Hot off the presses! Apr 29 Nature

The Apr 29 issue of the Nature is now up on Pubget (About Nature): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Under suspicion
  - Nature 464(7293):1245 (2010)
  Nature | Editorial Under suspicion Journal name:NatureVolume:464,Page:1245Date published:(29 April 2010)DOI:doi:10.1038/4641245aPublished online28 April 2010 When Nature or its sister journals receive serious allegations about data or author conduct, they follow a clear procedure to work out whether the published record needs to be revised. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg A particularly exciting research paper catches your eye. You start to read it in detail, carefully studying the methods, figures, data and logic. To your growing horror, you realize that a few of the blots and gel images look as though they have been digitally manipulated. You immediately inform the journal of your suspicions and are told that the editors will 'look into it'. But after months of silence, you begin to wonder if that phrase is just a euphemism for inaction. It isn't — certainly not at Nature or any of the other Nature-branded journals. We make a concerted effort to forestall such problems by spot-checking the images in at least two papers of each issue before publication. Even so, Nature journals that publish a substantial number of gels and blots still receive up to five reports of image manipulation per journal per year — and few of these cases can be handled quickly. When we receive a complaint, we first do our own tests on the figures to see whether the charges have merit. We also take a careful look at the paper as a whole. Some claims of fraudulent image manipulation turn out to be mistaken. Others we suspect of being clumsy attempts to slur the reputations of others. Occasionally, our examination suggests that something may be amiss. We then ask the authors for the original data and an explanation of what has happened. This is to help us understand whether the images really were manipulated and, if so, why. This request for authors to provide us with explanations holds true for almost all other types of allegations, from authors not sharing materials as expected to charges of fabricated data or plagiarism. Intent is key — we often find that no data have been fabricated, but that poor practice and a lack of education have allowed unexplained gel splices, for example, to slip past co-authors before submission or during the revision process. Taking into account the authors' response, together with our comparison of the original images with the published figures, we will hopefully find that the apparent problems are either nonexistent or easily remedied. If we conclude otherwise, we will then contact the authors' home institution. This step is necessary because, unlike universities and other such institutions, journals don't have the resources or the legal authority to investigate allegations fully, or to make formal findings of research misconduct. At Nature, we usually wait for the results of a formal inquiry before correcting the record — hence the seeming inaction. Institutions vary in their practices, and some are more efficient than others. Institutions that accept government grants in the United States must have a research-integrity officer to handle such allegations, but they are not obliged to share their information with us. We urge institutions to produce a redacted version of their final report that protects the innocent, but that indicates the extent of the investigation and the findings on each allegation. Because this is not general practice, we are not always sure that we concur with the actions suggested by the institution's investigating committee. To see exactly what was examined, we are forced to request clarifications, which delays revisions to the public record further. At times, we have to resort to the US Freedom of Information Act to obtain enough information to correct the literature appropri! ately. If the institute is not in the United States, lines of responsibility are less clear. Determining whom to contact is not straightforward and convincing parties that an investigation is needed and getting useful information back is not a reliable process. Sometimes, this means it can be difficult to judge if the investigation has been thorough and fair. The complexity of a case, which is not always readily apparent, also has a bearing on how quickly a verdict can be reached. If an institution's report concludes that misconduct occurred, we usually insist on a retraction — and will issue the retraction ourselves if the authors refuse to comply. But when an institution's investigation cites lesser problems such as 'beautification' of the images, 'sloppy science' or 'inadequate record-keeping' — sometimes misconduct is suspected but cannot be proven — we will base our response on the specifics of the case. If there were no data fraud and no intent to deceive, for example, and if only one or two images were involved, we would allow the authors to publish an erratum and supply appropriate data, figures, original gels or images as supplementary information. Such an erratum can enhance the authors' reputation for honesty. But if most of the figures are problematic, we will strongly urge the authors to retract the paper, even if they were cleared of misconduct and even if the paper's main conclusions have been verified independently by other labs. The logic is that the published paper did not accurately reflect the data as they were collected. We urge all readers or reviewers who think that images or other information have been inappropriately handled to bring your concerns to the attention of the editors. By doing so you help increase the reliability of the literature, and so prevent the waste of both time and money following up fraudulent leads and fabricated insights. We strongly believe that it is in our best interest to correct errors that we have published, once we have as much information as we are likely to get — a practice that all journals should embrace. Additional data
• Time to adapt
  - Nature 464(7293):1245 (2010)
