property] are not going to disappear," Tanunchaiwatana told the European Patent Forum last week in Madrid, where the new energy database was unveiled. But whether this will help scientists working on clean technologies is an open question. "As a scientist, I'd rather rely on scientific journals than on patent descriptions," says Michael Grätzel, a chemist at the Swiss Federal Institute of Technology in Lausanne, who owns several patents on photovoltaic technologies. There is no guarantee that data contained in patent descriptions are reliable, he warns — nor even that the experiments have been conducted as described. "A patent first and foremost signals an investor interest, but it tells you little about the actual science." The EPO now plans to create similar databases for clean technology in the fields of transport, buildings and agriculture. 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.
• Greeks hope crisis may spark reform
  - Nature 465(7294):22 (2010)
  Financial troubles could be the stimulus for a fairer distribution of science research funding. Achilleas Mitsos hopes to establish research funding councils and competitive grants in Greece.A. ABBOTT As Greece teeters on the edge of bankruptcy, austerity measures are already hitting researchers hard in their pockets. But their labs will be buffered by a huge reserve of European Union (EU) structural funds — subsidies for poor regions — already earmarked for research. And Greek research leaders think the crisis could help shake up a system they say emphasizes security over excellence. As part of a national package of emergency measures, Greek scientists' pay was cut by around 10% in March. Institutional research funding, already among the lowest in Europe, was slashed by around 15%. Further cuts are now on the cards after Greece signed a financial bail-out deal with the EU and the International Monetary Fund on 2 May. Hiring of new staff has mostly stopped. "Lower salaries make Greece even less competitive, and even Greeks abroad may be less tempted to come home," says George Kollias, the director of the Alexander Fleming Biomedical Sciences Research Centre in Vari. But research leaders hope that the financial crisis will ultimately help them to push through much-needed reforms. "We are not going to sit and cry," says George Thireos, a research director at the prestigious new Bioacademy in Athens. "The crisis here is an opportunity to restructure science policy in Greece, to make better use of low budgets." At the forefront of the reform effort is Achilleas Mitsos, recently appointed general secretary for research and technology (see go.nature.com/hIga1J). He is planning legislation that will establish research councils and introduce evaluation at all levels, with funds distributed according to performance. Initial resistance to the changes from researchers comfortable with an undemanding civil-service life has dwindled in the face of the economic crisis. Mitsos says that he will "spend fast" the €1.5 billion (US$2 billion) pot of EU structural funds, made available to Greece for the 2007–13 period but which are so far untouched. Any money remaining by the end of 2013 must be returned to Brussels. He will tap €300 million to €400 million of these funds each year for the next three years. This will financially compensate for most of the institutional austerity cuts, he says, adding that the funds "will all be distributed through competition". He says that he will announce a call for infrastructure proposals imminently; a call for postdoctoral fellowships in June; and calls for strategic research programmes around October. All applications will have to be in English, and "we will do as much as possible to impose peer review to the highest standard on these calls", he says. The EU-funded plans offer more support than has been available in the past five or six years, when the Greek government did not make any major calls for research proposals, says physicist Costas Fotakis, director of the Institute of Electronic Structure and Laser in Heraklion. "If they really are realized quickly, they will dispel the negative cloud that the general atmosphere has cast over us," he says. 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.
• European funding may get simpler
  - Nature 465(7294):22 (2010)
  Research commissioner promises to cut red tape in framework programmes. Too many top scientists avoid applying for funds from the European Union (EU) framework research programmes because they can't stand the bureaucracy involved, says EU research commissioner Máire Geoghegan-Quinn. European research funding should be based on trust, she says. So last week she unveiled a plan that would reduce the detailed accounting demanded by the current funding system, which releases funds bit by bit as project milestones are met. She hopes to win approval from the financially risk-averse European Parliament and the Council of the European Union for the rule changes, which would award funds in lump sums with only a single audit. The changes would take effect with the next big EU funding round, the Eighth Framework Programme (FP8), which is due to start in 2014. Scientists in Europe enjoy the imaginative collaborations created by EU research projects, which require partnerships across different countries and tackle problems relevant to EU policies, such as health and energy. But the red tape is extreme. Form-filling requirements have been relaxed slightly under the Seventh Framework Programme (FP7), and Geoghegan-Quinn promises that she will extend this relaxation as far as possible under existing rules. But scientists must still show how their research plans affect diverse EU policies, from gender issues to innovation. They must also define numerous milestones, and estimate how many months each participant will need for his or her part in achieving them — estimates that must be revised every year, when all money spent has to be accounted for, and any deviations from the plan have to be re-costed and justified. If framework projects could be funded with a lump sum it would transform the whole programme, says neuroscientist Gilles Pourtois from the University of Ghent in Belgium. In 2008, Pourtois won a prestigious Starting Grant from the European Research Council, which awards generous individual grants, but he has so far avoided framework programmes, which he says are overwhelming. He would, however, apply for FP8 funding if the process were simplified. The complexity of the framework programmes is partly a result of precautionary auditing measures instituted after a 1999 corruption scandal involving the then research commissioner Edith Cresson. Geoghegan-Quinn, a former member of the European Court of Auditors, insists that simplification will not compromise good financial management — provided that the final audits are sound — and will not increase the risk of fraud. 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.
• Seismology: The biggest one
  - Nature 465(7294):24 (2010)
  Fifty years ago this month, a massive earthquake in Chile broke new ground in seismic science. Roff Smith looks back at the largest quake ever recorded. Download a PDF of this story. When a massive earthquake rocked southern Chile early one Saturday morning in May 1960, those residents who were lucky enough to rise from the rubble could have been forgiven for thinking that they'd just come through the worst that nature could deliver. The force of the earthquake that had just levelled their villages would later be estimated at magnitude 8.1 — the largest shock Earth had produced in more than a year. As authorities in Santiago scrambled to send aid to the stricken region, they could not have foreseen that such a monumental earthquake was merely a drum roll for the main event. The following afternoon, on 22 May, the earth convulsed so violently that it wobbled the planet and sent it ringing for days on end. In the decades afterwards, seismologists would pore over their printouts trying to understand just how incredibly strong that earthquake was. They would go on to devise a whole new way to measure seismic tremors and assign the 1960 event a value of 9.5 on the logarithmic magnitude scale — to this day the most powerful earthquake on record. With an energy more than 20,000 times greater than the bomb that destroyed Hiroshima, the earthquake killed at least 1,500 people in Chile and spawned a tsunami 25 metres high that obliterated coastal villages and threw ships at anchor more than a kilometre inland. The tsunami raced across the Pacific Ocean, taking 61 lives in Hilo, Hawaii, before hammering an unsuspecting Japan and killing about 140 people there, 17,000 kilometres away from the quake's epicentre. "This was a planetary monster," says Tom Jordan, director of the Southern California Earthquake Center in Los Angeles. "An earthquake in South America that killed people in Japan." Half a century after the event, the monster continues to fascinate and intrigue, even in the face of recent, deadlier quakes, such as January's disastrous shock in Haiti. This month, the American Geophysical Union will hold a conference on giant earthquakes and tsunamis in Valparaíso, Chile, with many delegates making a 50th anniversary pilgrimage to the site of the 1960 quake to marvel at the seismic scars in the landscape and the sediments deposited by the tsunami that followed. "Here is the benchmark, the superlative event in recent seismic history." "Here is the benchmark, the superlative event in recent seismic history," says Brian Atwater, of the US Geological Survey's Earthquake Hazards Team in Seattle, Washington, who is a convenor of the conference. It was a benchmark in the history of seismology as well. The Great Chilean Earthquake of 1960 provided seismologists with their first unambiguous evidence of the planet's free oscillations — the harmonic vibrations that ring the planet like a bell after it has been hit by a major jolt. Over the intervening years, researchers have learned how to use those free oscillations like a planetary CAT scan to discern the inner structure of Earth. Lifesaving legacy In the decade after 1960, the Chilean quake and the magnitude-9.2 Alaska earthquake of 1964 would both become persuasive arguments in support of the radical theory of plate tectonics — providing textbook examples of subduction zone earthquakes, in which one tectonic plate is forced under another. Beyond teaching basic lessons about the planet, the quake also left a legacy that has saved lives. It spurred nations around the Pacific to set up an international tsunami warning system in the 1960s. The tsunami deposits left by this event give geologists a model for identifying other spots that might be prone to giant earthquakes, such as the Cascadia subduction zone off the western coast of North America. In many ways, however, the Chilean monster was a quake before its time, coming as it did just on the cusp of a technological and theoretical revolution in Earth sciences. "Had this earthquake happened only ten years later, we could have learned so much more from it," says Seth Stein, a seismologist at Northwestern University in Evanston, Illinois. In 1960, with the concept of plate tectonics still in the future, researchers did not understand how to place the quake in a geophysical context. And the global network of seismometers that could have provided so much information would not be in place for another three years. Click for a larger version.SOURCE: USGS The 1960 event happened when a fault zone running down Chile's coastline ruptured along about 1,000 kilometres of its length (see map). The tectonic plates on either side of the fault slipped 20–30 metres past each other — releasing centuries of accumulated energy in several terrifying minutes. The earthquake was not only the biggest ever recorded, at 9.5 it approaches the upper limit of what the planet is likely to ever produce in a single event. "This is not to say a bigger quake couldn't eventually happen," says Richard Aster, a geophysicist at the New Mexico Institute of Mining and Technology in Socorro and president of the Seismological Society of America. "It could. But you wouldn't get one much bigger. Faults are only so big and so strong." To illustrate the size of this quake, Aster has added up the seismic energy of all the world's earthquakes throughout the twentieth century, including the monster in Chile, and the 9-plus quakes in Kamchatka in 1952 and Alaska in 1964. He threw in the magnitude-9.2 Sumatra quake of 2004 for good measure and imagined all this energy unleashed in a single cataclysmic event. That would equal a magnitude-9.95 earthquake. "You're just not going to get a 10," says Aster. And yet of that mountain of energy — the entire planet's seismic release for more than 100 years — one-quarter of it can be attributed to the single catastrophic event centred near Cañete, on the southern Chilean coast. It was twice as powerful as its nearest rival, the 1964 Alaska quake. Groundbreaking behaviour Among those who will be attending the anniversary commemoration at Valdivia is Hiroo Kanamori of the California Institute of Technology in Pasadena, one of the doyens of seismology who helped create the moment magnitude scale to accurately measure the size of great earthquakes. He has spent the past year re-examining the 50-year-old data from the 1960 earthquake, intrigued not only by the quake's sheer size and scale, but also by its unique behaviour. Kanamori, who recalculated the size of the earliest earthquake in the sequence says "who would have imagined that you could have an 8.1 as a foreshock? And yet this is just the beginning of a spectacular foreshock sequence." In the 33 hours before the main event, there were about 6 quakes larger than magnitude 6, and one with an estimated magnitude 7.8 coming just 15 minutes before the big one itself, he says. "As far as I am aware there has never been a foreshock sequence like this." "Who would have imagined that you could have a magnitude-8.1 earthquake as a foreshock?" Perhaps even more curious are some strange, long-period vibrations recorded by a seismogram at Pasadena less than 15 minutes before the main earthquake, says Kanamori. Those readings suggest the big one might have been preceded by a powerful, slow earthquake deep underground, which helped catapult what might otherwise have been 'merely' a giant earthquake into a category all its own. There are some hints that other great earthquakes, such as the 1944 Tonankai shock in Japan, may also have had these slow precursors, which on their own do not produce damaging vibrations. But as with the Great Chilean Earthquake, the fragmentary evidence tantalizes more than reveals. Unfortunately, the violence of the foreshocks in Chile obscured the readings on the handful of other high-quality seismometers that were working at the time, so there is no independent confirmation for the curious readings at Pasadena. But local eyewitnesses also hint that something unusual happened in the moments preceding the magnitude-9.5 main shock. Two geophysicists in Concepción, about 200 kilometres from the quake's epicentre, recalled that the quake began with a gentle rocking sensation rather than an abrupt jolt that typically heralds the start of a giant shock. "One of them noticed parked cars rolling back and forth on the street," Kanamori says. "This is a very unusual description of the beginnings of a great earthquake, but these were trained seismologists so you have to take them seriously." If there was indeed such a deep, slow precursor event, it could make the Great Chilean Earthquake of 1960 of wider relevance. "This is very similar to how many scientists believe a great subduction-zone earthquake would start along the Cascadia plate boundary," says Kanamori. That region has bouts of slow earthquakes about every 14 months or so, which prompts some researchers to suspect that the subduction zone there might share similarities with the one off Chile. ADVERTISEMENT There are no written records of great earthquakes happening in the Pacific Northwest, but Atwater and other geoscientists have become convinced that quakes in the magnitude-9 range have pummelled that region in the past. In fact, sand deposits left by the 1960 Chilean tsunami helped Atwater and others discover that giant waves once pounded the coasts of western North America and Japan from a Cascadian earthquake centuries ago. Giant jolts such as these make difficult subjects for scientists to study because they strike only once every 300 years — or even less frequently. But the globe is now wired up with hundreds of sensitive and readily accessible seismometers. So when the next monster strikes, whenever and wherever it may be, says Kanamori, "we will be able to understand it far better than we did for the 1960 Chile earthquake". Roff Smith is a freelance writer based in Hastings, UK. 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.
• Neuroscience: Illuminating the brain
  - Nature 465(7294):26 (2010)
  Systems neuroscientists are pushing aside their electrophysiology rigs to make room for the tools of 'optogenetics'. Lizzie Buchen reports from a field in the process of reinvention. Download a PDF of this story. The centrifuge tube was the first that neuroscientist Philip Sabes had held in his hand for 15 years. The small, polypropylene container, no larger than a AAA battery, held a few drops of liquid at its base. It looked like water but, Sabes had been told by his collaborators, it contained a high concentration of viruses — and he had to get them into the brain of a monkey. "Honestly, I really felt like I didn't know what I was doing," says Sabes, of his work last November at the Keck Center for Integrative Neuroscience at the University of California, San Francisco (UCSF). "I basically knew nothing about molecular biology. This was way outside my area of expertise." Sabes's training was in physics, machine learning and human perception, and his lab has been working with humans and non-human primates to develop models of how the brain turns perceptions into actions; for example, seeing a fly and swatting it away. He's not alone in his molecular-biology naivety at the Keck Center — there is no cell-culture facility, no PCR machine and no bench-top centrifuge. The centre's one ice machine spits out large cubes instead of the crushed ice routinely used for chilling reagents — it was ordered by mistake, and no one has cared enough to fix the situation. Sabes and his colleagues have had no need for such apparatus. Researchers in their field of 'systems neuroscience' try to understand how networks of neurons process sensations and control behaviours such as learning and decision-making. And up to this point, much of their progress has been made using electrophysiology, stimulating and recording from the brains of animals as they perform a ! task or develop a new skill. Now though, advances in a five-year-old field called optogenetics are convincing these scientists to crack open molecular-biology textbooks. Using a hybrid of genetics, virology and optics, the techniques involved enable researchers to instantaneously activate or silence specific groups of neurons within circuits with a precision that electrophysiology and other standard methods do not allow. Systems neuroscientists have longed for such an advance, which allows them their first real opportunity to pick apart the labyrinthine jumble of cell types in a circuit and test what each one does. "It has revolutionized my approach to science," says Antonello Bonci, a neurophysiologist at the UCSF Ernest Gallo Clinic and Research Center in Emeryville who began using the technique in 2007. "It can clarify unequivocally the role of specific classes of cells, and solve controversies that have been going on for many, many years." Among the clarifications sought is the precise function of '! place' cells, hippocampal neurons that fire only when an animal finds itself in a specific location; another is the function of complex activity patterns observed when an animal is paying attention or executing a movement. "Optogentics can solve controversies that have been going on for many, many years." A field's evolution The transition phase isn't easy. Optogenetic tools were first used in cell cultures and mice, which are amenable to genetic manipulation. Now systems neuroscientists must adapt them to function in organisms they traditionally study such as rats, birds and primates. With the technical challenge comes a personal one, as researchers leave their experimental comfort zone for a new field. Most, however, anticipate that any discomfort will be worthwhile. "This is God's gift to neurophysiologists," says Robert Desimone, director of the McGovern Institute for Brain Research at the Massachusetts Institute of Technology (MIT) in Cambridge, who has been using electrophysiology for more than 30 years. "Molecular techniques were always beyond us, so this is our first opportunity. It's a revolution. But we're catching up to the revolution that had been going on for the rest of the world." Optogenetics started out in 2005, when a team at Stanford University in California led by Karl Deisseroth and his then-postdoc Ed Boyden inserted a light-sensitive channel from green algae, called channelrhodopsin-2 (ChR2), into neurons growing in a dish. Exposed to a pulse of blue light, the channels opened and a flood of positive ions poured into the neurons, making them fire1. Within a year, 30 labs had contacted Deisseroth to ask for the technology. By March 2010, Deisseroth had sent protocols or genetic constructs to more than 500 labs around the world, and Boyden, now at MIT, had sent them to in excess of 250. Click for a larger version. The technique has been refined greatly in the past five years, but the basic steps are the same (see 'Six steps to optogenetics'). First, researchers create a genetic construct containing the ChR2 gene or another 'opsin' gene, along with genetic elements that control its expression — for example, a specific 'promoter' sequence. Then, they package up the construct in a virus. When the virus is injected into an animal's brain, it widely infects neurons and delivers the construct, but the opsin is expressed in only a subgroup of cells with the necessary machinery to activate its promoter. The opsin proteins sit in the membrane of those neurons, and researchers trigger them with light of a specific wavelength, typically delivered through an optic fibre threaded through an animal's skull. Deisseroth and Boyden have discovered or engineered many other opsins that allow neurons to be manipulated in different ways, including neural silencers. The technique is popular, but complex. The fastest adopters were those who work with cells grown in vitro and animals such as flies, worms and mice, for which they could take advantage of established genetic tools and well-characterized animal lines. "The number of tangible results are still of the order of half a dozen or so. But we're on the rising phase of the exponential," says Karel Svoboda, a neuroscientist at the Howard Hughes Medical Institute's Janelia Farm research campus in Ashburn, Virginia, who last year started mapping mouse cortical circuits using optogenetics2. From the start, these developments sent quivers through the systems-neuroscience community. "When I first saw this stuff, at a meeting where Karl was presenting some of the earliest results, I thought, 'Oh God, finally'," says Loren Frank, another neuroscientist at the Keck Center. "And then I thought, oh great. Here I was, I'd gotten pretty good at the stuff I thought I needed to do, and now I have to learn an entirely new field." Frank — who says he has "always had a bit of molecular-biology envy" — began collaborating with Deisseroth to use optogenetics on rats just over three years ago, for his studies of place cells and hippocampal circuits. Silencing or activating specific cells could help show whether or how they help an animal explore a new location or recognize a familiar one. "If you want to actually understand the system, you have to start trying to get control of the system and actually dissect the circuit," says Frank. Standard techniques have not allowed that type of dissection. Electrodes inserted into an animal's brain typically stimulate hundreds of thousands of cells; using lesions or drugs also hits circuits like a hammer. Optogenetics could be a scalpel, turning particular neurons in a circuit on or off within milliseconds. From brain to behaviour By April 2009, Frank was making progress in rats, achieving ChR2 expression in a discrete set of hippocampal neurons and getting them to fire. And down the hall, Sabes was ready to try the technique in primates as part of his efforts to understand circuits involved in hand-eye coordination. "I knew optogenetics was on the horizon, and it was potentially exciting, but realistically, I just didn't know anything about this stuff," he says. Sabes and two songbird researchers at the Keck Center, Michael Brainard and Allison Doupe, teamed up with Frank, Deisseroth and another colleague, Linda Wilbrecht, a neuroscientist at the Gallo Center. The group, one of the first big collaborations aiming to apply optogenetics to rats, birds and primates, received a US$1.6-million National Institutes of Health grant in September 2009 through the financial stimulus. The neuroscientists describe what they'd like to do — in Sabes's case, for example, alter patterns of activity that occur in the parietal lobe when an animal reaches for something, and work out which patterns are important for planning, initiating or adjusting the movement. Wilbrecht's lab leads efforts to generate the appropriate constructs and select the best viruses, and Deisseroth tries to build new viral and optogenetic tools that they need. One huge advantage for mouse researchers has been the ready-made bank of animal lines engineered to express an enzyme called Cre recombinase in subsets of neurons, such as all dopaminergic ones, which they can use in combination with specially designed genetic constructs to achieve the cellular specificity they want. In other animals, a promoter must be found that will only be turned on in dopaminergic neurons. Some promoters and viruses that work in mice do not work in rats or primates, meaning that researchers have to start from scratch. Progress has been faster in rats because the animals are relatively easy to breed and are similar enough to mice for methods to be transferable. In March 2009, Deisseroth was the first to publish a rat optogenetic study, in which he manipulated circuit components in a rat model of Parkinson's disease to work out which parts might account for the relief afforded by deep-brain stimulation3. An additional complication for primate researchers is that primate brains are larger than those of rodents, making it difficult to ensure the injected virus and the activating light penetrate deep enough. And troubleshooting in monkeys will take much longer than in rats, given the long lifetime and high value — experimental, financial and ethical — of the animals. But in April 2009, Desimone and his colleagues worked with Boyden to publish the first experiment showing that viruses can be used to insert opsin channels and control neural activity in a macaque4. "It felt like garage-development days, cutting stuff up to see what works." By November 2009, Sabes could be found holding his tube of virus, trying to get a similar primate system going in his lab. This was a pilot experiment: he was simply trying to see if he could get some of the virus into neurons at all. After bending and breaking a few needles, he successfully injected the tube's contents into a monkey's brain. He and two graduate students then hacked together an 'optrode' by gluing together a fibre-optic cable and an electrode. They fed the wires through a head fixture normally used for electrophysiology, and rigged half of a syringe as a support. "It felt very much like garage-development days, cutting stuff up to see what works," says Sabes. In January, with the optrode inserted into the region where the virus had been injected two months earlier, Sabes flipped on a blue laser and watched a screen showing electrical readout from the optrode. Yellow waveforms flashed across the screen, paired with a flurry of clicking noises: spikes of neural activity. Experts on hand Like Sabes, the few other electrophysiologists starting to tackle primate optogenetics are keeping experts in the technique close by to avoid making a novice's mistakes (see 'Opto school'). "It's critical that at least the initial phase is collaborative," says Krishna Shenoy, a primate electrophysiologist at Stanford University who has been working closely with Deisseroth for two years to explore how neurons in the brain's motor cortex control arm movements. Boyden's paper is still the only optogenetics publication on primates, and the technique is some way from generating new discoveries. It's still not known whether the opsins will be expressed consistently for the year or two required to train monkeys in sophisticated behaviours and then record from neurons repeatedly. "If it only expresses at the right level for a few months and then dies off or expresses too much, it's just untenable," says Shenoy. All these questions take time and money to answer, and not every lab has an appetite for the work. "It's probably going to have a big impact, and I'm definitely interested," says Tirin Moore, a neurobiologist at Stanford. "But I'm less interested in pioneering the approach in monkeys and more interested in using the tools once it's clear that they work." Meanwhile, Boyden and Deisseroth are hammering out some of the problems. Last month, Deisseroth reported a system in mice that could make detailed knowledge of promoters unnecessary: two viruses containing separate genetic constructs are injected into two connected brain regions. Only neurons that run between the two regions will receive doses of both constructs, which then interact to express the opsin5. Boyden is designing a light source that would weigh a fraction of a gram so that animals can walk around freely rather than being tethered to a fibre-optic cable. "Soon enough, this is going to be standard technology," says Sabes. "The hardware will be there, the viruses will be there, there will be a handful of constructs that everyone agrees works reasonably well." That aim is likely to be furthered by a two-year, $14.9-million grant from the US Defense Advanced Research Projects Agency in Arlington, Virginia, that Sabes, Deisseroth and six other labs, led by Shenoy, won in April. The team will attempt to use primate optogenetics to explore brain repair after injury, including possible light-based neural prosthetics, devices that might stimulate appropriate patterns of activity in the surviving neurons. ADVERTISEMENT For now, Sabes is still trying to analyse the results of his first monkey experiment. He has sent the animal's brain to a friend competent in histology, who will slice it, paper thin, onto slides. Then Sabes will have to grapple with a fluorescent microscope for the first time, trying to work out where and how well the opsin was actually expressed. "I'm sure it's not that hard," says Sabes, "but I've never done it". Lizzie Buchen is a freelance writer based in San Francisco. * References * Boyden, E. S. , Zhang, F. , Bamberg, E. , Nagel, G. & Deisseroth, K.Nature Neurosci.8, 1263-1268 (2005). * Petreanu, L. , Mao, T. , Sternson, S. M. & Svoboda, K.Nature457, 1142-1145 (2009). * Gradinaru, V. , Mogri, M. , Thompson, K. R. , Henderson, J. M. & Deisseroth, K.Science324, 354-359 (2009). * Han, X.et al. Neuron62, 191-198 (2009). * Gradinaru, V.et al. Cell141, 154-165 (2010). 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: Brick by brick
  - Nature 465(7294):29 (2010)
  A small non-profit organization shows how to reduce the vulnerability of poor countries to earthquakes, says Daniel Sarewitz. Driven by population growth, urbanization and poverty, earthquake casualties worldwide continue to rise. The latest event struck on 14 April in western China, killing more than 2,200 people — a grisly coda to January's catastrophe in Haiti, which left about 230,000 dead. These disasters are no surprise, and they teach us little that is new. After each one, offers of help come from many quarters. Scientists want to do their part, which often means promising new information that will help to make things better in the future. For example, the Global Earthquake Model (GEM), a public–private partnership initiated by the Organisation for Economic Co-operation and Development and funded in significant part by insurance companies, says it will focus on "underserved areas such as Haiti … [to] make sure that organizations, (local) governments and individuals have access to its state-of-the-art risk assessment software and tools as a necessary first step towards taking mitigation action". Yet "access" to information delivered via the latest technological interfaces is not what developing countries such as Haiti need to better protect themselves against earthquakes. Much more important are institutional and social arrangements that can mobilize existing knowledge and resources. Such arrangements do not emerge spontaneously in countries that are struggling to meet the basic needs of citizens. A catalyst is required. You don't have to be rich In 1991, seismologist Brian Tucker left his job as deputy chief at the California Division of Mines and Geology and founded GeoHazards International (GHI) in Palo Alto, California, to help reduce earthquake vulnerability in developing countries. The non-profit organization's approach is improvisational and personal. "When we go to a new setting, we try to find out who is really interested in doing something to improve earthquake safety," Tucker says. "We have to find people who are really passionate and will carry on once we're gone. We try to build up the credibility of these people, and get more resources to do what they want. We work with who we find, in their profession, not try to change them into something they're not." In the mid-1990s when GHI wanted to start a project in Nepal's Kathmandu Valley, Tucker met Amod Dixit, a geotechnical engineer who hoped to start a local non-profit organization to reduce the risk from earthquakes in his country. GHI worked with Dixit to support demonstration projects around Kathmandu that could build visibility and a sense of possibility. In one such project, local engineers trained masons to strengthen a school. Walls were connected together with steel mesh, and joined to the roof and floor with iron bars. The building's single exit door was rehung so that it opened outwards, and a second exit was added. "People who lived nearby watched as the work progressed," says Tucker. "The magic thing is that when I came back ten years later, I learned that when people in this village wanted to add onto their house or build a new house, they would get advice from the masons from our project on how to do it correctly. And the masons trained other masons in the area, ! while Dixit's non-profit exported the approach to many other villages in the region." In contrast to the Nepal project, GHI's work in Delhi, India, found its passionate collaborators in the city's public-works department, where officials were concerned about the vulnerability of crucial public buildings. India has many highly qualified seismologists and earthquake engineers at its excellent technical universities, but they weren't well connected to one other or to government workers responsible for protecting the city against earthquakes. So GHI acted as a neutral organizer, using international earthquake experts to get the attention of the nation's top academics, and bringing them together with city officials to design ways to strengthen existing hospitals, schools and police stations. "Believe it or not," says Tucker, "our project was the first chance for many of these people to come together to show what they could do." By the project's end, two buildings were retrofitted, five other schools were identified for future repair and the public-works department! had the capacity to continue this work after GHI was gone. GHI's newest project is in Padang, Indonesia, a city of about 1 million inhabitants that occupies a flat plain at sea level. Last September 1,000 people died there in an earthquake. But given Padang's location, the much greater danger is tsunamis. The latest research on wave height and return period doesn't address Padang's needs; the real problem is simply that there is not enough time to evacuate. Immediately after September's earthquake many residents, fearing a tsunami, sought higher ground but instead ended up in a massive traffic jam. No tsunami occurred, but the likelihood of one in the future is high, and the death toll could reach 100,000. How to save 100,000 lives Unlike other cities where thousands of buildings would need to be retrofitted to save 100,000 lives, in Padang it would only take a half-dozen or so elevated parks in the city to allow for 'vertical evacuation'. Constructing these facilities would not only be relatively cheap and simple, but would yield immediate psychological benefits by assuaging the sense of foreboding and powerlessness that Padang's residents live with every day. GHI is now seeking funds to start this work. "Knowledge that is useful is knowledge that emerges within a particular social and institutional context." What makes GHI distinct from big-science, high-tech endeavours such as GEM is that Tucker starts by understanding and immersing himself in the local context of the problem that needs to be solved. GEM starts in the opposite place, offering the latest science and tools to solve a problem regardless of whether that's what the problem demands. This approach reflects a great fallacy of the modern ideology of science: that scientific knowledge is a public good, equally available and potentially equally beneficial to all. But knowledge that is useful — and used — is knowledge that emerges within a particular social and institutional context. If scientists are serious about helping to reduce the vulnerability of poor regions to earthquakes and other hazards, they would do well to emulate the model of GeoHazards International. Daniel Sarewitz, co-director of the Consortium for Science, Policy and Outcomes at Arizona State University, is based in Washington DC. e-mail: dsarewitz@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.
• European money could end delays on essential facilities
  - Nature 465(7294):31 (2010)
  I endorse the proposal for the European Union (EU) to increase its financial support of large European research facilities (Nature464, 659; 2010). But it would be better to concentrate this on a few essential facilities, rather than using the money to subsidize the running costs of hundreds of different ones.
• Independent research offers freedom and opportunities
  - Nature 465(7294):31 (2010)
  Andrea Schweitzer makes a strong case, in her Prospects article, for independently pursuing science outside academia (Nature 464, 945; 2010). Another bonus is the freedom to pursue lines of inquiry that run counter to prevailing paradigms.
• Earthquake defence and the price of a telescope
  - Nature 465(7294):31 (2010)
  We welcome the European Southern Observatory's decision to site the European Extremely Large Telescope (E-ELT) at Cerro Armazones in Chile.In his Correspondence on the subject, Francisco Sánchez argues that the high seismicity of Chile's Armazones region could damage the telescope's optical systems (Nature464, 977; 2010).
• Questionable value of planting thirsty trees in dry regions
  - Nature 465(7294):31 (2010)
  To alleviate land degradation, China's government is investing huge amounts of money in afforestation. But long-term results indicate that these projects could be exacerbating environmental degradation in arid and semi-arid regions, damaging soil ecosystems, reducing vegetation diversity and cover, and increasing water shortages (S. Cao Environ. Sci. Technol. 42, 1826–1831; 2008
• Financial pain should focus universities
  - Nature 465(7294):32 (2010)
  The tightening of the US science budgets could improve both teaching and research, argues Diane Auer Jones — by forcing academics and their institutions to play to their strengths.
• Reflections on the ozone hole
  - Nature 465(7294):34 (2010)
  Jonathan Shanklin, one of the team who discovered the thinning ozone layer over the Antarctic 25 years ago, reflects on lessons learned from a tale of luck, public perception and fast environmental change.
• Chemistry's visual origins
  - Nature 465(7294):36 (2010)
  Vivid imagination was key to unlocking the secrets of molecular structure in the nineteenth century, finds Andrew Robinson.
• Managing career moves
  - Nature 465(7294):37 (2010)
  Scientific excellence is widely believed to result from an individual's talents and creativity, rather than from their circumstances. In today's era of mobility, top talent in any discipline seems free to glide from institution to institution in search of the best rewards.
• Medical treasures on show
  - Nature 465(7294):37 (2010)
  Marking the 200th anniversary this year of Stockholm's Karolinska Institute — Sweden's leading medical university — are more than 100 rare medical illustrations from its historic collection, on display at Stockholm's Waldemarsudde Museum.From Andreas Vesalius's anatomical depictions to digitally enhanced visualizations of the human body by photographer Lennart Nilsson, the exhibition Läke Konst (Art of Medicine) highlights beautiful and unusual medical images dating from the fifteenth century to the present day.
• Geophysics: A new turn for Earth's rotation
  - Nature 465(7294):39 (2010)
  Earth's spin rate varies with time. A six-year periodic signal in the planet's core is partly responsible, and increases the interior magnetic-field strength to much higher levels than previously thought.
• Biochemistry: Getting the metal right
  - Nature 465(7294):40 (2010)
  Controversy has raged over the identity of the metal cofactor of membrane-bound methane monooxygenase, a methane-oxidizing enzyme. A study suggests that the answer is a cluster of two copper ions.
• Nonlinear dynamics: Optoelectronic chaos
  - Nature 465(7294):41 (2010)
  Optoelectronic circuits with delayed feedback provide a convenient bench-top platform to study a wide range of nonlinear dynamic systems, from ultrastable clocks to complex chaotic devices.
• Hepatitis C: An unsuspected drug target
  - Nature 465(7294):42 (2010)
  Infection with hepatitis C is one of the main causes of liver disease, yet there are no broadly effective treatments. Discovery of a potent inhibitor of this virus shows that researchers must think outside the box.
• 50 & 100 years ago
  - Nature 465(7294):43 (2010)
  Health in Industry. By Donald Hunter — The history of occupational disease spreads over many years and, until comparatively recently, ailments like beat knee, 'stagmus', writer's cramp, grocer's itch and cotton-workers' throat were accepted as heavenly or other visitations about which little could be done.
• Materials science: Muscle mimic
  - Nature 465(7294):44 (2010)
  An elastic polymer has been made whose molecular structure mimics that of titin, a protein found in muscle. The resulting material is tough, stretchy and dissipates energy — just like muscle itself.
• Gene regulation: Breaking the second genetic code
  - Nature 465(7294):45 (2010)
  Diverse messenger RNAs, and thus proteins, can be generated from a single piece of DNA. A computational approach is helping to uncover complex combinatorial rules by which specific gene instructions are selected.