  Nature | Editorial Time to adapt Journal name:NatureVolume:464,Pages:1245–1246Date published:(29 April 2010)DOI:doi:10.1038/4641245bPublished online28 April 2010 A new generation of clinical trials could yield breakthroughs, but must be handled with care. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg At the American Association for Cancer Research annual meeting in Washington DC last week, a recurrent theme was complexity. The deeper scientists have delved into the fundamental nature of cancer, the more they have come to recognize its vast genetic diversity, which can make even tumours of the same cancer type seem unrelated. It is encouraging to see researchers embracing new methods to deal with that complexity. One especially promising technique highlighted in several talks was the 'adaptive' clinical trial, which allows researchers to avoid being locked into a single, static protocol for the duration of the trial. Instead, investigators can evaluate data as they come in, and use that information to change a trial's structure (see page 1258). Such flexibility is particularly important in cancer research. Investigators have struggled to plan clinical trials that can incorporate an ever-proliferating list of molecular biomarkers — features such as mutations or gene-expression patterns that can be used to distinguish one person's tumour from the next person's. The idea is to find markers that can identify a subset of people for which a given therapy is working, even when it seems to have little effect on the patient population as a whole. Adaptive trials thus allow investigators to analyse the data midstream, correlate those results with known biomarkers, and then alter the course of the trial in light of that information — perhaps by enrolling additional people with cancer on the basis of their biomarker status. The trial then continues, targeting those people most likely to benefit. Researchers have dabbled with such experiments for years. But it was only in 2007 that the European Medicines Agency (EMA) published a paper outlining appropriate adaptive-trial conduct, and only in February 2010 that the US Food and Drug Administration (FDA) followed suit with its draft guidance to industry. The FDA draft is open for public comment until 1 June. "Undertaking adaptive clinical trials is an experiment in itself: there is much still to be learned about the unforeseen pitfalls, and what the best practices are." Guidance from these key agencies is likely to spur interest in the trials, but it will take more than that to fully exploit the technique's potential. Because adaptive trials require more statistical sophistication than conventional ones, for example, medical researchers will have to work with statisticians on trial design from the outset. And because the trials require extra months of planning time, pharmaceutical companies will have to revise the common practice of financially rewarding the speed with which a clinical-trial team enrols its first patient, to avoid tempting researchers to shortcut the planning. And there are potential pitfalls with adaptive trials. Perhaps most importantly, researchers who use adaptive techniques will have to take care that they do not fool themselves. By changing the patient population to one that is more likely to benefit from the treatment, they can inflate the risk of reaching a false-positive conclusion. They also run the risk that the interim data required to take that step might compromise a trial's double-blind safeguards, influence patient and investigator behaviour, and colour the results even further. For these reasons, the FDA and the EMA advise against using an adaptive trial when a standard trial will do, and urge extra caution in designing the late-stage clinical trials that are crucial to determining drug approvals. The two documents also outline the statistical methods that can be used to control the false-positive rate, and call for appointing an independent body to handle the interim review. But these guidelines cannot be taken as the final word. Undertaking adaptive clinical trials is an experiment in itself: there is much still to be learned about the unforeseen pitfalls, and what the best practices are. As always in science, investigators must be ready to adapt their approaches as the data come in. Additional data
• Security first
  - Nature 464(7293):1246 (2010)
  Nature | Editorial Security first Journal name:NatureVolume:464,Page:1246Date published:(29 April 2010)DOI:doi:10.1038/4641246aPublished online28 April 2010 Scientists must be more proactive in encouraging good cybersecurity practices. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Most scientists, like most Internet users, probably think of cybercrime as a misfortune that happens to others — to banks, say, or to online retailers who are careless with customers' credit-card information, or to individuals who fall for a get-rich-quick e-mail from Nigeria. But the unsettling truth is that academic institutions are among hackers' prime targets. Not only do campuses tend to be richly supplied with personal computers, servers and other computing resources, but they are connected to the world by high-bandwidth networks and populated by inexperienced, casual and sometimes reckless students (see page 1260). This wide-open computational environment is ripe for being co-opted, whether it is to send out spam, run illegal file-sharing sites or launch further cyberattacks. Worse, from researchers' point of view, is that much — if not all — of their hard-won laboratory data live in that environment, where the information is vulnerable to theft and malicious damage. Computer security has moved up the agenda of universities and other research institutions over the past decade, and most places now have teams of professionals to monitor suspicious traffic and maintain a safe environment. But such structured, centralized efforts can result in controls that raise scientists' hackles and violate their impulse to do things their own way. As a result, too many researchers set up their own computer systems and ignore any security help the university's professionals can give them. This attitude is unhelpful, bordering on reckless. University information-technology administrators do need to manage things with as light and as unobtrusive a hand as possible — for example, by making sure that researchers retain the freedom to use the software they choose. But laboratories, especially the smaller ones, need to avail themselves of the professionals' skills as much as possible. Larger research projects with heavy data needs may have the resources to exercise more autonomy. But even so, it is imperative that such projects put a qualified person in charge of cybersecurity who can take sole responsibility for keeping up with the fast-moving requirements that security issues present. Large group or small, the ultimate responsibility for protecting data and other resources has to rest with the laboratories that own them. Every lab director must be aware of the risks, and must treat cybersecurity with the same respect as laboratory safety, patient safety and scientific integrity. Additional data