• Addendum
  - Nature 465(7294):46 (2010)
  Nature | Addendum Addendum Journal name:NatureVolume:465,Page:46Date published:(06 May 2010)DOI:doi:10.1038/465046aPublished online05 May 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Gökhan S. Hotamisligil, a co-author of the News & Views article 'Metabolism: Host and microbes in a pickle' (Nature464, 1287–1288; 2010) declared a competing financial interest that was not noted in the print or PDF versions of the article. The declaration can be found in the fulltext online version. Additional data
• Olfactory pattern classification by discrete neuronal network states
  Niessing J Friedrich RW - Nature 465(7294):47 (2010)
  Nature | Article Olfactory pattern classification by discrete neuronal network states * Jörn Niessing1 Search for this author in: * NPG journals * PubMed * Google Scholar * Rainer W. Friedrich1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:47–52Date published:(06 May 2010)DOI:doi:10.1038/nature08961Received27 July 2009Accepted24 February 2010Published online14 April 2010 Abstract * Abstract * 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 The categorial nature of sensory, cognitive and behavioural acts indicates that the brain classifies neuronal activity patterns into discrete representations. Pattern classification may be achieved by abrupt switching between discrete activity states of neuronal circuits, but few experimental studies have directly tested this. We gradually varied the concentration or molecular identity of odours and optically measured responses across output neurons of the olfactory bulb in zebrafish. Whereas population activity patterns were largely insensitive to changes in odour concentration, morphing of one odour into another resulted in abrupt transitions between odour representations. These transitions were mediated by coordinated response changes among small neuronal ensembles rather than by shifts in the global network state. The olfactory bulb therefore classifies odour-evoked input patterns into many discrete and defined output patterns, as proposed by attractor models. This compu! tation is consistent with perceptual phenomena and may represent a general information processing strategy in the brain. View full text Subject terms: * Neuroscience * Biophysics * Physiology Figures at a glance * Figure 1: Concentration dependence of mitral cell odour responses. , Mitral cell (MC) marker expression (left) and raw, time-averaged calcium signals evoked by different concentrations of Lys, a blank (Bl), and the similar control odour Arg. Bottom: raw calcium signals of mitral cells depicted by arrows as a function of time. Scale bar: 25 μm. , Temporally deconvolved calcium signals (TDCa signals) as a function of time, evoked by the same stimuli in five individual mitral cells (different mitral cells than in ). Grey bar indicates odour application. , TDCa signals averaged over the population of all recorded mitral cells (n = 140 mitral cells from 4 olfactory bulbs). Apparent increases in TDCa signals before response onset (t = 0) are mainly due to low-pass filtering of signals (see Methods). , Time series of correlation matrices depicting the pairwise similarity between mitral cell activity patterns evoked by all stimuli in successive time bins. , Representations of odour-evoked activity patterns as a function of time in principal comp! onent space (2,048 ms before response onset through to 4,096 ms after response onset). Time is indicated by increasing size of plot symbols (interval: 256 ms). Arrowheads mark response onset and point in the direction of time. , Mitral cell activity patterns in principal component space, time-averaged during the steady state (1,536–2,304 ms). * Figure 2: Morphing of similar odours. , TDCa signals as a function of time evoked by the morphing series Phe/Trp in four mitral cells. The grey bar indicates odour application. , TDCa signals averaged over the population of all recorded mitral cells (n = 156 mitral cells from 9 olfactory bulbs). , Correlation between activity patterns in successive time bins. Arrows in corners depict correlations between patterns of pure odours. Bottom: sections through correlation matrices at the position indicated by the line; autocorrelations were replaced by interpolated values. The steep transition at later time points shows the sharp separation of clusters of patterns. , Representation of activity patterns in principal component space (1,280 ms before response onset through to 2,304 ms after response onset). Time is indicated by increasing size of plot symbols (interval: 256 ms); arrowheads mark response onset and point in the direction of time. , Mitral cell activity patterns in principal component space, time-ave! raged during the steady state (1,536–2,432 ms). * Figure 3: Morphing of dissimilar odours. , Correlation between mitral cell activity patterns evoked by the morphing series Arg/His in successive time bins (n = 141 mitral cells in 7 olfactory bulbs). Arrows in corners depict correlations between patterns evoked by pure odours. Bottom: sections through correlation matrices at the position indicated by the line; autocorrelations were replaced by interpolated values. Two transition points and a stable intermediate range are apparent, indicating that patterns become separated into three clusters. , Representation of activity patterns in principal component space. Conventions as in Fig. 2d. , Mitral cell activity patterns in principal component space, time-averaged during the steady state (1,536–2,432 ms). * Figure 4: Transitions between activity patterns are mediated by subsets of mitral cells. , Left: response matrix depicting responses of all mitral cells (n = 156 from 9 fish) to a morph of similar odours (Phe/Trp) at 768 ms after response onset. Responses were centred and normalized to the maximum of the population response. Mitral cells were ranked by the covariance of their response profiles with a template (bottom) that specifies the transition point between population activity patterns (see Fig. 2c). Right: response matrix from the same data set after shuffling of stimulus identities for each mitral cell. , Response matrices of mitral cells from three individual fish, each ranked in the same fashion and scaled individually. , Correlation between mitral cell activity patterns evoked by the morphing series Phe/Trp after eliminating the 10% of mitral cells with the most pronounced transitions (highest absolute covariance with template in ). The sharp transition between patterns was completely abolished (compare to Fig. 2c; same data set). , Left: matrix of al! l mitral cell responses (n = 141 from 7 fish) to a morph of dissimilar odours (Arg/His), ranked by covariance with a template specifying both pattern transitions (see Fig. 3a). Centre, right: matrices of mitral cell responses ranked by covariance with templates specifying only the first (centre) or second (right) transition. Author information * Abstract * Author information * Supplementary information * Comments Affiliations * Friedrich Miescher Institute for Biomedical Research, Maulbeerstr. 66, CH-4058 Basel, Switzerland * Jörn Niessing & * Rainer W. Friedrich Contributions J.N. performed all experiments and analysed the data. R.W.F. constructed equipment and participated in data analysis. R.W.F. and J.N. conceived the study and wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Rainer W. Friedrich (Rainer.Friedrich@fmi.ch) Supplementary information * Abstract * Author information * Supplementary information * Comments Movies * Supplementary Movie 1 (3.6M) In this movie file we see that the trajectories, in 3D-principal component space, show the temporal evolution of odor response patterns evoked by different concentrations of Lys and the control odor Arg (10-5 M). Conventions are as in Figure 1e. * Supplementary Movie 2 (6.5M) In this movie file we see that the trajectories, in 3D-principal component space, show the temporal evolution of odor response patterns evoked by different concentrations of Phe and the control odor Trp (10-5 M). Conventions are as in Supplementary Figure 2g. * Supplementary Movie 3 (6.1M) In this movie file we see that the trajectories, in 3D-principal component space, show the temporal evolution of odor response patterns evoked by a morphing series from Phe to Trp, projected into the space defined by the first three principal components. Conventions are as in Figure 2d. * Supplementary Movie 4 (3.1M) In this movie file we see that the trajectories, in 3D-principal component space, show the temporal evolution of odor response patterns evoked by a morphing series from Arg to His, projected into the space defined by the first three principal components. Conventions are as in Figure 3b. PDF files * Supplementary Information (2.2M) This file contains Supplementary Figures 1-11 with legends and Supplementary References. Additional data
• Deciphering the splicing code
  - Nature 465(7294):53 (2010)
  Nature | Article Deciphering the splicing code * Yoseph Barash1, 2, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * John A. Calarco2, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Weijun Gao1 Search for this author in: * NPG journals * PubMed * Google Scholar * Qun Pan2 Search for this author in: * NPG journals * PubMed * Google Scholar * Xinchen Wang1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ofer Shai1 Search for this author in: * NPG journals * PubMed * Google Scholar * Benjamin J. Blencowe2 Search for this author in: * NPG journals * PubMed * Google Scholar * Brendan J. Frey1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:53–59Date published:(06 May 2010)DOI:doi:10.1038/nature09000Received09 December 2009Accepted09 March 2010 Abstract * Abstract * 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 Alternative splicing has a crucial role in the generation of biological complexity, and its misregulation is often involved in human disease. Here we describe the assembly of a 'splicing code', which uses combinations of hundreds of RNA features to predict tissue-dependent changes in alternative splicing for thousands of exons. The code determines new classes of splicing patterns, identifies distinct regulatory programs in different tissues, and identifies mutation-verified regulatory sequences. Widespread regulatory strategies are revealed, including the use of unexpectedly large combinations of features, the establishment of low exon inclusion levels that are overcome by features in specific tissues, the appearance of features deeper into introns than previously appreciated, and the modulation of splice variant levels by transcript structure characteristics. The code detected a class of exons whose inclusion silences expression in adult tissues by activating nonsense-m! ediated messenger RNA decay, but whose exclusion promotes expression during embryogenesis. The code facilitates the discovery and detailed characterization of regulated alternative splicing events on a genome-wide scale. View full text Subject terms: * Molecular biology * Medical research * Genetics * Genomics * Computing science Figures at a glance * Figure 1: Assembling the splicing code. , The code extracts hundreds of RNA features (known/new/short motifs and transcript structure features) from any exon of interest (red), its neighbouring exons (yellow) and intervening introns (blue). It then predicts whether or not the exon is alternatively spliced, and if so, whether the exon's inclusion level will increase or decrease in a given tissue, relative to others. , , Code assembly proceeds by recursively adding features to maximize an information measure of code quality (), and different feature types are preferred at different stages of assembly (). , The final assembled code achieves higher code quality than simpler codes derived using previously reported features and feature subsets. Cons, conservation; w/o, without. Error bars represent 1 s.d. * Figure 2: Predicting tissue-regulated alternative splicing. , Classification rates for the final assembled code and simpler codes, assessed using microarray data (n = 28,920). , Accuracy of the code in predicting microarray- and RT–PCR-measured changes in exon inclusion levels between pairs of tissues (n = 346 and n = 208). Error bars represent 1 s.d. , For each exon and pair of tissues, the RT–PCR-measured change in the percentage inclusion is plotted against the code-predicted change in the probability of exon inclusion. Dashed lines indicate RT–PCR differences exceeding 1 s.d. in measurement error. , RT–PCR data for four exons, plus code predictions indicating relative increases (dark shading) or decreases (light shading) in the exon inclusion level. * Figure 3: Graphical depiction of the splicing code. , The region-specific activity of each feature in increased exon inclusion (red bar) or exclusion (blue bar) is shown for CNS (C), muscle (M), embryo (E) and digestive (D) tissues, plus a tissue-independent mixture (I). A bar with/without a black hat indicates activity due to feature depletion/enrichment. Bar size conveys enrichment P-value; P < 0.005 in all cases. Potential feature binding proteins are shown in parentheses. –, Unexpectedly frequent feature pairs were identified and used to generate feature interaction networks for CNS (), muscle () and embryonic () tissues. Node size and colour indicate the feature's P-value and region (see colour key in ). Red/blue edges correspond to increased inclusion/exclusion and edge thickness conveys interaction P-value (false discovery rate-corrected Fisher test); P < 0.05 in all cases. A thick/thin node boundary indicates activity due to feature depletion/enrichment. * Figure 4: Validation of a regulatory feature map. Regulatory elements in the intron upstream of exon 16 in Daam1 predicted to be associated with CNS-specific increased exon inclusion. , Putative features (grey blocks), along with code-selected features from the compendium and the unbiased motif set (red blocks). Twelve segments were selected for testing (blue blocks), including one not overlapping with predictions (7), and 15 minigene reporters with single- or combined-segment substitutions were constructed and transfected into neuroblastoma (N2A) and epithelial (NIH-3T3) cells. , RT–PCR results for the wild type and 15 mutants. , Mutations of several nPTB-like elements support code-predicted synergistic interactions. , Mutations of several CU and CUG elements between 55 and 90 nucleotides support code-predicted antagonistic interactions. Symbol size indicates the percentage exon inclusion (0–83.7%). * Figure 5: The code predicts a mechanism for developmental regulation. , The code identified a class of PTC-introducing exons predicted to activate NMD when included in adult tissues, but to allow mRNA expression when skipped in embryonic tissues. , RT–PCR data monitoring splicing and mRNA expression levels of transcripts from Xpo4, which contains a code-predicted PTC-introducing exon, in four adult tissues (cortex, cerebellum, kidney and liver) and three embryonic samples (embryonic day (E)9.5, E12.5 and E15). , RT–PCR data monitoring mRNA levels of the NMD factor Upf1 and the PTC-containing Xpo4 isoform in neuroblastoma (N2A) cells transfected with control siRNAs or Upf1 siRNAs. The Xpo4 PTC-containing isoform was selectively amplified using an exon-specific primer. Gapdh mRNA levels represent a loading control. Author information * Abstract * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Yoseph Barash & * John A. Calarco Affiliations * Biomedical Engineering, Department of Electrical and Computer Engineering, University of Toronto, 10 King's College Road, Toronto M5S 3G4, Canada * Yoseph Barash, * Weijun Gao, * Xinchen Wang, * Ofer Shai & * Brendan J. Frey * Banting and Best Department of Medical Research and Department of Molecular Genetics, Donnelly Centre, University of Toronto, 160 College Street, Toronto M5S 3E1, Canada * Yoseph Barash, * John A. Calarco, * Qun Pan, * Xinchen Wang, * Benjamin J. Blencowe & * Brendan J. Frey * Microsoft Research, 7 J. J. Thomson Avenue, Cambridge CB3 0FB, UK * Brendan J. Frey Contributions Y.B. and B.J.F. developed the predictive framework and code assembly algorithms, analysed validation rates, and with B.J.B. and J.A.C. extracted predictions for regulatory mechanisms. Y.B., B.J.B. and B.J.F. produced the feature compendium. J.A.C. performed wet laboratory experiments. Q.P. generated exon and intron datasets. W.G. and Y.B. developed the web tool with input from the other authors. X.W. analysed exons from neurological disorder-associated genes. O.S. estimated the percentage inclusion values. B.J.F., B.J.B. and Y.B. designed the study and wrote the manuscript with input from the other authors. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Brendan J. Frey (frey@psi.toronto.edu) or * Benjamin J. Blencowe (b.blencowe@utoronto.ca) Supplementary information * Abstract * Author information * Supplementary information * Comments PDF files * Supplementary information (2.4M) This file contains Supplementary Information and Data, Supplementary Figures 1-3, Supplementary Tables 1-2 and References. Additional data
• H2 emission arises outside photodissociation regions in ultraluminous infrared galaxies
  - Nature 465(7294):60 (2010)
  Nature | Letter H2 emission arises outside photodissociation regions in ultraluminous infrared galaxies * Nadia L. Zakamska1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Pages:60–63Date published:(06 May 2010)DOI:doi:10.1038/nature09037Received15 June 2009Accepted18 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 Ultraluminous infrared galaxies are among the most luminous objects in the local Universe and are thought to be powered by intense star formation1, 2. It has been shown that in these objects the rotational spectral lines of molecular hydrogen observed at mid-infrared wavelengths are not affected by dust obscuration3, but left unresolved was the source of excitation for this emission. Here I report an analysis of archival Spitzer Space Telescope data on ultraluminous infrared galaxies and demonstrate that dust obscuration affects star formation indicators but not molecular hydrogen. I thereby establish that the emission of H2 is not co-spatial with the buried starburst activity and originates outside the obscured regions. This is unexpected in light of the standard view that H2 emission is directly associated with star-formation activity3, 4, 5. I propose the alternative view that H2 emission in these objects traces shocks in the surrounding material that are excited by inter! actions with nearby galaxies. Large-scale shocks cooling by means of H2 emission may accordingly be more common than previously thought. In the early Universe, a boost in H2 emission by this process may have accelerated the cooling of matter as it collapsed to form the first stars and galaxies, and would make these first structures more readily observable6. View full text Subject terms: * Astronomy * Astrophysics Figures at a glance * Figure 1: Wavelengths of emission features present in ULIRG spectra and representative opacity curves. If emission regions are embedded in dust or ice, those emission features that are near the peaks of opacity should be the ones most strongly affected. If H2 emission originates inside silicate dust obscuration (example opacities25, 26, 27 in black), then S(3) should be strongly extinguished, S(1) somewhat less so, and other lines still less. If PAH emission originates inside obscuration, the features centred at 8.5 μm and 11.3 μm should be more affected by silicates than are the other features, and PAH[6.2 μm] is the only feature that may be affected by water ice (grey; smoothed data for the whole complex28 and laboratory data for water ice29, shown at the maximum strength according to the S[6.0 μm] = 0.6S[9.7 μm] relation; Supplementary Information). * Figure 2: PAH features are affected by dust extinction. Evidence for the effect of dust extinction on PAH features comes from correlations of the observed ratios of PAH fluxes (, ) and the PAH/F(IR) ratios (, ) with the apparent strength of the silicate opacity feature. Spearman's rank probabilities of the null hypothesis that the plotted values are uncorrelated are P[NH] = 10-4 (), P[NH] = 10-5 () and P[NH] = 10-5 (). In , the observed PAH[11.3 μm]/PAH[6.2 μm] ratio (grey points) is uncorrelated with the absorption strength (P[NH] = 0.22); but when PAH[6.2 μm] is corrected for water-ice absorption (black points), the correlation becomes apparent (P[NH] = 2 × 10-3), suggesting that the PAH emitting region is located behind both silicate absorption and water-ice absorption. In and , PAH ratios calculated for the comparison sample of nearby star-forming galaxies12, 30 are shown by an ellipse whose semi-axes are determined by the standard deviation of the corresponding measure. Although PAH ratios are known to vary a! s functions of physical conditions30, those seen in ULIRGs are consistent with those found in the comparison sample when extrapolated to low absorption. The dashed lines in – illustrate how unobscured ratios would change in the presence of an increasing amount of cold dust between the emitter and the observer for representative opacity curves26, 27. In and , the model calculation assumes that all absorbed flux is re-emitted at longer wavelengths, but that the total flux does not change. PAHs constitute a greater fraction of the total luminosity output in low-luminosity galaxies (estimates shown with dotted ellipses) than they do in ULIRGs13. The grey shaded areas show the 1σ range in the vertical offset around the best linear fit for ULIRG data. Points denote detections, arrows denote 3σ upper limits, and 1σ standard errors are shown in each panel except , where individual error bars are omitted for clarity and the median error is shown in the bottom left corner. * Figure 3: H2 emission in ULIRGs is not affected by extinction and shows excess over the H2/PAH ratio observed in normal galaxies. The ratios of H2 fluxes (, ) and the H2/F(IR) ratios () for ULIRGs from two samples (points7; crosses3) are uncorrelated with the apparent strength of the silicate absorption. In , R[J1/J2, J3] is the ratio of the observed flux of the line S(J1) to that expected on the basis of S(J2) and S(J3) assuming all three lines come from a region with a single excitation temperature. Grey areas in and and black dashed lines in show the expected trends of line ratios with apparent silicate strength if H2 emission is behind a screen of dust. Dark grey areas correspond to models with an ortho/para ratio of 3 and a realistic range of excitation temperatures, whereas light grey areas are an extension of the model to include ortho/para ratios between 1 and 3. Although correlations are expected if H2 is affected by silicate absorption, none are detected (P[NH] = 5–75%). In , if H2 and PAH emission had the same spatial distribution, the H2/PAH ratios would be expected to decrease (dashed ! lines as in Fig. 2) because dust opacity at the wavelength of the H2 line is greater than that at the wavelength of the PAH feature; but in fact an increase is observed (P[NH] = 0.007 (top), 0.016 (bottom)). The H2/PAH ratios are described better by a model that combines an obscured component of H2 associated with star formation and an unobscured H2 component with luminosity equal to or somewhat greater than that of the obscured component (solid lines: L[H2, outer]/L[H2, inner] = 1 (top), 1.5 (bottom)). Arrows denote 3σ upper and lower limits, and 1σ standard errors are shown for all measurements. Ellipses show flux ratios for comparison galaxies (semi-axes are determined by the standard deviation of the corresponding measure). Author information * Author information * Supplementary information * Comments Affiliations * Institute for Advanced Study, Einstein Drive, Princeton, New Jersey 08540, USA * Nadia L. Zakamska Competing financial interests The author declares no competing financial interests. Corresponding author Correspondence to: * Nadia L. Zakamska (zakamska@ias.edu) Readers are welcome to comment on the online version of this article at www.nature.com/nature. Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary information (230K) This file contains Supplementary Information and Data, Supplementary Figures 1-3, Supplementary Tables 1-2 and References. Additional data
• Phase-preserving amplification near the quantum limit with a Josephson ring modulator
  - Nature 465(7294):64 (2010)
  Nature | Letter Phase-preserving amplification near the quantum limit with a Josephson ring modulator * N. Bergeal1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * F. Schackert1 Search for this author in: * NPG journals * PubMed * Google Scholar * M. Metcalfe1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * R. Vijay1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * V. E. Manucharyan1 Search for this author in: * NPG journals * PubMed * Google Scholar * L. Frunzio1 Search for this author in: * NPG journals * PubMed * Google Scholar * D. E. Prober1 Search for this author in: * NPG journals * PubMed * Google Scholar * R. J. Schoelkopf1 Search for this author in: * NPG journals * PubMed * Google Scholar * S. M. Girvin1 Search for this author in: * NPG journals * PubMed * Google Scholar * M. H. Devoret1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:64–68Date published:(06 May 2010)DOI:doi:10.1038/nature09035Received07 December 2009Accepted17 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 Recent progress in solid-state quantum information processing1 has stimulated the search for amplifiers and frequency converters with quantum-limited performance in the microwave range. Depending on the gain applied to the quadratures of a single spatial and temporal mode of the electromagnetic field, linear amplifiers can be classified into two categories (phase sensitive and phase preserving) with fundamentally different noise properties2. Phase-sensitive amplifiers use squeezing to reduce the quantum noise, but are useful only in cases in which a reference phase is attached to the signal, such as in homodyne detection. A phase-preserving amplifier would be preferable in many applications, but such devices have not been available until now. Here we experimentally realize a proposal3 for an intrinsically phase-preserving, superconducting parametric amplifier of non-degenerate type. It is based on a Josephson ring modulator, which consists of four Josephson junctions in a Wh! eatstone bridge configuration. The device symmetry greatly enhances the purity of the amplification process and simplifies both its operation and its analysis. The measured characteristics of the amplifier in terms of gain and bandwidth are in good agreement with analytical predictions. Using a newly developed noise source, we show that the upper bound on the total system noise of our device under real operating conditions is three times the quantum limit. We foresee applications in the area of quantum analog signal processing, such as quantum non-demolition single-shot readout of qubits4, quantum feedback5 and the production of entangled microwave signal pairs6. View full text Subject terms: * Applied physics * Engineering Figures at a glance * Figure 1: The JPC and its microwave measurement set-up. , JPC sample (outlined in red) whose signal ports are connected to two attenuated input lines and two output lines using cryogenic circulators, and whose pump port is fed by a fifth line. The output signals are first amplified by high-electron-mobility transistor (HEMT) cryogenic amplifiers at the 4.2-K stage. Two isolators are placed at the 4.2-K and 1.6-K stages to minimize the back-action of the amplifier on the sample. At room temperature (300-K stage), the signals are further amplified by about 60 dB before being measured. , Optical picture of the JPC. It consists of two coplanar-stripline aluminium resonators respectively 17 and 3.6 mm long coupled to the Josephson ring modulator on one side and to contact pads via input capacitors on the other side. A third coplanar stripline carries the pump signal. The input capacitors are built from two aluminium layers separated by a SiOx dielectric layer. , Close-up of the connection between the Josephson ring modulator, the ! resonators and the pump line. The pump is weakly coupled to the resonators through the SiOx dielectric layer, which provides a small capacitance of order 20 fF. The crossing point of the two resonators is isolated by the same SiOx layer. , Scanning electron microscope pictures of the Josephson ring modulator showing its four Al/AlOx/Al junctions. Each junction is surrounded by the two shadow electrodes produced by the Dolan bridge double-angle evaporation technique. The loop of the ring has an area of 3 μm × 17 μm and the junction area is 5 μm × 1 μm. * Figure 2: Gain of the JPC. , Power cis-gain of the JPC as a function of the input signal frequency, for different values of the pump power, P, measured at port 1 (left) and port 2 (right). The solid lines correspond to the theoretical expressions for |r1|2 and |r2|2 (equation (3)) obtained for the indicated values of the fit parameter, |ρ|. Inset, curves obtained at higher gain. The fits correspond to |ρ| = 0.994 (left) and |ρ| = 0.992 (right). , Photon trans-gain of the JPC as a function of the input signal frequency (bottom axis) and the converted frequency (top axis), measured between port 1 and port 2 (left) and between port 2 and port 1 (right) for different values of the pump power. The solid lines correspond to the theoretical expressions for |s1|2 and |s2|2 (equation (4)) obtained for the indicated values of |ρ|. , Photon cis-gain of the JPC plotted (colour, dB) as a function of the drive frequencies and the pump power measured at port 1 (left) and port 2 (right). The data shown in , and c! orrespond to different runs. * Figure 3: Tuning the bandwidth of the JPC. Cis-gains |r1|2 () and |r2|2 () as functions of the corresponding drive frequency, for different values of the pump frequency, fp, as indicated. The pump amplitude has been adjusted at each frequency for optimal gain. The triangular symbols indicate the theoretical location of the centre frequency. * Figure 4: Noise measurement of the JPC for a 30-dB gain. , Spectral noise power at the output of port 1 (colour) as a function of frequency and voltage across the resistor. , Cuts of the spectral noise power corresponding to V = 0 μV and V = 85 μV. The noise floor obtained with the pump off is given as reference. , Noise power at the output of port 1 (open dots; same units as in ), averaged over a 1-MHz band around fa, as a function of the voltage across the resistor. Red line, theoretical expression (equation (6) in Methods) with fitted added noise; green line, same as red line but assuming quantum shot noise for the resistor; black line, theoretical expression (6) plus an ideal quantum-limited amplifier. Inset, schematic of the resistor embedded in its thick and wide thermal reservoirs. , Same as but with the voltage axis converted into the effective temperature of the noise source, Teff. The dashed lines indicate asymptotes of the high-temperature variation. Also shown in this panel is the total added noise power of the s! ystem and the ideal case of the quantum limit (QL). Inset, temperature variation profile inside the resistor (Methods). Author information * Author information * Supplementary information * Comments Affiliations * Department of Physics and Applied Physics, Yale University, New Haven, Connecticut 06520-8284 USA * N. Bergeal, * F. Schackert, * M. Metcalfe, * R. Vijay, * V. E. Manucharyan, * L. Frunzio, * D. E. Prober, * R. J. Schoelkopf, * S. M. Girvin & * M. H. Devoret * LPEM-UPR5, CNRS, ESPCI ParisTech, 10 Rue Vauquelin, 75005 Paris, France * N. Bergeal * The Joint Quantum Institute, University of Maryland, College Park, Maryland 20742, USA * M. Metcalfe * Department of Physics, University of California, Berkeley, California 94720-7300, USA * R. Vijay Contributions N.B. and L.F. fabricated the device. N.B., assisted by F.S. and M.M., performed the measurements. N.B. and M.H.D. carried out the analysis of the results and wrote the paper. R.V., V.E.M., R.J.S. and S.M.G. contributed extensively to discussions of the results. D.E.P. suggested the hot-electron noise source for calibration. R.J.S. contributed through his knowledge of ultralow-noise microwave circuits and measurements. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * N. Bergeal (nicolas.bergeal@espci.fr) or * M. H. Devoret (michel.devoret@yale.edu) Readers are welcome to comment on the online version of this article at www.nature.com/nature. Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (637K) This file contains Supplementary Information and Data, Supplementary Tables 1-3, Supplementary Figures 1-5 with legends and References. Additional data
• Designed biomaterials to mimic the mechanical properties of muscles
  - Nature 465(7294):69 (2010)
  Nature | Letter Designed biomaterials to mimic the mechanical properties of muscles * Shanshan Lv1 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel M. Dudek2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Yi Cao1 Search for this author in: * NPG journals * PubMed * Google Scholar * M. M. Balamurali1 Search for this author in: * NPG journals * PubMed * Google Scholar * John Gosline2 Search for this author in: * NPG journals * PubMed * Google Scholar * Hongbin Li1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:69–73Date published:(06 May 2010)DOI:doi:10.1038/nature09024Received22 September 2009Accepted09 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 The passive elasticity of muscle is largely governed by the I-band part of the giant muscle protein titin1, 2, 3, 4, a complex molecular spring composed of a series of individually folded immunoglobulin-like domains as well as largely unstructured unique sequences5. These mechanical elements have distinct mechanical properties, and when combined, they provide the desired passive elastic properties of muscle6, 7, 8, 9, 10, 11, which are a unique combination of strength, extensibility and resilience. Single-molecule atomic force microscopy (AFM) studies demonstrated that the macroscopic behaviour of titin in intact myofibrils can be reconstituted by combining the mechanical properties of these mechanical elements measured at the single-molecule level8. Here we report artificial elastomeric proteins that mimic the molecular architecture of titin through the combination of well-characterized protein domains GB112 and resilin13. We show that these artificial elastomeric proteins ! can be photochemically crosslinked and cast into solid biomaterials. These biomaterials behave as rubber-like materials showing high resilience at low strain and as shock-absorber-like materials at high strain by effectively dissipating energy. These properties are comparable to the passive elastic properties of muscles within the physiological range of sarcomere length14 and so these materials represent a new muscle-mimetic biomaterial. The mechanical properties of these biomaterials can be fine-tuned by adjusting the composition of the elastomeric proteins, providing the opportunity to develop biomaterials that are mimetic of different types of muscles. We anticipate that these biomaterials will find applications in tissue engineering15 as scaffold and matrix for artificial muscles. View full text Subject terms: * Materials science * Biophysics Figures at a glance * Figure 1: Force–extension curves of two polyproteins. , (G–R)4. , GRG5RG4R. The force peaks, characterized by a ΔLc of ~18 nm and an unfolding force of ~180 pN, result from the mechanical unfolding of GB1 domains. Stretching resilins does not result in any unfolding force peaks; instead we see a featureless spacer of length L0. The notable difference between the force–extension curves of (G–R)4 and GRG5RG4R is the shorter featureless spacer of GRG5RG4R, which is due to fewer resilin repeats in GRG5RG4R. Grey lines correspond to the worm-like chain model fits to the experimental data. * Figure 2: Mechanical properties of (G–R)4 and GRG5RG4R-based biomaterials. , Photographs of moulded rings built from (G–R)4 (left, intact) and GRG5RG4R (right, after being loaded to failure in tensile test) under white light (middle panel) and ultraviolet illumination (top panel). , , Representative stress–strain curves of (G–R)4 () and GRG5RG4R () measured in PBS. For clarity, stress–strain curves are offset relative to one another. Final strains are shown on the curves. Insets show the superposition of the stress–strain curves at different strains. , Resilience of GB1–resilin-based biomaterials decreases with the increase of strain. In contrast, biomaterials constructed from resilin do not show any appreciable hysteresis (data taken from ref. 13). , GRG5RG4R-based biomaterials can recover hysteresis under residual stress. During stretching–relaxation experiments, when the biomaterial is partially relaxed to a strain above 35%, no recovery of hysteresis was observed. When the biomaterial was relaxed to below 35% strain, we started to! observe partial recovery. The degree of recovery increased with the decrease of residual stress. For clarity, the initial stretching trace is coloured blue. The inset shows the experimental protocol of the partial relaxation experiments. The pulling speed used in the experiments was 25 mm min-1. Error bars indicate standard deviation of the data. * Figure 3: GB1–resilin-based biomaterials exhibit pronounced stress relaxation behaviours. , Representative stress-relaxation curves of GRG5RG4R at varying strains. , Relaxation rates of GRG5RG4R-based biomaterials depend upon the initial stress. The relaxation rates were obtained by fitting the stress-relaxation to a double-exponential equation: σ(t)  = σ0 + A1exp(-k1t) + A2exp(-k2t), where σ(t) is the stress at time t, σ0 is the offset, A1 and A2 are decay amplitudes and k1 (filled squares) and k2 (open triangles) are relaxation rates. Error bars indicate fitting errors. * Figure 4: The macroscopic mechanical properties of GB1–resilin-based biomaterials can be fine-tuned by controlling the nanomechanical properties of the constituting elastomeric proteins at the single-molecule level. , Force–extension curves of single GRG5RG4R molecules in PBS and in 4 M urea. The long featureless spacers observed in force-extension curves of GRG5RG4R in 4 M urea largely correspond to the stretching of mechanically labile, unfolded GB1 domains. The unfolding force of GB1 domains that remain folded in 4 M urea is also significantly reduced. Grey lines are WLC fits. , Young's modulus of GRG5RG4R-based biomaterial can be modulated by chemical denaturant urea. The conversion of folded GB1 domains into unfolded sequence leads to the dramatic decrease in Young's modulus of the biomaterials in a urea-concentration-dependent manner. Error bars indicate standard deviation of the data. Author information * Author information * Supplementary information * Comments Affiliations * Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada * Shanshan Lv, * Yi Cao, * M. M. Balamurali & * Hongbin Li * Department of Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada * Daniel M. Dudek & * John Gosline * Present address: Department of Engineering Science and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA. * Daniel M. Dudek Contributions H.L. conceived the project. H.L. and J.G. designed the overall experiments. S.L., D.M.D., Y.C., M.M.B. and J.G. designed, performed individual experiments and analysed data. H.L. wrote the manuscript and all authors edited the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Hongbin Li (hongbin@chem.ubc.ca) or * John Gosline (gosline@zoology.ubc.ca) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (473K) This file contains Supplementary Information comprising Protein Engineering; Single-Molecule AFM Measurements; Preparation of Biomaterials; Tensile Testing; Monte Carlo simulations on the force-relaxation of GRG5RG4R and Mimicking the passive elasticity of muscle in the full range of sarcomere length; Supplementary Figures S1-S8 with legends and References. Additional data
• Fast torsional waves and strong magnetic field within the Earth's core
  - Nature 465(7294):74 (2010)