• Organic chemistry: An open and shut case
  - Nature 464(7293):1248 (2010)
  
• Developmental biology: Hidden differences
  - Nature 464(7293):1248 (2010)
  
• Immunology: Misplaced target
  - Nature 464(7293):1248 (2010)
  
• Wildlife biology: Fussy eaters
  - Nature 464(7293):1248 (2010)
  
• Evolution: Sex and immunity
  - Nature 464(7293):1248 (2010)
  
• Cancer biology: Cellular battering ram
  - Nature 464(7293):1248 (2010)
  
• Biogeochemistry: Bogs of change
  - Nature 464(7293):1249 (2010)
  
• Planetary science: Martian cold traps
  - Nature 464(7293):1249 (2010)
  
• Bioengineering: Cell culture on a chip
  - Nature 464(7293):1249 (2010)
  
• Evolutionary biology: Good times and bad
  - Nature 464(7293):1249 (2010)
  
• Journal club
  - Nature 464(7293):1249 (2010)
  
• News briefing: 29 April 2010
  - Nature 464(7293):1250 (2010)
  The week in science. This article is best viewed as a PDF. Policy|Research|Business|Business watch|Events|People|The week ahead|Number crunch|Sound bites The US administration has proposed sweeping changes to a burdensome system that controls the export of technology and knowledge to foreign nations. The system has been accused of stifling academic research and technological development. In a 20 April speech, defence secretary Robert Gates proposed centralizing the disparate bodies that oversee technology exports to create a single licensing agency, export-control list and enforcement agency. See go.nature.com/dHvvt9 for more. Mexico's Congress last week voted to create a national space agency, which would invest in space-related technology and infrastructure, and help to develop the country's space policy. Headquartered in the state of Hidalgo and with visions of building a rocket-launching centre on the Yucatán Peninsula, the agency has been allocated 10 million pesos (US$800,000) this year. The Australian government has shelved plans to create a carbon-trading scheme until the end of 2012, when the Kyoto Protocol expires. Prime Minister Kevin Rudd blamed political opposition and "slow progress" in global action on climate change. His legislation, which aimed to cut Australia's emissions by at least 5% from 2000 levels by 2020, had twice been defeated in the Senate. US climate legislation faltered last week, when Democratic congressional leaders said that the Senate would tackle immigration before it discussed a long-awaited climate bill. That bill, sponsored by Senators John Kerry (Democrat, Massachusetts), Joe Lieberman (Independent, Connecticut) and Lindsay Graham (Republican, South Carolina), was scheduled for introduction to the Senate on 26 April but has been postponed indefinitely. The Senate has three months before its August recess, after which senators' time is likely to be consumed by the November elections. See go.nature.com/hsj7gY for more. A proposal from the International Whaling Commission could afford de facto recognition of commercial whaling for the first time in 25 years. The 88-nation organization published a draft document on 22 April suggesting that it should set decadal catch limits for nations such as Iceland, Japan and Norway — which currently hunt whales under special permits or objections to a 1986 moratorium and impose their own catch quotas. The agreement would save thousands of whales, the commission claims. The proposal will be debated at an annual meeting in Morocco in June. See go.nature.com/e7YqVz for more. NASA SDO/AIA NASA has released the first images from its Sun-monitoring Solar Dynamics Observatory (SDO). Launched in February (see Nature 463, 414; 2010), the SDO is on a five-year mission to study the Sun's magnetic field, and the influence on Earth of events such as coronal mass ejections and solar flares. Richard Fisher, director of NASA's Heliophysics Division in Washington DC, says that the mission's impact on science will be comparable to that of the Hubble Space Telescope on astrophysics. The false-colour ultraviolet image, pictured, shows differing gas temperatures on the Sun, with reds around 60,000 kelvin and blues and greens above 1 million kelvin. The €800-million (US$1.1-billion) European Extremely Large Telescope will be built at Cerro Armazones, in Chile's Atacama Desert. The European Southern Observatory's council chose the site on 26 April. Its advisory committee had, in March, recommended the location ahead of Spain's La Palma and three other Chilean competitors. A long-running legal dispute over Arizona researchers' use of genetic samples from a Native American tribe was settled on 20 April. The Havasupai, a small band living in the Grand Canyon, had filed lawsuits in 2004 alleging that scientists from Arizona State University had violated research rules by using the tribe's DNA for undisclosed studies, such as some on mental illness (see Nature 430, 500–502; 2004). Arizona State will now pay 41 members of the Havasupai a total of US$700,000, and will work to improve education and health services for the tribe. See go.nature.com/l3UHMQ for more. The US government last week awarded a US$73.6-million contract to build a fisheries research ship, the second ocean-going vessel now under construction for the nation's ageing fleet (see Nature 453, 7; 2008). The ship, due to be completed in three years, will support the National Oceanic and Atmospheric Administration's Southwest Fisheries Science Center in La Jolla, California. Last December, the National Science Foundation awarded a $123-million contract to build the Alaska Regional Research Vessel, to be operated by the University of Alaska in Fairbanks. A controversial 11.2-gigawatt hydroelectric plant in Brazil looks set to be built despite opposition from environmental campaigners and native populations. Brazil's government last week awarded contracts to a domestic consortium to build the Belo Monte dam on the Xingu river, a tributary of the Amazon in the state of Pará. The project would cost around US$11 billion and is billed as the world's third-largest hydroelectric dam. Charles River Laboratories said on 26 April that it would acquire WuXi AppTech, a leading drug research and development outsourcing company based in Shanghai, for around US$1.6 billion in cash and shares. The deal would create a global company providing outsourcing services to pharmaceutical, biotech and medical-device firms, said Charles River Laboratories, which is based in Wilmington, Massachusetts, and is one of the world's largest providers of animals for laboratory testing. The United States' busiest week for initial public offerings (IPOs) since November 2007 saw the public debut of Codexis, the first of a number of IPOs in green technology that investors anticipate this year. Based in Redwood City, California, Codexis sells enzymes and biocatalysts to pharmaceutical companies, and has a partnership with Shell, for whom it is developing genetically engineered enzymes that convert cellulose to sugar and ethanol. Click to enlarge.SOURCE: NASDAQ The company — which aborted a proposed public offering in September 2008 — had an unspectacular debut on 22 April. Raising $78 million, it sold 6 million shares at $13 each, the lower end of its previously stated $13–15 range, and had crept up 12% by 26 April (see chart). By contrast, last year's large green IPO, A123Systems (a lithium-ion battery company based in Watertown, Massachusetts) saw its share price rocket from $13.50 to more than $20 in its first day's trading last September, although six months later it is trading back down at $13. Codexis's launch presages IPOs from other green-tech companies, such as rival biofuels firm Amyris Biotechnologies, in Emeryville, California; electric-car company Tesla Motors in San Carlos, California, and solar-power firm Solyndra of Fremont, California. The biggest IPO in the sector may be smart-grid firm Silver Spring Networks, also of Redwood City. US COAST GUARD About 160,000 litres of oil per day is gushing from the well dug by the Deepwater Horizon oil rig, which went up in flames in the Gulf of Mexico last week (pictured) before sinking beneath the water. Eleven people are still missing, presumed dead. Earlier this week, frantic clean-up efforts and favourable winds were preventing thousands of square kilometres of oil slick and sheen from reaching the shore. The slick threatens major environmental damage if it approaches the marshy coast near Venice, Louisiana. See go.nature.com/uhUj4j for more. A workplace-related dispute is believed to be behind the murder of a Yale University researcher. Vajinder Toor, a postdoctoral fellow at the school of medicine's infectious-diseases department in New Haven, Connecticut, was gunned down outside his home in Bradford on 26 April. Former colleague Lishan Wang, a 44-year-old doctor who had worked with Toor at Kingsbrook Jewish Medical Center in Brooklyn, New York, has been charged with the killing. Paul Nurse has been nominated as the next president of the Royal Society, Britain's most prestigious scientific organization. The 61-year-old geneticist, who shared the 2001 Nobel Prize in Physiology or Medicine for his work on the cell cycle, is currently president of the Rockefeller University in New York. Once approved by ballot, Nurse would begin his five-year term on 30 November. He would replace astronomer Martin Rees, of the University of Cambridge, who has headed the society since 2005. India's Central Bureau of Investigation on 22 April arrested Ketan Desai, president of the Medical Council of India (MCI), on corruption charges. The MCI sets national medical-education standards and accredits medical schools; Desai and three others are alleged to have taken a bribe of 20 million rupees (US$450,000) for clearing a medical college in Punjab to admit students in 2010–11. The general assembly of the European Geosciences Union in Vienna will discuss the implications of the eruption of the Icelandic volcano Eyjafjallajökull. → meetings.copernicus.org/egu2010 Chicago, Illinois, hosts this year's BIO international biotechnology convention. → convention.bio.org Four universities in and near London plan a simultaneous strike to protest over impending job losses, which include positions in life sciences and engineering departments. Source: Miller, D. D. & Mariani, S. Front. Ecol. Environ. doi:10.1890/090212 (2010). "I wish I had this kind of streamlined report form when I was running research projects supported by federal agencies." John Holdren, chief science adviser to US President Barack Obama, enthuses over the 23 April release of a standardized form for scientists to report progress on federally funded research projects (see go.nature.com/9DJRjd). 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.
• Hasty switch for space magnet
  - Nature 464(7293):1252 (2010)
  Longer-lasting part could make cosmic-ray detector less sensitive. Fifteen years into the development of a US$2-billion experiment to detect cosmic rays, its designers have abruptly changed course. Less than six months before the Alpha Magnetic Spectrometer (AMS) is due to fly out to the International Space Station, they swapped the superconducting magnet at the heart of the seven-tonne particle detector for a weaker, permanent magnet. AMS researchers say the swap will preserve the sensitivity of the experiment and extend its lifetime. But some physicists say that problems with the superconducting magnet forced the swap, and fear that it could hamper the ability of the AMS to find evidence of dark matter, thought to make up 85% of the Universe's mass. The Alpha Magnetic Spectrometer (circled) will perch on the International Space Station.NASA Designed to measure the properties of cosmic rays — high-energy particles reaching Earth from space — the AMS is the brainchild of Nobel-prizewinning physicist Samuel Ting of the Massachusetts Institute of Technology in Cambridge (Nature 455, 854–857; 2008). Such cosmic rays might be produced by collisions between dark-matter particles. The project, an international collaboration led by the US Department of Energy, won the support of NASA administrator Dan Goldin in 1995, but looked as if it might be dropped after the Space Shuttle Columbia disaster in 2003. The administration of former US president George W. Bush reinstated it two years ago, but it will now miss its scheduled July shuttle flight and is instead likely to take off in the autumn. According to Ting, the decision to switch the magnets, which are needed to discriminate between different kinds of cosmic-ray particle according to their charge and momentum, was taken after the present US administration said it would like to extend the life of the space station from 2015 to 2020, or perhaps even 2028. Poor resolution? The liquid-helium coolant required to keep the superconducting magnet at its operating temperature of 2 °C above absolute zero would run out after no more than three years. Ting's team have calculated that the weaker permanent magnet will require more data to identify particles with the same level of precision as its superconducting counterpart. But, they say, the permanent magnet's longer running time will more than make up for this loss of resolution. In reality, Ting