  Nature | Letter Fast torsional waves and strong magnetic field within the Earth's core * Nicolas Gillet1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dominique Jault1 Search for this author in: * NPG journals * PubMed * Google Scholar * Elisabeth Canet1 Search for this author in: * NPG journals * PubMed * Google Scholar * Alexandre Fournier2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:74–77Date published:(06 May 2010)DOI:doi:10.1038/nature09010Received26 January 2010Accepted03 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 The magnetic field inside the Earth's fluid and electrically conducting outer core cannot be directly probed. The root-mean-squared (r.m.s.) intensity for the resolved part of the radial magnetic field at the core–mantle boundary is 0.3 mT, but further assumptions are needed to infer the strength of the field inside the core. Recent diagnostics obtained from numerical geodynamo models1 indicate that the magnitude of the dipole field at the surface of a fluid dynamo is about ten times weaker than the r.m.s. field strength in its interior, which would yield an intensity of the order of several millitesla within the Earth's core. However, a 60-year signal found in the variation in the length of day2 has long been associated with magneto-hydrodynamic torsional waves carried by a much weaker internal field3, 4. According to these studies, the r.m.s. strength of the field in the cylindrical radial direction (calculated for all length scales) is only 0.2 mT, a figure even! smaller than the r.m.s. strength of the large-scale (spherical harmonic degree n ≤ 13) field visible at the core–mantle boundary. Here we reconcile numerical geodynamo models with studies of geostrophic motions in the Earth's core that rely on geomagnetic data. From an ensemble inversion of core flow models, we find a torsional wave recurring every six years, the angular momentum of which accounts well for both the phase and the amplitude of the six-year signal for change in length of day detected over the second half of the twentieth century5. It takes about four years for the wave to propagate throughout the fluid outer core, and this travel time translates into a slowness for Alfvén waves that corresponds to a r.m.s. field strength in the cylindrical radial direction of approximately 2 mT. Assuming isotropy, this yields a r.m.s. field strength of 4 mT inside the Earth's core. View full text Subject terms: * Earth sciences * Geology * Geophysics Figures at a glance * Figure 1: High coherence is found not only on long timescales, but also on an approximately six-year period. Coherence () and phase () spectra are calculated over the time span 1925–1990 for the ΔLOD time series LUNAR97 (ref. 13) and the predictions from the average of an ensemble of quasi-geostrophic core flow models (see Supplementary Information). Green segments correspond to frequency ranges over which the phase shift is smaller than 30°. * Figure 2: The six-year ΔLOD signal is carried by geostrophic wave-like patterns travelling from the inner core to the outer core Equator. , Comparison of ΔLOD time series, bandpass-filtered between five and eight years, of the LUNAR97 data13 (green), the predictions from the ensemble average of the quasi-geostrophic core flow models (black), and the result (red) of the torsional wave assimilation of the flow coefficients for 1960–1982 (see Supplementary Information). , Time versus cylindrical radius map of the band-pass filtered angular velocity ũg(s, t) for the ensemble average of the quasi-geostrophic core flow model. Distance is in outer core radius units. The colour scale ranges between -0.4 km yr-1 (blue) and +0.4 km yr-1 (yellow) with contours every 0.02 km yr-1. The horizontal dashed line at s = 0.35 corresponds to the position of the tangent cylinder. The black box corresponds to the space-time domain used for the assimilation of torsional waves (Fig. 3). * Figure 3: Torsional Alfvén waves can account for the six-year geostrophic oscillation. Time–cylindrical radius map of the bandpass-filtered angular velocity ũg(s, t). The colour scale ranges between -0.4 km yr-1 (blue) and +0.4 km yr-1 (yellow) with contours every 0.02 km yr-1. , Filtered ensemble average. As inside the black box in Fig. 2b (outside the tangent cylinder for 1960–1982) but truncated at spherical harmonic degree n = 9. This corresponds to the observation used for the data assimilation. , Assimilation output (n  9). Predictions resulting from the torsional wave assimilation of the for damping parameters (αG, αB) = (100, 3 × 10-7), with a normalized misfit of 0.87 (see Supplementary Information for details). * Figure 4: The magnetic field exceeds 2–3 mT in most of the fluid domain outside the tangent cylinder, except towards the Equator, where it reaches values close to what is observed at the CMB. r.m.s. value of the cylindrical radial magnetic field versus cylindrical radius obtained by assimilation of the , using the torsional waves dynamical model (equation (2)). The grey shaded area corresponds to the domain in which acceptable solutions have been found. The colour curves result from assimilation runs using different damping parameters (αG, αB) (see the Methods and the Supplementary Information for details). Author information * Author information * Supplementary information * Comments Affiliations * Laboratoire de Géophysique Interne et Tectonophysique, CNRS, Université Joseph Fourier, BP 53, 38041 Grenoble cedex 9, France * Nicolas Gillet, * Dominique Jault & * Elisabeth Canet * Equipe de Géomagnétisme, Institut de Physique du Globe de Paris, Université Paris-Diderot, CNRS, 4 place Jussieu, F-75252 Paris cedex 5, France * Alexandre Fournier Contributions The ensemble core flow inversions, data analysis and error covariances were carried out by NG. The ΔLOD time series analysis was performed by N.G. and D.J. E.C. and A.F. developed the torsional wave variational data assimilation code; runs were performed by N.G. and E.C. The manuscript was mainly written by N.G. and D.J., with a little help from A.F. D.J. played an important part in the discussion of the theoretical background. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Nicolas Gillet (nicolas.gillet@obs.ujf-grenoble.fr) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (202K) This file contains Supplementary Data, Supplementary Figures 1-3 with legends and References. Additional data
• Seismic and aseismic slip on the Central Peru megathrust
  - Nature 465(7294):78 (2010)
  Nature | Letter Seismic and aseismic slip on the Central Peru megathrust * Hugo Perfettini1, 2, 6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Philippe Avouac3 Search for this author in: * NPG journals * PubMed * Google Scholar * Hernando Tavera2 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew Kositsky3, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Mathieu Nocquet4 Search for this author in: * NPG journals * PubMed * Google Scholar * Francis Bondoux1, 2, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Mohamed Chlieh1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Anthony Sladen3 Search for this author in: * NPG journals * PubMed * Google Scholar * Laurence Audin1, 2, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel L. Farber5, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Pierre Soler1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:78–81Date published:(06 May 2010)DOI:doi:10.1038/nature09062Received31 August 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 Slip on a subduction megathrust can be seismic or aseismic, with the two modes of slip complementing each other in time and space to accommodate the long-term plate motions. Although slip is almost purely aseismic at depths greater than about 40 km, heterogeneous surface strain1, 2, 3, 4, 5, 6, 7, 8 suggests that both modes of slip occur at shallower depths, with aseismic slip resulting from steady or transient creep in the interseismic and postseismic periods9, 10, 11. Thus, active faults seem to comprise areas that slip mostly during earthquakes, and areas that mostly slip aseismically. The size, location and frequency of earthquakes that a megathrust can generate thus depend on where and when aseismic creep is taking place, and what fraction of the long-term slip rate it accounts for. Here we address this issue by focusing on the central Peru megathrust. We show that the Pisco earthquake, with moment magnitude Mw = 8.0, ruptured two asperities within a patch that had re! mained locked in the interseismic period, and triggered aseismic frictional afterslip on two adjacent patches. The most prominent patch of afterslip coincides with the subducting Nazca ridge, an area also characterized by low interseismic coupling, which seems to have repeatedly acted as a barrier to seismic rupture propagation in the past. The seismogenic portion of the megathrust thus appears to be composed of interfingering rate-weakening and rate-strengthening patches. The rate-strengthening patches contribute to a high proportion of aseismic slip, and determine the extent and frequency of large interplate earthquakes. Aseismic slip accounts for as much as 50–70% of the slip budget on the seismogenic portion of the megathrust in central Peru, and the return period of earthquakes with Mw = 8.0 in the Pisco area is estimated to be 250 years. View full text Subject terms: * Earth sciences * Geophysics * Geology * Methods * Materials Figures at a glance * Figure 1: Seismotectonic setting of the South Peru megathrust. Shown are co-seismic slip, aftershocks and postseismic displacements from the Mw = 8.0 Pisco earthquake in 2007. The focal mechanism shows the Global Centroid Moment Tensor solution (http://www.globalcmt.org/). The 2-m slip contour lines of the 2007 earthquake shown in cyan were derived from the joint analysis of InSAR, teleseismic and tsunami data13. Aftershocks (red dots) were located from the Instituto Geofísico del Perú (IGP) local seismic network. The rupture area of the Mw8.1, 1974 Lima earthquake was estimated from teleseismic data28, and that of the Mw7.7, 1996 Nazca earthquake was derived from the joint inversion of InSAR and teleseismic waveforms29. Grey vectors show the Nazca plate motion relative to South America14. Black vectors show the horizontal postseismic displacements between days 20 and 408 after the mainshock, and the blue vectors show the modelled displacements. The time series of displacements recorded at LAGU, with 2σ uncertainties, is shown in the! upper inset. The continuous curve shows the theoretical displacements predicted from the afterslip model shown in Fig. 2. The box in the lower inset represents the area of the main figure panel. * Figure 2: Fault slip derived from modelling of geodetic displacements between days 20 and 408 after the mainshock. The model shown here assumes variable rake. Details regarding the weight put on smoothing and the three principal components selected in this model are given in the Supplementary Information. The 2-m slip contour lines of the 2007 earthquake are shown in cyan13. Pink contour lines show the density of aftershocks in the first month following the mainshock derived from the IGP catalogue. Insets show the slip at the centres of patches A and B, deduced from the inversion of geodetic measurements (blue circles). Red continuous lines show theoretical displacements predicted from rate-strengthening frictional sliding, assuming that frictional stress τ increases linearly with the logarithm of the sliding velocity , as observed in laboratory experiments30. According to this model, postseismic slip U(t) evolves as20 . For patch A, the best fitting parameters are tr ≈ 2.1 years and , assuming a value for the long-term velocity of the order of the convergence rate (that is, V0 ! = 62 mm yr-1; ref. 14). For patch B, we found tr ≈ 1.2 years and , making the same assumptions as for patch A. * Figure 3: Comparison of interseismic coupling with the rupture areas of recent large earthquakes. Rupture areas of the large interplate earthquakes as in Fig. 1. Also shown is the pattern of interseismic coupling, defined as (1 - Vi/Vpl), where Vi is the interseismic slip rate, derived from modelling of geodetic data collected between January 1993 and March 2001, all referenced to stable South America14, 15. Data (white vectors) were corrected for 5 mm yr-1 of shortening across the Andes by least-squares adjustment of the Euler pole describing the long-term motion of the fore-arc with respect to South America. The rectangular fault model has a strike of 321° and dips 18° to the east. The inversion procedure is described in the Supplementary Information, and the modelled velocities are shown as light blue vectors. The small coupling near the trench may reflect the lack of resolution there, except in the north, where sea-bottom measurements are available15. This model shows that, on average over the study area, aseismic slip in the interseismic period accounts fo! r about 38% to 59% of interplate slip at depths shallower than 40 km (the average interseismic coupling is between 0.41 and 0.62). Author information * Author information * Supplementary information * Comments Affiliations * Institut de Recherche pour le Développement, 44 Boulevard de Dunkerque, 13572 Marseille cedex 02, France * Hugo Perfettini, * Francis Bondoux, * Mohamed Chlieh, * Laurence Audin & * Pierre Soler * Instituto Geofisico del Perú, Calle Badajos 169, Urb. Mayorazgo, Ate, Lima, Peru * Hugo Perfettini, * Hernando Tavera, * Francis Bondoux & * Laurence Audin * Tectonics Observatory, Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, California 91125, USA * Jean-Philippe Avouac, * Andrew Kositsky & * Anthony Sladen * GéoAzur, 250 Rue Albert Einstein, 06560 Valbonne, France * Jean-Mathieu Nocquet & * Mohamed Chlieh * Department of Earth and Planetary Sciences, University of California Santa Cruz, Santa Cruz, California 95064, USA * Daniel L. Farber * Laboratoire de Géophysique Interne et Tectonophysique, Université Joseph Fourier/CNRS/IRD/LCPC, Observatoire des Sciences de l'Univers de Grenoble, BP 53, 38041 Grenoble cedex 9, France * Hugo Perfettini & * Francis Bondoux * Laboratoire des Mécanismes de Transfert en Géologie, Université Paul Sabatier/CNRS/IRD, Observatoire Midi-Pyrénées, 14 Avenue Edouard Belin, 31400 Toulouse, France * Hugo Perfettini & * Laurence Audin * Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94550, USA * Daniel L. Farber * Ashima Research, Pasadena, 600 S. Lake Ave., Pasadena, California 91106, USA * Andrew Kositsky Contributions H.P. edited the paper and did modelling and field work; J.-P.A. edited the paper and did modelling; H.T. handled the IGP aftershocks data; A.K. did modelling of postseismic deformation; J.-M.N. did the GPS processing; F.B. was in charge of the GPS network; M.C. did modelling of interseismic deformation; A.S. did modelling of the co-seismic deformation; L.A. did field work; D.L.F. did field work, and helped with editing the paper; P.S. helped with logistics. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Hugo Perfettini (hugo.perfettini@ird.fr) Readers are welcome to comment on the online version of this article at www.nature.com/nature. Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (1.2M) This file contains Supplementary Information and Data, Supplementary Tables 1-3, Supplementary Figures 1-5 with legends and References. Additional data
• Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease
  Craven L Tuppen HA Greggains GD Harbottle SJ Murphy JL Cree LM Murdoch AP Chinnery PF Taylor RW Lightowlers RN Herbert M Turnbull DM - Nature 465(7294):82 (2010)
  Nature | Letter Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease * Lyndsey Craven1 Search for this author in: * NPG journals * PubMed * Google Scholar * Helen A. Tuppen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Gareth D. Greggains3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen J. Harbottle3 Search for this author in: * NPG journals * PubMed * Google Scholar * Julie L. Murphy1 Search for this author in: * NPG journals * PubMed * Google Scholar * Lynsey M. Cree1 Search for this author in: * NPG journals * PubMed * Google Scholar * Alison P. Murdoch3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick F. Chinnery1 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert W. Taylor1 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert N. Lightowlers1 Search for this author in: * NPG journals * PubMed * Google Scholar * Mary Herbert3, 4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Douglass M. Turnbull1, 2, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:82–85Date published:(06 May 2010)DOI:doi:10.1038/nature08958Received11 February 2010Accepted26 February 2010Published online14 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 Mutations in mitochondrial DNA (mtDNA) are a common cause of genetic disease. Pathogenic mutations in mtDNA are detected in approximately 1 in 250 live births1, 2, 3 and at least 1 in 10,000 adults in the UK are affected by mtDNA disease4. Treatment options for patients with mtDNA disease are extremely limited and are predominantly supportive in nature. Mitochondrial DNA is transmitted maternally and it has been proposed that nuclear transfer techniques may be an approach for the prevention of transmission of human mtDNA disease5, 6. Here we show that transfer of pronuclei between abnormally fertilized human zygotes results in minimal carry-over of donor zygote mtDNA and is compatible with onward development to the blastocyst stage in vitro. By optimizing the procedure we found the average level of carry-over after transfer of two pronuclei is less than 2.0%, with many of the embryos containing no detectable donor mtDNA. We believe that pronuclear transfer between zygotes, a! s well as the recently described metaphase II spindle transfer, has the potential to prevent the transmission of mtDNA disease in humans. View full text Subject terms: * Medical research * Genetics * Genomics Figures at a glance * Figure 1: Pronuclear transfer using abnormally fertilized human zygotes. –, Transfer of two pronuclei between human zygotes. , Recipient zygote (one pronucleus removed) and donor zygote (three pronuclei, two of which are removed and fused with the recipient zygote). , Recipient zygote containing a single pronucleus (marked with arrow), which is removed by a biopsy pipette to leave an enucleated zygote (). , Donor zygote with three pronuclei (marked with arrows), two of which are removed as karyoplasts (). , Enucleated recipient zygote with two pronuclear karyoplasts from the donor zygote (arrows) before fusion. , Recipient zygote 20 min after transfer, already showing fusion of the karyoplast membranes (arrow). , Development of unmanipulated abnormally fertilized zygotes (n = 76; black bars), embryos receiving one transferred pronucleus (n = 44; grey bars) and embryos receiving two transferred pronuclei (n = 36; white bars). , , Hatching blastocyst on day 6 () and hatched blastocyst on day 7 () containing two donor pronuclei. Scale bars, 50�! �µm. * Figure 2: Mitochondrial DNA analysis of pronuclear-transfer embryos. , The potential transfer of donor zygote mtDNA to the recipient zygote. , Sequence electropherograms of mtDNA non-coding control region in donor and recipient zygotes with the sequence variant used for the last hot cycle PCR RFLP assay highlighted. , Scheme of RFLP designed using the sequence variant. , Last hot cycle PCR RFLP analysis of donor mtDNA carry-over detected in embryos receiving two transferred pronuclei with products separated by 12% non-denaturing polyacrylamide gel electrophoresis. U, undigested; C1 and C2, controls (C1, donor embryo for E3, recipient embryo for E1 and E2; C2, donor embryo for E1 and E2, recipient embryo for E3). bp, base pairs. , Mitochondrial DNA copy number in human mature oocytes. * Figure 3: Mitochondrial DNA analysis of individual blastomeres disaggregated from pronuclear-transfer embryos. , Last hot cycle PCR RFLP of individual blastomeres from a pronuclear-transfer embryo showing variable levels of mtDNA donor genotype in individual blastomeres. The arrow indicates the band representing carry-over mtDNA. , Levels of donor mtDNA carry-over in individual blastomeres from eight embryos before modifications to minimize levels of donor mtDNA in pronuclear karyoplasts. In some embryos not all blastomeres could be collected. Figures represent the percentage mtDNA carry-over in individual blastomeres after pronuclear transfer. n.d., Non-detectable. , Pronuclear karyoplasts after additional manipulation showing minimal amount of donor cytoplasm compared with Fig. 1e. Scale bar, 25 µm. , Last hot cycle PCR RFLP of individual blastomeres from a pronuclear-transfer embryo showing no detectable levels of mtDNA donor genotype in individual blastomeres. The arrow indicates the band representing carry-over mtDNA. , Levels of donor mtDNA carry-over in individual blastomer! es from nine embryos after improvements to pronuclear karyoplast removal. In some embryos, not all blastomeres could be collected. Figures represent the percentage of mtDNA carry-over in individual blastomeres after pronuclear transfer. n.d., Non-detectable. Author information * Author information * Supplementary information * Comments Affiliations * Mitochondrial Research Group, Institute for Ageing and Health, * Lyndsey Craven, * Helen A. Tuppen, * Julie L. Murphy, * Lynsey M. Cree, * Patrick F. Chinnery, * Robert W. Taylor, * Robert N. Lightowlers & * Douglass M. Turnbull * Newcastle University Centre for Brain Ageing and Vitality, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE2 4HH, UK * Douglass M. Turnbull * Newcastle Fertility Centre, International Centre for Life, * Gareth D. Greggains, * Stephen J. Harbottle, * Alison P. Murdoch & * Mary Herbert * Institute for Ageing and Health, International Centre for Life, * Gareth D. Greggains & * Mary Herbert * North East England Stem Cell Institute (NESCI), Bioscience Centre, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 4EP, UK * Alison P. Murdoch, * Mary Herbert & * Douglass M. Turnbull Contributions M.H., A.P.M., R.N.L. and D.M.T. conceived the project and designed the experiments. L.C., H.A.T., S.J.H., G.D.G., J.L.M., L.M.C., P.F.C. and R.W.T. performed experiments and analysed data. L.C., M.H., H.A.T. and D.M.T. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Mary Herbert (mary.herbert@ncl.ac.uk) or * Douglass M. Turnbull (d.m.turnbull@ncl.ac.uk) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (158K) This file contains Supplementary Figure 1 with legend and Supplementary Tables 1-2. Additional data