and his colleagues may have had little choice. In February, while testing the detector with particle beams at CERN, Europe's particle-physics laboratory near Geneva, Switzerland, the collaboration observed the magnet warming up unexpectedly during operation. Ting says that space-readiness tests of the detector subsequently made at the European Space Research and Technology Centre in Noordwijk, the Netherlands, showed that in the lower pressure and gravity of orbit warming would be reduced and would not be a problem. But collaboration member Martin Pohl, a physicist at the University of Geneva, says that although one of the models used to test the detector at Earth-orbit conditions showed that there would be no significant warming, another showed that consumption of helium coolant would increase, shortening the lifetime of the experiment to less than two years. The AMS team plans to carry out more beam tests in August at CERN with the permanent magnet, which was originally used in a pilot flight aboard a US shuttle in 1998. Some warn that making the switch to the magnet this late on could compromise the detector. "Testing and verification is a very exacting process and you really shouldn't be rushing it," says Bob O'Dell, the first project scientist of NASA's Hubble Space Telescope, now at Vanderbilt University in Nashville, Tennessee. "The risk is that they fail to find everything that could go wrong or, more seriously, things that have gone wrong." Even assuming that the magnet does work as planned, Gregory Tarlé, an astrophysicist at the University of Michigan at Ann Arbor, says that the collaboration has overstated the scientific capability of the new configuration. ADVERTISEMENT In 2008, the Italian-led PAMELA satellite provided tentative evidence of dark matter in the Milky Way, when it observed what looked like an excess of positrons (anti-electrons) at high energies — which would be given off when two dark-matter particles collide. Ting's team says that, over the 18 years that the space station might now fly, changes that they have made to silicon trackers inside the detector will increase the chances of detecting such positrons by four to six times, depending on the energy of the particles. The PAMELA data extended up to about 150 gigaelectronvolts, whereas the AMS, says Ting's team, will be able to go all the way up to 1 teraelectronvolt (TeV), so extending the search considerably. But Tarlé disagrees. "Ting's claim that he will still be able to identify positrons up to 1 TeV with the weaker permanent magnet is laughable," he says. But would the team have gone to the trouble and expense of developing the superconducting magnet if they had the idea with the silicon trackers earlier? "That is hard to say," says Ting. "I try to look forward and not to look back." 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.
• Questions fly over ash-cloud models
  - Nature 464(7293):1253 (2010)
  Uncertainty remains on dangers of volcanic plume to jet aircraft. The Icelandic volcano Eyjafjallajökull, still spewing ash, beneath the eerie light of the aurora borealis.L. Jackson/REUTERS Scientists have leapt to defend the predictions made by their models of volcanic ash dispersal, the results of which grounded more than 100,000 flights across Europe this month over fears about safety. But with Europe's airspace virtually paralysed for six days, the real question now is precisely how much ash can a jet engine safely tolerate? With planes once again flying after the biggest disruption to European aviation in decades, critics have been quick to dispute the model used by the Met Office's London Volcanic Ash Advisory Centre, responsible for predicting the movement of ash cloud from the Icelandic volcano Eyjafjallajökull. Researchers say that their model tracked the cloud successfully: "I would completely defend the model as correct," says Derrick Ryall, head of the Met Office's climate programme. But critics argue that it overestimated the extent of the ash cloud, and therefore gave the impression that the risk to aircraft was far greater than in reality. "We must make decisions based on the real situation in the sky, not on theoretical models," said Giovanni Bisignani, director-general and chief executive of the International Air Transport Association, the global trade organization for airlines, on 19 April. "I don't see that the model has not done what it's supposed to do." The atmospheric dispersion model under fire was originally developed to track radioactive fallout from the Chernobyl nuclear disaster in 1986. This nuclear accident model (NAME) calculates how particles spread through the atmosphere — how far, how fast and how high — based on information about wind speed and direction, along with data about the concentration, composition and size of the ash particles. During the days after the eruption in Iceland, a barrage of research showed the ash plume spreading as the model predicted. Ground-based laser ranging picked out clumps of ash; satellite images tracked the overall plume; and research aircraft sampled the plume directly. "I don't see that the model has not done what it's supposed to do," says Hugh Coe, an atmospheric scientist at the University of Manchester, UK, and chair of aircraft operations at the Met Office's Facility for Airborne Atmospheric Measurements (FAAM) at Cranfield, near Bedford, UK. "The observations so far have been consistent with the predicted plumes," agrees Ryall, who helped to develop NAME. Despite the model's success, the question of how much ash is unsafe remains unanswered. "One of the problems is that we don't know what level of ash concentration is hazardous to aircraft," says Fred Prata, senior scientist with the Climate and Atmosphere Department of the Norwegian Institute for Air Research near Oslo, who has been investigating volcanic ash for more than 20 years. He is frustrated that, until now, airlines and engine manufacturers have been reluctant to commission studies on the impact of ash on their aircraft. In 1991, Prata suggested that a monitor on board an aircraft could link with radar data so that pilots could detect and steer around ash hazards (A. J. Prata et al. Nature 354, 25; 1991). But the device was never developed. "Planes would be flying if they had this," he told Nature at the height of the crisis last week. Ulrich Schumann, director of the Institute of Atmospheric Physics at the German Aerospace Centre (DLR) near Munich — which sent up a research flight to sample ash over Germany and the Netherlands on 19 April — says that on the basis of that evidence, grounding flights was the correct decision. International aviation guidelines recommend that no planes should fly though airspace that contains volcanic ash. This 'zero tolerance' approach stemmed from two incidents in the 1980s that saw airborne volcanic ash shut down the engines of passenger jets. But Denis Chagnon, a spokesman for the International Civil Aviation Organization (ICAO), insists that this approach is merely "guidance", not an international regulation. ADVERTISEMENT Flights were restarted in Europe last week once Britain's Civil Aviation Authority declared that airspace with less than 2,000 micrograms of dust per cubic metre was safe after all, based on test flights conducted by the aviation industry. "At these levels, you'd be flying in fairly thick goo," says Coe. The DLR research flight found concentrations of just 60 micrograms of ash per cubic metre, and the latest information from the FAAM's two aircraft shows that the ash plume is dominated by relatively tiny particles measuring just 0.1 micrometres in diameter, although most of the plume's mass comes from particles measuring 3 micrometres across. Such microscopic measurements can help to predict the plume's long-distance reach, because smaller ash particles can travel much farther than larger ones. Understanding the plume's composition could also help to estimate how much ash might actually get into a jet engine, but there has been little research on such questions. The ICAO says that it will now set up a multidisciplinary team as a matter of urgency to address how to handle a similar situation in future, and to try to determine a threshold for safe aircraft operation in volcanic ash. "If the world wants to move forward, maybe we want to research better what is safe," says Ryall. 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.
• High stakes for science in UK election
  - Nature 464(7293):1254 (2010)
  The new government may have to make cuts — but which party will slice deepest? Robin Weiss was one of 22 prominent scientists to sign a recent letter to The Independent newspaper, endorsing the United Kingdom's ruling Labour Party in the run-up to next week's general election. But Weiss, a virologist at University College London, is now unsure whether he will vote Labour on 6 May, partly because of his unhappiness with the government's recent push to milk more short-term economic value from fundamental research. "I'm pretty pissed off with Labour as a whole," he says. Weiss is not alone. An informal e-mail poll by Nature of more than 260 researchers in Britain has found reduced support for Labour compared with the last election, and roughly a quarter of respondents said they were unsure how they would vote (see 'The science vote'). But, like many scientists in the United Kingdom, Weiss holds a dim view of the main opposition party, the Conservatives, who slashed public spending on research and higher education in the 1980s. Click to enlarge. According to national opinion polls, Labour will struggle to get re-elected, but the Conservatives may not win enough parliamentary seats to form a majority government. The third major party, the left-leaning Liberal Democrats, is rapidly gaining support, and the election could produce a hung parliament, in which two or more parties form a coalition government. More than a quarter of the scientists polled by Nature said they planned to vote Liberal Democrat. Regardless of the outcome, Britain's next government will face a soaring budget deficit, rising inflation and a sluggish economy, and it will have to move quickly to raise taxes, cut public spending, or both (see Nature 463, 410–411; 2010). How those cuts fall could dramatically alter the research landscape in Britain, says Nick Dusic, director of the Campaign for Science and Engineering in the UK, a think tank devoted to increasing the profile of science in government. The economic crisis could mark a turning point for a nation that, in recent years, has enjoyed relatively strong growth in fundamental research. Since Labour came to power in 1997, annual funding for basic research has more than doubled to £3.7 billion (US$5.7 billion), along with extra cash for university facilities and laboratories. But more recent actions by the Labour government have not sat well with scientists. The party has increasingly emphasized the need for scientists to show the 'economic and societal impact' of their research, and its new Research Excellence Framework (REF) will take such metrics into account in allocating research and development money to universities. Many scientists were also riled by the government's decision to fire drugs adviser David Nutt over his statements playing down the risks of the drug ecstasy, based on his research (see Nature 462, 11–12; 2009). All three parties are courting scientists with their agendas, and roughly 80% of scientists polled by Nature say that the candidates' attitudes towards science will affect how they vote. Labour vows not to raid the science budget to fund other priorities, and the Conservatives promise a multi-year budget to "provide a stable investment climate for Research Councils". They would also delay the unpopular REF and review the metrics it uses. The Liberal Democrats have responded to the Nutt affair by promising reforms to "prevent government from bullying or mistreating advisers". Dusic says that, in a nation where roughly 3.3 million people have some scientific training, the commitments are evidence of science's growing profile (see 'A guide for the scientific voter'. According to Nature's poll, scientists see the Liberal Democrats as the party most likely to formulate scientifically based policies. Evan Harris, member of parliament (MP) for Oxford West and Abingdon and the Liberal Democrat spokesman on science, says that the party has a proven track record of respecting scientific advice on issues such as research involving human embryos. "Do we think there's a sizeable science vote? Yes we do," he says. The science supremos for Labour and the Conservatives declined Nature's interview requests. "Do we think there's a sizeable science vote? Yes we do." The Conservatives seem to have seen little benefit from their science pledges. Only one in ten scientists polled by Nature say they would vote Conservative, and 70% feel that the party would make the deepest cuts to funding if elected. Martin Rees, an astronomer at the University of Cambridge (not speaking in his capacity as president of the Royal Society), says that despite campaign pledges, "the average MP from the party has very little understanding of science". ADVERTISEMENT Ultimately, the tight financial situation is likely to be the biggest player in the election. Because of it, none of the parties has committed to increasing or even maintaining the current level of science spending. And none has promised to roll back the cuts already planned, notes Keith O'Nions, the acting rector of Imperial College in London. Late last year, the Labour government announced that universities and research would face £600 million in cuts by the 2012–13 fiscal year. And there remains the strong possibility that universities and science will see further budget pressure. All will be determined by the emergency budget that is expected to be drawn up immediately after the election by the new government. "There are some very big questions that have to be answered," O'Nions says. Click here for the full survey results. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Russia to boost university science