• Cis-interactions between Notch and Delta generate mutually exclusive signalling states
  Sprinzak D Lakhanpal A Lebon L Santat LA Fontes ME Anderson GA Garcia-Ojalvo J Elowitz MB - Nature 465(7294):86 (2010)
  Nature | Letter Cis-interactions between Notch and Delta generate mutually exclusive signalling states * David Sprinzak1 Search for this author in: * NPG journals * PubMed * Google Scholar * Amit Lakhanpal1 Search for this author in: * NPG journals * PubMed * Google Scholar * Lauren LeBon1 Search for this author in: * NPG journals * PubMed * Google Scholar * Leah A. Santat1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michelle E. Fontes1 Search for this author in: * NPG journals * PubMed * Google Scholar * Graham A. Anderson2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jordi Garcia-Ojalvo3 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael B. Elowitz1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:86–90Date published:(06 May 2010)DOI:doi:10.1038/nature08959Received27 April 2009Accepted26 February 2010Published online25 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 Notch–Delta signalling pathway allows communication between neighbouring cells during development1. It has a critical role in the formation of 'fine-grained' patterns, generating distinct cell fates among groups of initially equivalent neighbouring cells and sharply delineating neighbouring regions in developing tissues2, 3, 4, 5. The Delta ligand has been shown to have two activities: it transactivates Notch in neighbouring cells and cis-inhibits Notch in its own cell. However, it remains unclear how Notch integrates these two activities and how the resulting system facilitates pattern formation. Here we report the development of a quantitative time-lapse microscopy platform for analysing Notch–Delta signalling dynamics in individual mammalian cells, with the aim of addressing these issues. By controlling both cis- and trans-Delta concentrations, and monitoring the dynamics of a Notch reporter, we measured the combined cis–trans input–output relationship in ! the Notch–Delta system. The data revealed a striking difference between the responses of Notch to trans- and cis-Delta: whereas the response to trans-Delta is graded, the response to cis-Delta is sharp and occurs at a fixed threshold, independent of trans-Delta. We developed a simple mathematical model that shows how these behaviours emerge from the mutual inactivation of Notch and Delta proteins in the same cell. This interaction generates an ultrasensitive switch between mutually exclusive sending (high Delta/low Notch) and receiving (high Notch/low Delta) signalling states. At the multicellular level, this switch can amplify small differences between neighbouring cells even without transcription-mediated feedback. This Notch–Delta signalling switch facilitates the formation of sharp boundaries and lateral-inhibition patterns in models of development, and provides insight into previously unexplained mutant behaviours. View full text Subject terms: * Developmental biology * Cell biology * Molecular biology * Biophysics Figures at a glance * Figure 1: System for analysing signal integration in the Notch–Delta pathway. , Notch (blue) and Delta (red) interactions are indicated schematically. , Notch activity integrates cis-and trans-Delta. , T-REx-CHO-K1 cell line for analysing Notch activity. The hN1G4esn cell line stably incorporates a variant of human NOTCH1 in which the activator Gal4esn replaces the Notch intracellular domain (here hN1(ECD) is the extracellular domain of hN1). This cell line also contains genes for histone 2B (H2B)–citrine (YFP) reporter controlled by an upstream activating sequence (UAS) promoter, a tetracycline-inducible (TO) Delta–mCherry fusion protein and a constitutively expressed H2B–cerulean (cyan fluorescent protein, or CFP) for image segmentation (not shown). A similar cell line expressing full-length human NOTCH1 (the hN1 cell line) was also analysed (Supplementary Figs 1 and 2). These cells exhibit no detectable endogenous Notch or Delta activities. Notch–Delta interactions are indicated schematically and do not represent molecular interaction mecha! nisms11. * Figure 2: Transactivation of Notch occurs in a graded fashion. , Experimental design. The rate of increase of fluorescence (slope of green line) is a measure of Notch activity. , Typical hN1G4esn filmstrip showing activation of Notch reporter (green), with Dplate = 1.16 μg ml-1 and frame times as indicated (Supplementary Movie 1; compare with Supplementary Fig. 6). , hN1G4esn cells respond in a graded manner to variations in Dplate. The data show the median fluorescence of individual cells within a single field of view for the indicated values of Dplate (see Supplementary Fig. 15 for distributions). RFU, relative fluorescence unit. , The relationship between Dplate and Notch activity (in RFU per hour, from the linear regime in ). The Hill-function fit is indicated by the black line, which has Hill coefficient n = 1.7 (95% confidence interval, n = 0.8–2.7). Similar results were obtained using the hN1 cell line (Supplementary Fig. 1). We note that doxycycline does not directly affect Notch activation or cell growth, nor does Dplate! affect cell growth (Supplementary Fig. 12). * Figure 3: Cis–trans signal integration by Notch. , Experimental protocol. Inset, the rise time, τrise, is the time required for Notch activity (black line or slope of green line) to change by a factor of e. dox, doxycycline. , Filmstrip of hN1G4esn cells, with Dplate = 1.45 μg ml-1 (Supplementary Movie 2), showing Delta–mCherry fluorescence (red) and concomitant activation of Notch reporter (green) at the indicated times (compare with Supplementary Fig. 6). , Population average (median) response for the same movie shows a slow decay of Delta–mCherry fluorescence (red data), but a sharp response of reporter expression (green data). Constitutively expressed pCMV–H2B–cerulean (blue data) remains constant (control). Compare with the single-cell tracks in Supplementary Fig. 13 and the response to modulation of doxycycline in Supplementary Fig. 14. , Single-cell response for two individual cells (solid and dashed lines, colours as in ). Black arrows mark cell divisions. , Single-cell traces in replotted, but shifte! d up after each cell division event to 'add back' sister-cell fluorescence, to show the continuity of Notch activity (see also Supplementary Fig. 13). , Histogram of τrise from 26 non-overlapping cell lineages (Supplementary Fig. 13). , Notch response to both cis- and trans-Delta. Data shown are from two duplicate movies acquired at each of 12 Dplate values for hN1G4esn cells. Green colouring indicates data that exceed a detection threshold. Note that onset (the black-to-green transition) occurs at approximately the same time for all Dplate values. , Simulations based on the model in Box 1 are qualitatively similar to data in (see Supplementary Information and Supplementary Fig. 16 for model details). a.u., arbitrary units. * Figure 4: The mutual-inactivation model in multicellular patterning. , Signal amplification. The two interacting cells have the same amount of Notch (here, two molecules) but different amounts of Delta (one or three molecules). Owing to the cis-interaction between Notch and Delta, signalling is strongly biased to cell 1. , Notch amplifies differences between cells. Signal amplification, (S1/S2 - 1)/(  - 1), for two interacting cells, with different Delta production rates, = 1.35 (see model in Supplementary Information). The x axis shows the average Delta production rate, βD = (  +  )/2. Maximum amplification occurs when Delta production rates flank βN (vertical dashed line). Stronger mutual inactivation (smaller kc/kt) increases signal amplification. , , Sharp boundary formation in response to a gradient of Delta production. , Simulation of a field of interacting cells in which Delta production rates decay exponentially from the centre, according to βD(x) = exp(-x/x0) with x0 = 7 cells (dashed red line). The Notch production ra! te, βN, is constant (dashed blue line). The resulting free Notch and Delta protein levels are indicated (solid lines). Notch activation occurs in two sharply defined columns of cells (green line in plot and green cells in cellular diagram). , Suppression of mutant phenotypes is explained by the mutual-inactivation model. Grey lines indicate positions where βN = βD(x), leading to Notch activity peaks. Simultaneous reduction of both Notch and Delta production rates by half maintains boundary positions (dotted lines) (Supplementary Fig. 10). , , Mutual inactivation facilitates lateral-inhibition patterning (). In the absence of cooperativity in regulatory feedback, a standard lateral-inhibition model24 cannot pattern (, left) but a model of lateral inhibition with mutual inactivation can (, right). Author information * Author information * Supplementary information * Comments Affiliations * Howard Hughes Medical Institute, Division of Biology and Department of Applied Physics, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA * David Sprinzak, * Amit Lakhanpal, * Lauren LeBon, * Leah A. Santat, * Michelle E. Fontes & * Michael B. Elowitz * Department of Chemical and Systems Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, California 94305, USA * Graham A. Anderson * Department de Física i Enginyeria Nuclear, Universitat Politècnica de Catalunya, Colom 11, E-08222 Terrassa, Spain * Jordi Garcia-Ojalvo Contributions D.S. and M.B.E. designed the research. D.S., L.A.S., M.E.F. and G.A.A. built cell lines and performed experiments. D.S., A.L., L.L., J.G.-O. and M.B.E. performed data analysis and mathematical modelling. D.S. and M.B.E. wrote the manuscript with substantial input from the other authors. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Michael B. Elowitz (melowitz@caltech.edu) Supplementary information * Author information * Supplementary information * Comments Movies * Supplementary Movie 1 (10.2M) This movie shows the trans-activation of hN1G4esn by plate bound Delta. Movie used to generate filmstrip in Figure 2B. * Supplementary Movie 2 (21.4M) This movie shows the effect of cis-Delta on hN1G4esn activation. Movie used to generate filmstrip in Figure 3B. * Supplementary Movie 3 (5.2M) This movie shows the trans-activation of hN1G4esn-No-Delta by co-culture with Delta-expressing cells. Movie used to generate filmstrip in Fig S5. PDF files * Supplementary Information (3.5M) This file contains Supplementary Figures S1-S17 with legends, Supplementary Tables S1-S3, Supplementary Methods and Data Analysis and Data and References for the Supplementary Material. Additional data
• The molecular basis for water taste in Drosophila
  Cameron P Hiroi M Ngai J Scott K - Nature 465(7294):91 (2010)
  Nature | Letter The molecular basis for water taste in Drosophila * Peter Cameron1 Search for this author in: * NPG journals * PubMed * Google Scholar * Makoto Hiroi1 Search for this author in: * NPG journals * PubMed * Google Scholar * John Ngai2 Search for this author in: * NPG journals * PubMed * Google Scholar * Kristin Scott1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:91–95Date published:(06 May 2010)DOI:doi:10.1038/nature09011Received16 November 2009Accepted16 March 2010Published online04 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 detection of water and the regulation of water intake are essential for animals to maintain proper osmotic homeostasis1. Drosophila and other insects have gustatory sensory neurons that mediate the recognition of external water sources2, 3, 4, but little is known about the underlying molecular mechanism for water taste detection. Here we identify a member of the degenerin/epithelial sodium channel family5, PPK28, as an osmosensitive ion channel that mediates the cellular and behavioural response to water. We use molecular, cellular, calcium imaging and electrophysiological approaches to show that ppk28 is expressed in water-sensing neurons, and that loss of ppk28 abolishes water sensitivity. Moreover, ectopic expression of ppk28 confers water sensitivity to bitter-sensing gustatory neurons in the fly and sensitivity to hypo-osmotic solutions when expressed in heterologous cells. These studies link an osmosensitive ion channel to water taste detection and drinking behavio! ur, providing the framework for examining the molecular basis for water detection in other animals. View full text Subject terms: * Neuroscience * Molecular biology * Cell biology Figures at a glance * Figure 1: ppk28-Gal4 labels neurons that respond to water. , , ppk28-Gal4 drives GFP in gustatory neurons () and their axons () in the suboesophageal ganglion (SOG). PPK28 was previously reported in larval tracheae27. , , PPK28 neurons (magenta) do not contain markers for sugar neurons (GR5A, green) () or bitter neurons (GR66A, green) (). Scale bars, 50 μm. , ppk28-Gal4 neurons respond to water. G-CaMP fluorescent changes to water, NaCl, sucrose, ribose, NMDG and PEG (maximum percentage change in fluorescence (ΔF/F)). Responses that are different from water measured by t-test are 0.2 M NaCl (P = 0.046), 0.5 M NaCl (P = 0.004), 1 M NaCl (P = 0.0003), 0.5 M sucrose (P = 3.27 × 10-5), 1 M sucrose (P = 1.11 × 10-5), 0.5 M ribose (P = 0.0008), 1 M ribose (P = 0.0003), 1 M NMDG (P = 0.0014) and 20% PEG (P = 0.028). n = 4–11 flies per compound ± s.e.m. * Figure 2: The ppk28 gene is necessary for cellular and behavioural water responses. , Extracellular bristle recordings of ppk28 control, mutant and rescue flies after water (left) or 100 mM sucrose (right) stimulation, showing action potentials. Stimulation begins at recording. , Scatter plot of water and sugar responses (mean ± s.e.m. in bars; data points as dots). Water responses are ***P = 0.001 by Dunn's multiple comparison. , G-CaMP fluorescence increase in ppk28 control, mutant and rescue projections to water (SOG, scale bar, 50 μm). , Fluorescence change summary after water, 0.1 M NaCl, 1 M NaCl and 1 M sucrose (n = 8–11 trials per concentration ± s.e.m.; t-test, ppk28 control versus mutant, water: ***P = 0.0008, 1 M NaCl: *P = 0.03). , Behavioural assays measuring water or 500 mM sucrose consumption time. Control flies drink more water than ppk28 mutants (*P = 0.017), ppk28 mutants + ppk28-Gal4 (*P = 0.037) or ppk28 mutants + UAS-ppk28 (**P = 0.008). Water consumption of control and rescue is not different (P = 0.53). Su! crose consumption is not different (versus control, mutant: P = 0.63; rescue: P = 0.53). n = 3 ± s.e.m. trials, 18–25 flies per trial per genotype, t-test. * Figure 3: Ectopic expression of ppk28 confers water sensitivity. , Extracellular bristle recordings of i-type sensilla (non-water responsive) from Gr66a-Gal4 flies lacking (-) or containing (+) UAS-ppk28 after water, 0.5 M NMDG, 1 M NMDG or 0.01 M caffeine stimulation (at recording). , Scatter plot of water responses (mean ± s.e.m. in bars; data points are dots) and summary of all responses (mean ± s.e.m.). Responses are different to water (***P = 2.52 × 10-16) and 0.5 M NMDG (*P = 0.016) (t-test; n = 7–27). , G-CaMP fluorescence increase in GR66A bitter-sensing projections (left) and GR66A projections expressing ppk28 (right), after water stimulation (maximum ΔF/F) (SOG, scale bar, 50 μm). , Responses of GR66A cells (left) and GR66A cells expressing ppk28 (right) to water (at arrow). , Summary of fluorescence changes in GR66A cells without (grey) or with (green) ppk28 tested with water, 0.5 and 1 M NMDG and 0.5, 1 and 2 M sucrose. n = 4–5 trials per concentration ± s.e.m.; t-test, versus GR66A cont! rol, water: **P = 0.013, 0.5 M NMDG: *P = 0.03; water: **P = 0.002, 0.5 M sucrose: ***P = 0.0002. * Figure 4: Heterologous cells expressing PPK28 respond to hypo-osmolarity. –, Pseudocolour images of maximum fluorescence increases to isotonic (303 mmol kg-1) and reduced (174 mmol kg-1) osmolality for HEK293 cells expressing PPK28, TRPV4 or vector. Colour bar indicates maximum ΔF ranging from -10 to 80. On the right, plots of fluorescence change per frame over the stimulation (bar) at 80%, 70% and 60% of isotonic osmolality (236, 216 and 174 mmol kg-1). , Concentration curve of responses to osmolalities. n = 4–5 trials per concentration ± s.e.m.; t-test, versus vector, PPK28: 70% **P = 0.00583; 60% **P = 0.00632; TRPV4: 80% **P = 0.00384; 70% ***P = 0.000120; 60% **P = 0.00615. Author information * Author information * Supplementary information * Comments Affiliations * Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, 16 Barker Hall, * Peter Cameron, * Makoto Hiroi & * Kristin Scott * Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute and Functional Genomics Laboratory, 142 Life Sciences Addition, * John Ngai * Howard Hughes Medical Institute, University of California-Berkeley, Berkeley, California 94720, USA * Kristin Scott Contributions P.C. performed most experiments and co-wrote the manuscript. M.H. performed the electrophysiological recordings and the HEK293 heterologous experiments. J.N. provided expertise on the microarray experiments. K.S. co-wrote the manuscript and supervised the project. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Kristin Scott (kscott@berkeley.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (8.2M) This file contains Supplementary Figures S1-S6 with legends and Supplementary Table S1. Additional data
• Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect
  Gao M Nettles RE Belema M Snyder LB Nguyen VN Fridell RA Serrano-Wu MH Langley DR Sun JH O'Boyle Ii DR Lemm JA Wang C Knipe JO Chien C Colonno RJ Grasela DM Meanwell NA Hamann LG - Nature 465(7294):96 (2010)
  Nature | Letter Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect * Min Gao1 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard E. Nettles2 Search for this author in: * NPG journals * PubMed * Google Scholar * Makonen Belema3 Search for this author in: * NPG journals * PubMed * Google Scholar * Lawrence B. Snyder3 Search for this author in: * NPG journals * PubMed * Google Scholar * Van N. Nguyen3 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert A. Fridell1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael H. Serrano-Wu3 Search for this author in: * NPG journals * PubMed * Google Scholar * David R. Langley4 Search for this author in: * NPG journals * PubMed * Google Scholar * Jin-Hua Sun1 Search for this author in: * NPG journals * PubMed * Google Scholar * Donald R. O'Boyle II1 Search for this author in: * NPG journals * PubMed * Google Scholar * Julie A. Lemm1 Search for this author in: * NPG journals * PubMed * Google Scholar * Chunfu Wang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jay O. Knipe5 Search for this author in: * NPG journals * PubMed * Google Scholar * Caly Chien2 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard J. Colonno1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dennis M. Grasela2 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas A. Meanwell3 Search for this author in: * NPG journals * PubMed * Google Scholar * Lawrence G. Hamann3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:96–100Date published:(06 May 2010)DOI:doi:10.1038/nature08960Received29 October 2009Accepted26 February 2010Published online21 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 worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people1. Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus2, 3. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B4. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log10 reduction ! in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors. View full text Subject terms: * Virology * Drug discovery Figures at a glance * Figure 1: Structures of the iminothiazolidinone BMS-858, BMS-790052, the biotin-tagged HCV NS5A inhibitor 1 and its inactive stereoisomer 2. * Figure 2: The active inhibitor 1 binds to genotype 1b HCV NS5A whereas the inactive stereoisomer 2 does not. Genotype 1b replicon cells were exposed to either or for approximately 18 h before the cells were lysed. A portion of the supernatant was set aside to serve as input control for immunoblot analysis (lanes 1 and 2) while the remainder was mixed with streptavidin–agarose beads and incubated for several hours. Bound proteins were detected by immunoblotting with primary antibodies directed to HCV NS5A. Lanes 1 and 3 depict the results of experiments with the active inhibitor compound whereas lanes 2 and 4 depict the results with the inactive stereoisomer . * Figure 3: Mean plasma concentration–time profile (time 0–72 h) of BMS-790052 after single oral administration of 1–200 mg of drug to healthy subjects. In a double-blind, placebo-controlled, sequential, single ascending-dose study, eight male or female subjects were randomized within each dose panel (1, 10, 25, 50, 100 and 200 mg) to drug or placebo in a ratio of 3:1. BMS-790052 or placebo was administered in the fasted state. The plasma samples obtained at various times were analysed for BMS-790052 by a validated liquid chromatography tandem mass spectrometry assay. Pharmacokinetic parameter values for individual subjects were derived by non-compartmental methods by a validated pharmacokinetic analysis programme. PBA EC90, protein-binding-adjusted EC90 for the individual genotype in a replicon assay. Error bars, standard deviation. * Figure 4: Mean change in log10 HCV RNA with 90% confidence intervals after administration of single oral doses of BMS-790052 to HCV-infected patients. In a double-blind, placebo-controlled, sequential, single ascending-dose study, six subjects were randomized within each dose panel (1, 10, 100 mg) to drug or placebo in a ratio of 5:1. BMS-790052 or placebo was administered in the fasted state. Owing to a dosing error, all six subjects received BMS-790052 in the 1 mg panel. One subject in the 10 mg panel withdrew from the study 8 h after administration of the study drug for non-drug-related reasons; HCV RNA data from the subject are included up until the subject withdrew. Author information * Author information * Supplementary information * Comments Affiliations * Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA * Min Gao, * Robert A. Fridell, * Jin-Hua Sun, * Donald R. O'Boyle II, * Julie A. Lemm, * Chunfu Wang & * Richard J. Colonno * Department of Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA * Richard E. Nettles, * Caly Chien & * Dennis M. Grasela * Department of Discovery Chemistry, * Makonen Belema, * Lawrence B. Snyder, * Van N. Nguyen, * Michael H. Serrano-Wu, * Nicholas A. Meanwell & * Lawrence G. Hamann * Department of Computer-Aided Drug Design, * David R. Langley * Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA * Jay O. Knipe Contributions R.A.F., J.A.L., D.R.O., J.-H.S., C.W. and M.G. designed and performed the replicon screen, constructed replicons and hybrid replicons, conducted genotype coverage and inhibitor-binding experiments, isolated and mapped resistant variants, designed in vitro combination studies and performed genotypic and phenotypic analysis of clinical samples. M.G., R.A.F., J.A.L. and R.J.C. designed the overall virology studies and provided input to the overall research direction. J.O.K. designed and interpreted in vivo pharmacokinetic studies and in vitro compound profiling. M.B., V.N.N., L.B.S. and M.H.S.-W. designed and synthesized the compounds, L.B.S., L.G.H. and N.A.M. provided direction to the chemistry research and contributed to the design of compounds. D.R.L. constructed models of HCV NS5A and contributed to the development of mechanistic hypotheses. R.E.N., C.C. and D.M.G. designed and interpreted human trials, and D.M.G. provided input to the overall research direction. M.G., R.E! .N. and N.A.M. co-authored the manuscript with input from all co-authors, and N.A.M. compiled and edited the article. Competing financial interests The authors are or were, at the time this work was conducted, employees of Bristol-Myers Squibb. Corresponding author Correspondence to: * Nicholas A. Meanwell (Nicholas.Meanwell@bms.com) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (401K) This file contains Supplementary Tables S1-S14, Supplementary References and data for Experimental Chemistry. Additional data
• The scaffold protein Ste5 directly controls a switch-like mating decision in yeast
  - Nature 465(7294):101 (2010)
  Nature | Letter The scaffold protein Ste5 directly controls a switch-like mating decision in yeast * Mohan K. Malleshaiah1, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Vahid Shahrezaei3, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter S. Swain4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen W. Michnick1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:101–105Date published:(06 May 2010)DOI:doi:10.1038/nature08946Received14 April 2009Accepted24 February 2010Published online18 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 Evolution has resulted in numerous innovations that allow organisms to increase their fitness by choosing particular mating partners, including secondary sexual characteristics, behavioural patterns, chemical attractants and corresponding sensory mechanisms1. The haploid yeast Saccharomyces cerevisiae selects mating partners by interpreting the concentration gradient of pheromone secreted by potential mates through a network of mitogen-activated protein kinase (MAPK) signalling proteins2, 3. The mating decision in yeast is an all-or-none, or switch-like, response that allows cells to filter weak pheromone signals, thus avoiding inappropriate commitment to mating by responding only at or above critical concentrations when a mate is sufficiently close4. The molecular mechanisms that govern the switch-like mating decision are poorly understood. Here we show that the switching mechanism arises from competition between the MAPK Fus3 and a phosphatase Ptc1 for control of the phosp! horylation state of four sites on the scaffold protein Ste5. This competition results in a switch-like dissociation of Fus3 from Ste5 that is necessary to generate the switch-like mating response. Thus, the decision to mate is made at an early stage in the pheromone pathway and occurs rapidly, perhaps to prevent the loss of the potential mate to competitors. We argue that the architecture of the Fus3–Ste5–Ptc1 circuit generates a novel ultrasensitivity mechanism, which is robust to variations in the concentrations of these proteins. This robustness helps assure that mating can occur despite stochastic or genetic variation between individuals. The role of Ste5 as a direct modulator of a cell-fate decision expands the functional repertoire of scaffold proteins beyond providing specificity and efficiency of information processing5, 6. Similar mechanisms may govern cellular decisions in higher organisms and be disrupted in cancer. View full text Subject terms: * Biochemistry * Cell biology * Evolution * Molecular biology Figures at a glance * Figure 1: Switch-like shmooing in yeast requires the Fus3–Ste5 interaction. , In MAT cells, α-factor pheromone activates a MAPK cascade that generates phosphorylated, active Fus3, which dissociates from Ste5 (ref. 30) and phosphorylates downstream targets to mediate mating3. Bottom panel: a MATα cell (red) secretes α-factor. Surrounding MAT cells display different morphologies determined by the α-factor concentration sensed. The MAT cell sensing a critical concentration of α-factor (green) 'shmoos' and mates with the MATα cell2. , , The fraction of different morphologies observed in MATste5Δ cells expressing either wild-type Ste5 (Ste5WT) () or the Ste5ND mutant (). Morphologies: axial (green) or bipolar (blue) budding, arrested (black) and shmooing (red). * Figure 2: Levels of the Fus3–Ste5 complex are determined by the Ste5 phosphorylation state. , Steady-state levels of Fus3–Ste5, Fus3–Ste5ND and kinase-dead Fus3(K42R)–Ste5 versus α-factor. Model fit: dashed line. RLU, relative luminescence units. , Ste5 peptide (residues 226–230) with four MAPK phosphorylation sites. , Levels of Fus3–Ste5 complex with non-phosphorylatable phosphosites on Ste5. WT, wild-type Ste5. Red and blue circles: model predictions. , As in , for pseudo-phosphorylated Ste5. Red and blue circles: model fits. , Fus3–Ste5 (ptc1Δ cells) and Ste5–Ptc1 (wild-type cells) interactions versus α-factor. Dashed red line: model fit. Hill coefficient (nH), EC50 values and their errors were calculated from fits to a Hill equation. Error bars, s.e.m. (n = 3). * Figure 3: A novel form of ultrasensitivity explains the switch-like mating decision. , Two-stage binding: Fus3 or Ptc1 first bind to their Ste5 docking sites (green) and then bind to individual phosphosites (red and grey enzyme domains). , Steady-state Ste5 phosphorylation (open circles) versus α-factor for Ste5 with four (solid) or one (dashed) phosphosites. Grey bar: threshold concentration of α-factor. , Predicted Hill coefficients for classic zero-order ultrasensitivity determined from Ste5 phosphorylation during α-factor dose–responses at fixed concentrations of Fus3 and Ste5 (insets). Asterisk: physiological Fus3 and Ste5 concentrations. , As in , for full two-stage binding and the steric hindrance model of Supplementary Fig. 23b. * Figure 4: Experimental validation of model predictions. , Changes in the steady-state levels of the Fus3–Ste5 complex with various Ptc1 concentrations in vivo: wild type, knockout (ptc1Δ) and overexpression (+Ptc1). , In vivo analysis of the steady-state levels of the Fus3–Ste5 complex as a function of α-factor using single (-1PS: AbCD), double (-2PS: abCD), triple (-3PS: Abcd) or quadruple (-4PS: abcd) non-phosphorylatable mutants of Ste5. The Hill coefficient (nH), EC50 values and their errors are calculated from fits of the data to a Hill function (solid lines). Error bars, s.e.m. (n = 3). Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Mohan K. Malleshaiah & * Vahid Shahrezaei Affiliations * Département de Biochimie, * Mohan K. Malleshaiah & * Stephen W. Michnick * Centre Robert-Cedergren, Bio-Informatique et Génomique Université de Montréal, C.P. 6128, Succursale centre-ville Montréal, Québec H3C 3J7, Canada * Stephen W. Michnick * Department of Mathematics, Imperial College London, South Kensington Campus, London SW7 2AZ, UK * Vahid Shahrezaei * Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montréal, Québec H3G 1Y6, Canada * Peter S. Swain * Centre for Systems Biology at Edinburgh, University of Edinburgh, Edinburgh EH9 3JD, UK * Peter S. Swain Contributions M.K.M. and S.W.M. planned and designed experiments; M.K.M. performed experiments; V.S. and P.S.S. planned and V.S. performed the mathematical modelling; M.K.M., S.W.M., V.S. and P.S.S. analysed the results; M.K.M., V.S., P.S.S. and S.W.M. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Stephen W. Michnick (stephen.michnick@umontreal.ca) or * Peter S. Swain (peter.swain@ed.ac.uk) Supplementary information * Author information * Supplementary information * Comments Movies * Supplementary Movie 1 (2.6M) This movie file shows axial Budding in the absence of α-factor stimulus. * Supplementary Movie 2 (1.7M) This movie file shows bipolar Budding in response to 0.1μM of α-factor stimulus. * Supplementary Movie 3 (2.6M) This movie file shows shmooing in response to 1.0μM of α-factor stimulus. PDF files * Supplementary Information (7.8M) This file contains Supplementary Material and Methods, Supplementary Figures 1-31 with legends, Supplementary Tables 1-3 and Supplementary References. Additional data
• An RNA polymerase II- and AGO4-associated protein acts in RNA-directed DNA methylation
  Gao Z Liu HL Daxinger L Pontes O He X Qian W Lin H Xie M Lorkovic ZJ Zhang S Miki D Zhan X Pontier D Lagrange T Jin H Matzke AJ Matzke M Pikaard CS Zhu JK - Nature 465(7294):106 (2010)
  Nature | Letter An RNA polymerase II- and AGO4-associated protein acts in RNA-directed DNA methylation * Zhihuan Gao1, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Hai-Liang Liu1, 2, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Lucia Daxinger3, 10, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Olga Pontes4, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Xinjian He1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Weiqiang Qian1 Search for this author in: * NPG journals * PubMed * Google Scholar * Huixin Lin1 Search for this author in: * NPG journals * PubMed * Google Scholar * Mingtang Xie1 Search for this author in: * NPG journals * PubMed * Google Scholar * Zdravko J. Lorkovic6 Search for this author in: * NPG journals * PubMed * Google Scholar * Shoudong Zhang1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Daisuke Miki1 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiangqiang Zhan1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Dominique Pontier7 Search for this author in: * NPG journals * PubMed * Google Scholar * Thierry Lagrange7 Search for this author in: * NPG journals * PubMed * Google Scholar * Hailing Jin8 Search for this author in: * NPG journals * PubMed * Google Scholar * Antonius J. M. Matzke3 Search for this author in: * NPG journals * PubMed * Google Scholar * Marjori Matzke3 Search for this author in: * NPG journals * PubMed * Google Scholar * Craig S. Pikaard9 Search for this author in: * NPG journals * PubMed * Google Scholar * Jian-Kang Zhu1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:106–109Date published:(06 May 2010)DOI:doi:10.1038/nature09025Received16 November 2009Accepted22 March 2010Published online21 April 2010Corrected online06 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 DNA methylation is an important epigenetic mark in many eukaryotes1, 2, 3, 4, 5. In plants, 24-nucleotide small interfering RNAs (siRNAs) bound to the effector protein, Argonaute 4 (AGO4), can direct de novo DNA methylation by the methyltransferase DRM2 (refs 2, 4–6). Here we report a new regulator of RNA-directed DNA methylation (RdDM) in Arabidopsis: RDM1. Loss-of-function mutations in the RDM1 gene impair the accumulation of 24-nucleotide siRNAs, reduce DNA methylation, and release transcriptional gene silencing at RdDM target loci. RDM1 encodes a small protein that seems to bind single-stranded methyl DNA, and associates and co-localizes with RNA polymerase II (Pol II, also known as NRPB), AGO4 and DRM2 in the nucleus. Our results indicate that RDM1 is a component of the RdDM effector complex and may have a role in linking siRNA production with pre-existing or de novo cytosine methylation. Our results also indicate that, although RDM1 and Pol V (also known as NRPE) may! function together at some RdDM target sites in the peri-nucleolar siRNA processing centre, Pol II rather than Pol V is associated with the RdDM effector complex at target sites in the nucleoplasm. View full text Subject terms: * Molecular biology * Genetics * Genomics * Plant sciences * Physiology Figures at a glance * Figure 1: Effects of rdm1 on RD29A-LUC and 35S-NPTII silencing, DNA methylation and small RNAs. , Effects of rdm1 on RD29A-LUC and 35S-NPTII silencing as indicated by luciferase activity and kanamycin resistance of the ros1 rdm1 mutants. Wild-type (WT), ros1, ros1 rdm1-1 and ros1 rdm1- plants were grown for 10 days and imaged after cold treatment (48 h, 4 °C). For kanamycin resistance test, the seeds were planted on Murashige–Skoog (MS) medium supplemented with kanamycin (50 mg l-1). Seedlings were photographed after 2 weeks. , Methylation status of the endogenous and transgene RD29A promoter as determined by bisulphite sequencing. , Detection of small RNAs in WT, ros1, rdm1-1 single mutant, ros1 rdm1-1 double mutant, and a rdm1-1 complementation line (rdm1+RDM1; T3 generation). U6 small nuclear RNA was used as loading control. nt, nucleotides. * Figure 2: Effects of rdm1-1 on siRNA and transcript levels and DNA methylation at endogenous RdDM target loci. , Detection of various small RNAs. U6 snRNA was used as loading control. The positions of size markers are indicated (24 or 21 nt). , DNA methylation status as determined by PCR-based assays. The At2g19920 gene, which lacks HaeIII sites, served as a PCR control for AtSN1. The same amounts of undigested DNA from different samples were used as controls for AtGP1, AtMu1 and AtLINE1. PCR cycles were 35 and 30, respectively, for McrBC-digested and undigested samples. , Southern blot analysis of the methylation status of 5S ribosomal DNA repeats using genomic DNA digested with the methylation-sensitive enzyme HaeIII. , Methylation status of AtSN1, MEA-ISR and SIMPLEHAT2 as determined by bisulphite sequencing. , Determination of transcript levels by real-time RT–PCR. The transcript levels were normalized using TUB8 as an internal standard. Error bars represent s.d. (n = 3). , RT–PCR analysis of a Pol V-dependent transcript from AtSN1. TUB8 was amplified as an internal control! . PCR reactions without reverse transcription (No RT) were carried out as controls to rule out DNA contamination. * Figure 3: Immunoblot analysis of RDM1 and its interaction with AGO4, DRM2 and NRPB1. , Western blot analysis of RDM1 protein levels. Coomassie-stained gel (lower panel) is shown as control for loading. , Co-immunoprecipitation (IP) between Myc–AGO4 and RDM1. , Co-immunoprecipitation between Flag–DRM2 and RDM1. , Co-immunoprecipitation between NRPB1 and RDM1. * Figure 4: Sub-nuclear localization of RDM1 and its co-localization with other components of the RdDM pathway. , The nuclear distribution of RDM1 was analysed by immunostaining using anti-RDM1 (green). , Dual immunolocalization using anti-RDM1 (green) in transgenic lines expressing recombinant full-length epitope-tagged Flag–NRPD1, Myc–AGO4, Flag–NRPE1 and Flag–DRM2 (red). , Dual immunolocalization using anti-NRPB1 and anti-RDM1 or anti-AGO4. In all panels the DNA was stained with DAPI (blue) and the scale bars correspond to 5 μm. Arrows point to the peri-nucleolar dot (siRNA processing centre). Change history * Change history * Author information * Supplementary information * CommentsCorrected online 06 May 2010Reference 23 was updated to reflect a change in the title. Author information * Change history * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Zhihuan Gao, * Hai-Liang Liu, * Lucia Daxinger & * Olga Pontes Affiliations * Institute for Integrative Genome Biology and Department of Botany and Plant Sciences, University of California, Riverside, California 92521, USA * Zhihuan Gao, * Hai-Liang Liu, * Xinjian He, * Weiqiang Qian, * Huixin Lin, * Mingtang Xie, * Shoudong Zhang, * Daisuke Miki, * Xiangqiang Zhan & * Jian-Kang Zhu * School of life science and technology, Tongji University, Shanghai 200092, China * Hai-Liang Liu * Gregor Mendel Institute of Molecular Plant Biology, Austrian Academy of Sciences, 1030 Vienna, Austria * Lucia Daxinger, * Antonius J. M. Matzke & * Marjori Matzke * Biology Department, Washington University, St Louis, Missouri 63130, USA * Olga Pontes * Center for Plant Stress Genomics and Technology, 4700 King Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of Saudi Arabia * Xinjian He, * Shoudong Zhang, * Xiangqiang Zhan & * Jian-Kang Zhu * Max F. Perutz Laboratory, Medical University of Vienna, 1030 Vienna, Austria * Zdravko J. Lorkovic * LGDP, CNRS/IRD/Université de Perpignan, UMR 5096, 66860 Perpignan, France * Dominique Pontier & * Thierry Lagrange * Institute for Integrative Genome Biology and Department of Plant Pathology and Microbiology, University of California, Riverside, California 92521, USA * Hailing Jin * Department of Biology and Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana 47405, USA * Craig S. Pikaard * Present address: Division of Genetics and Population Health, Queensland Institute of Medical Research, QLD 4006, Herston, Australia. * Lucia Daxinger Contributions Z.G., H.-L.L, X.H., W.Q., H.L., M.X., S.Z., D.M., and X.Z. contributed Figs 1, 2, 3b–d, Supplementary Figs 1–6 and 9–12, and Supplementary Table 2. L.D, Z.J.L., A.J.M. and M.M. contributed the rdm1-4 allele (Supplementary Fig. 5) and data on its characterization (Supplementary Fig. 7). O.P. and C.S.P contributed Fig. 4, Supplementary Fig. 8 and Supplementary Table 1. D.P and T.L. contributed Fig. 3a. J.-K.Z designed the experiments and wrote the paper together with Z.G., H.J., O.P., C.S.P. and M.M. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Jian-Kang Zhu (jian-kang.zhu@ucr.edu) Supplementary information * Change history * Author information * Supplementary information * Comments PDF files * Supplementary Information (1.8M) This file contains Supplementary Figures S1-S12 with legends, Supplementary Tables S1-S2 and References. Additional data
• X-ray crystal structure of the light-independent protochlorophyllide reductase
  - Nature 465(7294):110 (2010)