  - Nature 464(7293):1257 (2010)
  But can it break the dominance of the Russian Academy of Sciences without breaking the research base? Vladimir Putin wants universities to produce more science-based innovation.A. Nikolsky/Ria Novosti/Reuters Technological leadership, a matter of national pride during the Soviet glory days, has become a distant memory in modern Russia, where scientific output lags behind that of China, India and South Korea. Despite increased funding in recent years, Russian science has not yet recovered from a near collapse in the 1990s and the consequent exodus of thousands of researchers to the West. In an attempt to counter the decline and to foster science-driven innovation, the Russian government is betting on its universities, by promising to invest an extra 90 billion roubles (US$3 billion) into higher education and market-oriented university research over the next decade, on top of an annual university research budget of about 20 billion roubles. But doubts remain about whether the initiatives can overcome weaknesses in the universities and the long-standing dominance of the Russian Academy of Sciences (RAS), the largest basic research organization in the country. The RAS, which employs more than 50,000 researchers in 480 institutes across the country (see Table 1), gets about 50 billion roubles per year in funding from the federal government. Yet it suffers from an ageing scientific workforce and poor links with the international scientific community. As Russia struggles to overcome its economic dependence on mineral exports, academy researchers are criticized for contributing too little to Russia's transformation into a high-tech economy. "Increasing domestic high-tech production will require a flow of well trained people to industry," says Nikolay Ledentsov, a corresponding member of the RAS formerly with the Ioffe Physico-Technical Institute in St Petersburg, who now runs the optoelectronic company VI-Systems in Berlin, Germany, which he founded in 2006. "Improving universities, where most people are educated, makes sense." To strengthen neglected university research — mainly in applied sciences such as information technology — the government launched a competition in 2008 to transform a number of existing institutions into 'national research universities'. On top of their regular funding from regional governments, these institutions will each receive an extra 1.8 billion roubles per year over the next decade from federal budgets for purchasing modern laboratory equipment. Twelve winners were selected last year, and a further dozen or so will be chosen this month out of 128 institutions that applied in the second round of the competition. Last year, the government also created five 'federal universities' to bolster higher-education efforts in under-resourced areas; they will each receive around 380 million roubles annually in extra funding over the next three years. Separate budget lines were also set aside to support Moscow State University and St Petersburg University, the two largest and scientifically strongest institutes of higher education in the country. Finally, Russian Prime Minister Vladimir Putin announced a new grant programme earlier this month worth a total of 12 billion roubles. It is aimed at attracting high-profile scientists from within the country and abroad to work at Russian universities. Winners, chosen for their research and publication record, will receive up to US$1 million per year to set up a team at a Russian university of their choice. A first call for proposals is being prepared, and the first grantees are to be selected later this year. Hopes of creating a Russian match for Harvard or Oxford, voiced by some institutions bidding to become national research universities, are wildly premature, says Konstantin Severinov, a biochemist based at both Rutgers University in New Brunswick, New Jersey, and at the RAS Institute of Molecular Genetics in Moscow. He and others warn that the new funding is still being funnelled through a system that often fails to reward the best ideas, and lacks the transparent grant-assessment procedures developed and accepted by the international scientific community. Still, Severinov says, promoting university research is certainly a welcome step towards breaking the unhealthy dominance of the RAS in favour of a more diverse science and higher-education system. "Merging science and higher education is the right approach," he says. "If the new initiatives help get more Russian students involved in meaningful research early on it would be a good thing." Some researchers worry that boosting the universities could damage the RAS. "It's in every­body's interest to have strong universities, but please not at the expense of damaging the RAS where the best science is done," says Ledentsov. The best way to revitalize Russian science is to let both universities and RAS institutes to compete for public funding through a quality-based granting system, he says. "Russian science needs a fruitful combination of both, and it absolutely needs stronger links with Europe." ADVERTISEMENT Increased funding is only part of the remedy, adds Ledentsov. Russian government initiatives include a 318-billion-rouble nanotechnology programme started in 2007 (see Nature 461, 1036–1037; 2009) and plans for a new science city outside Moscow. But these must be supported by innovation-friendly business and legal reforms such as tax exemptions for company research and development. "You can't order innovation," says Ledentsov. "But you can force the economy to be innovative if you create the right incentives. Seed it and it will grow." 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.