  Nature | Letter X-ray crystal structure of the light-independent protochlorophyllide reductase * Norifumi Muraki1, 2, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jiro Nomata3, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Kozue Ebata3 Search for this author in: * NPG journals * PubMed * Google Scholar * Tadashi Mizoguchi4 Search for this author in: * NPG journals * PubMed * Google Scholar * Tomoo Shiba1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Hitoshi Tamiaki4 Search for this author in: * NPG journals * PubMed * Google Scholar * Genji Kurisu2 Search for this author in: * NPG journals * PubMed * Google Scholar * Yuichi Fujita3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:110–114Date published:(06 May 2010)DOI:doi:10.1038/nature08950Received21 October 2009Accepted22 February 2010Published online18 April 2010Corrected online06 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 Photosynthetic organisms adopt two different strategies for the reduction of the C17 = C18 double bond of protochlorophyllide (Pchlide) to form chlorophyllide a, the direct precursor of chlorophyll a (refs 1–4). The first involves the activity of the light-dependent Pchlide oxidoreductase5, 6, 7, 8, 9, and the second involves the light-independent (dark-operative) Pchlide oxidoreductase10 (DPOR). DPOR is a nitrogenase-like enzyme consisting of two components, L-protein (a BchL dimer) and NB-protein (a BchN–BchB heterotetramer), which are structurally related to nitrogenase Fe protein and MoFe protein, respectively10, 11. Here we report the crystal structure of the NB-protein of DPOR from Rhodobacter capsulatus at a resolution of 2.3 Å. As expected, the overall structure is similar to that of nitrogenase MoFe protein: each catalytic BchN–BchB unit contains one Pchlide and one iron–sulphur cluster (NB-cluster) coordinated uniquely by one aspartate and three cysteine! s. Unique aspartate ligation is not necessarily needed for the cluster assembly but is essential for the catalytic activity. Specific Pchlide-binding accompanies the partial unwinding of an α-helix that belongs to the next catalytic BchN–BchB unit. We propose a unique trans-specific reduction mechanism in which the distorted C17-propionate of Pchlide and an aspartate from BchB serve as proton donors for C18 and C17 of Pchlide, respectively. Intriguingly, the spatial arrangement of the NB-cluster and Pchlide is almost identical to that of the P-cluster and FeMo-cofactor in nitrogenase MoFe-protein, illustrating that a common architecture exists to reduce chemically stable multibonds of porphyrin and dinitrogen. View full text Subject terms: * Biochemistry * Evolution * Plant sciences * Structural biology Figures at a glance * Figure 1: Pchlide reduction and crystal structures of DPOR NB-protein and nitrogenase MoFe protein. , The C17 = C18 double bond of Pchlide D ring (yellow) is trans-reduced by DPOR or LPOR to form chlorophyllide a. L-protein transfers two electrons from ferredoxin (Fd) to NB-protein, coupled with ATP hydrolysis. NB-protein serves as the catalytic component providing the catalytic site for Pchlide reduction. LPOR catalyses the light-driven hydride transfer from NADPH. A, B, C and D indicate the four pyrrole rings of porphyrin, following IUPAC/IUB recommendations. λmax is the peak wavelength in the red spectral region in acetone. , Crystal structure of NB-protein. The [4Fe–4S] clusters (NB-clusters) are shown in a CPK model and the Pchlide molecules are shown in a stick model. The BchN and BchB subunits in one dimer are respectively coloured green and blue, and the identical subunits related by non-crystallographic two-fold symmetry are respectively coloured light green and light blue. , The crystal structure of MoFe protein (Protein Data Bank ID, 1M1Y). Structures of NifD! and NifK not corresponding to BchN and BchB are shown in orange and yellow, respectively (Supplementary Fig. 1b). * Figure 2: Structures around the NB-cluster and the activity of NB-protein mutants. –, Structures around the NB-cluster of the wild-type enzyme (), the D36C variant () and the D36A variant (), overlaid with the Fo–Fc omit map contoured at the 4.5σ level. In , the Fo–Fc difference Fourier map is also shown, contoured at 4.0σ level, to indicate the location of possible fourth ligand. Colour code is as in Fig. 1b. , Activity of wild-type (WT), BchN-C26A, BchN-C51A, BchN-C112A and BchB-C95A variants of NB-protein. The lower panel shows the SDS–polyacrylamide gel electrophoresis (SDS–PAGE) profile of the purified wild type and the four variants used for the assay. , Activity of wild-type, BchB-D36A, BchB-D36C and BchB-D36S variants of NB-protein. The lower panel shows the SDS–PAGE profile of the purified wild type and the three variants used for the assay. The specific activity of wild-type NB-protein was 53.8 nmol min-1 mg-1. * Figure 3: Pchlide-binding cavity and a proposed reaction mechanism for trans-specific reduction. , Pchlide-binding cavity. The NB-cluster and its coordinating residues, Pchlide and notable residues for interactions are shown in stick models. The C-terminal helix from the next protomer (BchB′) is partly unwound on Pchlide binding. For reference, the C-terminal helix of the Pchlide-free structure (grey) is superimposed on the Pchlide-bound structure. , Proposed mechanism for the stereospecific reduction of the C17 = C18 double bond of Pchlide. , The activity of wild-type, F25A, D274A, M408A and L410A variants of NB-protein. The wild-type NB-protein had activities of 66.7 and 53.2 nmol min-1 mg-1 in the assays for F25A and D274A, respectively. The lower panel shows the SDS–PAGE profile of purified NB-protein variants. , Lineweaver–Burk plot showing the competitive inhibition by chlorophyll c. The concentrations of chlorophyll c used are 0 μM (circles), 10 μM (up-triangles), 20 μM (diamonds), 40 μM (squares) and 80 μM (down-triangles). [Pchlide], ! Pchlide concentration; V, initial reaction rate. Inset, structure of chlorophyll c with the acrylate side chain at C17 shown in yellow. * Figure 4: Common architecture of DPOR and nitrogenase. , Comparison of redox-active elements in nitrogenase complex (left) and DPOR NB-protein (right), showing that both elements are extensively overlapped. The positions of all iron–sulphur clusters, FeMo-cofactor and Pchlide of the superimposed complexes are shown (centre). Colour code is as in Fig. 1b. , A conceptual model of DPOR complex with an architecture similar to that of the nitrogenase complex. Two symmetric functional units (BchN–BchB) of NB-protein interact through some amino-acid residues of BchB subunits. Accession codes * Accession codes * Change history * Author information * Supplementary information * Comments Primary accessions Protein Data Bank * 1M1Y * 3AEK * 3AEQ * 3AER * 3AES * 3AET * 3AEU * 1M1Y * 3AEK * 3AEQ * 3AER * 3AES * 3AET * 3AEU Change history * Accession codes * Change history * Author information * Supplementary information * CommentsCorrected online 06 May 2010The position of the Mg in Fig. 3d was corrected. Author information * Accession codes * Change history * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Norifumi Muraki & * Jiro Nomata Affiliations * Department of Life Sciences, University of Tokyo, Komaba, Meguro-ku, Tokyo 153-8902, Japan * Norifumi Muraki & * Tomoo Shiba * Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan * Norifumi Muraki & * Genji Kurisu * Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan * Jiro Nomata, * Kozue Ebata & * Yuichi Fujita * Department of Bioscience and Biotechnology, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan * Tadashi Mizoguchi & * Hitoshi Tamiaki * Presto, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan * Yuichi Fujita * Present address: Department of Biomedical Chemistry, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. * Tomoo Shiba Contributions Purification of NB-protein and site-directed mutagenesis were conducted by J.N., K.E. and N.M.; the enzymatic assay of NB-protein was conducted by J.N.; the crystal structures of NB-protein were solved by N.M., T.S. and G.K.; chlorophyll c was prepared by T.M. and H.T.; G.K. and Y.F. contributed to the design of the experiments and writing the manuscript. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Genji Kurisu (gkurisu@protein.osaka-u.ac.jp) or * Yuichi Fujita (fujita@agr.nagoya-u.ac.jp) Coordinates and structure factors for the structures reported here are available from the Protein Data Bank with accession codes of 3AEK (Pchlide-bound form), 3AEQ (anaerobic Pchlide-bound form), 3AER (Pchlide-free form), 3AES (selenomethionine-substituted Pchlide-free form), 3AET (D36C form) and 3AEU (D36A form). Supplementary information * Accession codes * Change history * Author information * Supplementary information * Comments PDF files * Supplementary Information (8.3M) This file contains Supplementary Figures 1-6 with legends, Supplementary Tables 1-2, a Supplementary Discussion and Supplementary References. Additional data
• Oxidation of methane by a biological dicopper centre
  Balasubramanian R Smith SM Rawat S Yatsunyk LA Stemmler TL Rosenzweig AC - Nature 465(7294):115 (2010)
  Nature | Letter Oxidation of methane by a biological dicopper centre * Ramakrishnan Balasubramanian1, 2, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen M. Smith1, 2, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Swati Rawat3 Search for this author in: * NPG journals * PubMed * Google Scholar * Liliya A. Yatsunyk1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Timothy L. Stemmler3 Search for this author in: * NPG journals * PubMed * Google Scholar * Amy C. Rosenzweig1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Corresponding authorsJournal name:NatureVolume:465,Pages:115–119Date published:(06 May 2010)DOI:doi:10.1038/nature08992Received21 November 2009Accepted05 March 2010Published online21 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 Vast world reserves of methane gas are underutilized as a feedstock for the production of liquid fuels and chemicals owing to the lack of economical and sustainable strategies for the selective oxidation of methane to methanol1. Current processes to activate the strong C–H bond (104 kcal mol-1) in methane require high temperatures, are costly and inefficient, and produce waste2. In nature, methanotrophic bacteria perform this reaction under ambient conditions using metalloenzymes called methane monooxygenases (MMOs). MMOs thus provide the optimal model for an efficient, environmentally sound catalyst3. There are two types of MMO. Soluble MMO (sMMO) is expressed by several strains of methanotroph under copper-limited conditions and oxidizes methane with a well-characterized catalytic di-iron centre4. Particulate MMO (pMMO) is an integral membrane metalloenzyme produced by all methanotrophs and is composed of three subunits, pmoA, pmoB and pmoC, arranged in a trimeric α! 3β3γ3 complex5. Despite 20 years of research and the availability of two crystal structures, the metal composition and location of the pMMO metal active site are not known. Here we show that pMMO activity is dependent on copper, not iron, and that the copper active site is located in the soluble domains of the pmoB subunit rather than within the membrane. Recombinant soluble fragments of pmoB (spmoB) bind copper and have propylene and methane oxidation activities. Disruption of each copper centre in spmoB by mutagenesis indicates that the active site is a dicopper centre. These findings help resolve the pMMO controversy and provide a promising new approach to developing environmentally friendly C–H oxidation catalysts. View full text Subject terms: * Biochemistry * Chemical biology Figures at a glance * Figure 1: Structure of the M. capsulatus (Bath) pMMO protomer. The amino-terminal cupredoxin domain of pmoB (spmoBd1) is shown in purple, the carboxy-terminal cupredoxin domain of pmoB (spmoBd2) is shown in green and the two transmembrane helices are shown in blue. In the recombinant spmoB protein, spmoBd1 and spmoBd2 are connected by a Gly-Lys-Leu-Gly-Gly-Gly sequence linking residues 172 and 265 (indicated), rather than the two transmembrane helices. Copper ions are shown as cyan spheres and ligands are shown as ball-and-stick representations. The pmoA (faint light green) and pmoC (faint light blue) subunits are composed of transmembrane helices. The location of the zinc ion (grey sphere) has been proposed to contain a di-iron centre. A hydrophilic patch of residues, marked with an asterisk, is the site of a proposed tricopper centre. Protein Data Bank ID, 1YEW. * Figure 2: Metal analysis. , Metal content of as-isolated pMMO and apo-pMMO prepared by cyanide treatment. Metal content is expressed per 100 kDa pMMO protomer, with copper in blue and iron in red. , Copper content of refolded spmoB variants. Reported values and errors represent the average and standard deviation of at least four independent measurements for pMMO samples and at least six independent refolding experiments for each spmoB variant. * Figure 3: Restoration of activity to apo-pMMO by the addition of copper. Copper equivalents added are expressed per 100 kDa pMMO protomer. Representative titrations are shown. Addition of 2–3 equiv. of copper restored ~70% of the propylene epoxidation activity () and ~90% of the methane oxidation activity (). Reported values represent the average and standard deviation of at least two measurements. * Figure 4: Copper EXAFS data and simulations for pMMO and spmoB variants. Raw k3-weighted EXAFS data and phase-shifted Fourier transforms are shown for as-isolated pMMO (, ), copper reconstituted pMMO (, ), spmoB (, ), spmoB_H48N (, ), and spmoB_H137,139A (, ). Raw unfiltered data are shown in black and best-fit simulations are shown in grey. χ, EXAFS region of the XAS spectrum; Δ, apparent shift in Fourier transform displayed bond distance (by ~-0.5 Å) due to a phase shift during calculation of the transform; k, photoelectron wavevector; R, metal–ligand bond length. * Figure 5: Catalytic activity of spmoB proteins. , Epoxidation of propylene to propylene oxide expressed as a percentage of the activity of as-isolated, membrane-bound M. capsulatus (Bath) pMMO. , Oxidation of methane to methanol expressed as a percentage of the activity of as-isolated, membrane-bound M. capsulatus (Bath) pMMO. All values are the average of at least two independent refolding preparations, with error bars representing standard deviations. The activity of each spmoB protein was compared with the activity of membrane-bound pMMO measured under the same experimental conditions. Accession codes * Accession codes * Author information * Supplementary information * Comments Primary accessions Protein Data Bank * 1YEW * 1YEW Author information * Accession codes * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Ramakrishnan Balasubramanian & * Stephen M. Smith Affiliations * Department of Biochemistry, Molecular Biology and Cell Biology, * Ramakrishnan Balasubramanian, * Stephen M. Smith, * Liliya A. Yatsunyk & * Amy C. Rosenzweig * Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA * Ramakrishnan Balasubramanian, * Stephen M. Smith, * Liliya A. Yatsunyk & * Amy C. Rosenzweig * Department of Biochemistry and Molecular Biology, Wayne State University, School of Medicine, Detroit, Michigan 48201, USA * Swati Rawat & * Timothy L. Stemmler Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Timothy L. Stemmler (tstemmle@med.wayne.edu) or * Amy C. Rosenzweig (amyr@northwestern.edu) Supplementary information * Accession codes * Author information * Supplementary information * Comments PDF files * Supplementary Information (1.9M) This file contains Supplementary Tables S1-S3 and Supplementary Figures S1-S5 with legends. Additional data
• Genome sequence of the palaeopolyploid soybean
  - Nature 465(7294):120 (2010)
  Nature | Corrigendum Genome sequence of the palaeopolyploid soybean * Jeremy Schmutz Search for this author in: * NPG journals * PubMed * Google Scholar * Steven B. Cannon Search for this author in: * NPG journals * PubMed * Google Scholar * Jessica Schlueter Search for this author in: * NPG journals * PubMed * Google Scholar * Jianxin Ma Search for this author in: * NPG journals * PubMed * Google Scholar * Therese Mitros Search for this author in: * NPG journals * PubMed * Google Scholar * William Nelson Search for this author in: * NPG journals * PubMed * Google Scholar * David L. Hyten Search for this author in: * NPG journals * PubMed * Google Scholar * Qijian Song Search for this author in: * NPG journals * PubMed * Google Scholar * Jay J. Thelen Search for this author in: * NPG journals * PubMed * Google Scholar * Jianlin Cheng Search for this author in: * NPG journals * PubMed * Google Scholar * Dong Xu Search for this author in: * NPG journals * PubMed * Google Scholar * Uffe Hellsten Search for this author in: * NPG journals * PubMed * Google Scholar * Gregory D. May Search for this author in: * NPG journals * PubMed * Google Scholar * Yeisoo Yu Search for this author in: * NPG journals * PubMed * Google Scholar * Tetsuya Sakurai Search for this author in: * NPG journals * PubMed * Google Scholar * Taishi Umezawa Search for this author in: * NPG journals * PubMed * Google Scholar * Madan K. Bhattacharyya Search for this author in: * NPG journals * PubMed * Google Scholar * Devinder Sandhu Search for this author in: * NPG journals * PubMed * Google Scholar * Babu Valliyodan Search for this author in: * NPG journals * PubMed * Google Scholar * Erika Lindquist Search for this author in: * NPG journals * PubMed * Google Scholar * Myron Peto Search for this author in: * NPG journals * PubMed * Google Scholar * David Grant Search for this author in: * NPG journals * PubMed * Google Scholar * Shengqiang Shu Search for this author in: * NPG journals * PubMed * Google Scholar * David Goodstein Search for this author in: * NPG journals * PubMed * Google Scholar * Kerrie Barry Search for this author in: * NPG journals * PubMed * Google Scholar * Montona Futrell-Griggs Search for this author in: * NPG journals * PubMed * Google Scholar * Brian Abernathy Search for this author in: * NPG journals * PubMed * Google Scholar * Jianchang Du Search for this author in: * NPG journals * PubMed * Google Scholar * Zhixi Tian Search for this author in: * NPG journals * PubMed * Google Scholar * Liucun Zhu Search for this author in: * NPG journals * PubMed * Google Scholar * Navdeep Gill Search for this author in: * NPG journals * PubMed * Google Scholar * Trupti Joshi Search for this author in: * NPG journals * PubMed * Google Scholar * Marc Libault Search for this author in: * NPG journals * PubMed * Google Scholar * Anand Sethuraman Search for this author in: * NPG journals * PubMed * Google Scholar * Xue-Cheng Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Kazuo Shinozaki Search for this author in: * NPG journals * PubMed * Google Scholar * Henry T. Nguyen Search for this author in: * NPG journals * PubMed * Google Scholar * Rod A. Wing Search for this author in: * NPG journals * PubMed * Google Scholar * Perry Cregan Search for this author in: * NPG journals * PubMed * Google Scholar * James Specht Search for this author in: * NPG journals * PubMed * Google Scholar * Jane Grimwood Search for this author in: * NPG journals * PubMed * Google Scholar * Dan Rokhsar Search for this author in: * NPG journals * PubMed * Google Scholar * Gary Stacey Search for this author in: * NPG journals * PubMed * Google Scholar * Randy C. Shoemaker Search for this author in: * NPG journals * PubMed * Google Scholar * Scott A. Jackson Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:120Date published:(06 May 2010)DOI:doi:10.1038/nature08957 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nature463, 178–183 (2010) During resubmission of this work, a paper was published1 that used a comparative genomics approach between soybean and maize to show that a single-base mutation in chromosome 19 accounts for the duplicate recessive epistasis needed to greatly reduce phytate production in soybean seed. In this Article, the statement that: "31,264 high-confidence soybean genes have recent paralogues with Ks ≈ 0.13 synonymous substitutions per site and 4dTv ≈ 0.0566 synonymous transversions per site" is inadvertently incorrect, and instead the correct statement is that "26,501 high-confidence soybean genes have recent paralogues with Ks ≈ 0.13 synonymous substitutions per site and 4dTv ≈ 0.0566 synonymous transversions per site". This change does not affect the overall conclusions. Also, this work was performed under the auspices of the US Department of Energy's Office of Science, Biological and Environmental Research Program and the Joint Genome Institute (DE-AC02-05CH11231, DE-AC52-07NA27344 and DE-AC02-06NA25396). References * Gillman, J. D., Pantalone, V. R. & Bilyeu, K.The low phytic acid phenotype in soybean line CX1834 is due to mutations in two homologs of the maize low phytic acid gene. Plant Genome2, 179–190 (2009) * ChemPort * Article Download references Additional data
• KYLE 7
  - Nature 465(7294):126 (2010)
  Virtual success.