• Clinical drug tests adapted for speed
  - Nature 464(7293):1258 (2010)
  Flexible approach allows cancer researchers to change course mid-trial according to patient response. Flexible trial designs allow targeted drug testing for lung cancer.S. FRASER/SPL When cancer researchers gathered in Washington DC for a major conference last week, much of the buzz was not about the results of clinical trials, but about a new way of doing them. Seeking to avoid slow clinical trials and their frequently disappointing results, pharma­ceutical companies are increasingly turning to 'adaptive' trials. These are revamped midstream, on the basis of early data, to focus on the patients for whom the drug shows hints of promise. The approach has been controversial, but is catching on with both researchers and regulators as companies struggle to combat the nearly 50% failure rate of drugs in large, expensive late-stage trials. "At this rate, drug development is just not sustainable," says Michael Krams, head of the neurology franchise at Johnson & Johnson in Collegeville, Pennsylvania. Cancer-genome sequencing has revealed tumours to be wildly diverse, with even those of the same cancer type harbouring a wide range of mutations. This means that some therapies work in only a subset of patients. Too often, averaging the effects of a drug across all patients with a given cancer drowns out the small signal of a subpopulation for which there is a clinical benefit. Two trials described at last week's annual meeting of the American Association for Cancer Research — a breast-cancer study called I-SPY 2 and a lung-cancer trial code-named BATTLE — address these issues by allowing researchers to analyse data in the middle of a trial. From this, they can determine which patients are responding to a given drug, and whether biomarkers such as specific mutations are linked to that response. The trial is then restructured, midcourse, to treat patients with the drug that best suits their specific biomarkers. I-SPY 2 is also designed for testing to stop if it becomes clear that the drug is not helping, a general ethical benefit to the approach. In addition to being faster, and therefore cheaper, than traditional approaches, the strategy should make trials more sensitive to small subpopulations of drug-responsive patients, says Laura Esserman, a surgeon at the University of California, San Francisco, and a lead investigator of I-SPY 2. "We are really hoping to drive down the cost of clinical trials 50-fold," she says. "Otherwise I don't think drug companies are going to be interested in taking the risk of developing a drug for these small numbers of patients." "We are really hoping to drive down the cost of clinical trials 50-fold." The concept of adaptive clinical trials dates back to the 1970s, although it is a route that few investigators have followed given the traditional emphasis on adhering to proven trial designs. This may be changing: a survey of 16 pharmaceutical companies and statistical consultants involved in trial designs identified only three or fewer adaptive trials that began each year between 2003 and 2006, but in 2007, there were 13 (J. Quinlan et al. Clin. Trials 7, 167–173; 2010). One reason for the shift is increasing guidance from regulators about what adaptive trial designs they deem acceptable. In 2007, the European Medicines Agency detailed its stance on the trials, and this February, the US Food and Drug Administration (FDA) released draft guidance for industry. Improvements in statistical techniques have eased the way for adaptive trials, which, according to regulators, should involve advanced statistical modelling. Such experiments can also require as much as six months more pre-trial planning than standard clinical trials, says Krams. And access to statisticians with expertise in adaptive trials has been a limiting factor, says Lesley Seymour of the clinical trials group of the National Cancer Institute of Canada in Ontario. Nevertheless, enthusiasm about adaptive trials has been building. It may even be outstripping reality, cautions Stuart Pocock, a medical statistician at the London School of Hygiene & Tropical Medicine. "They have been hyped by some people, but we're still trying to determine what potential these trials have," he says. Krams also notes that some investigators use the term 'adaptive' as an excuse to get away with doing shorter trials in fewer patients. "Unfortunately there are cowboys out there who abuse the term 'adaptive design' and use it as a tool to cut corners," he says. ADVERTISEMENT Some regulators — including the FDA — have also expressed concerns that even legitimate adaptive trials can compromise an experiment's integrity because of the requirement that data be unblinded and analysed mid-trial. Changing the course of a trial midstream could allow investigators and participants to infer how the therapy is performing, possibly colouring their perception of the drug's efficacy and introducing bias. But Seymour says that there are ways to construct a trial to minimize this risk, and an independent statistician can be included on data-monitoring boards to prevent undue influence on data analysis by trial sponsors. Ultimately, Pocock says, some of these details will have to be worked out as researchers gain more experience with adaptive trials. "We're all on a learning curve together," 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.
• Twin study surveys genome for cause of multiple sclerosis
  - Nature 464(7293):1259 (2010)
  Mapping milestone emphasizes complexity of disease. Researchers looking for the genetic roots of disease have long dreamed of inspecting a patient's entire DNA sequence for telltale changes — now achievable thanks to the falling cost of sequencing. So the first in-depth comparison of the genomes of identical female twins — one with multiple sclerosis (MS) and the other free of the disease — is something of a milestone. But the study shows that even deep genetic analysis doesn't always yield clear answers. There is no doubt that MS, which causes the body's own immune cells to attack the insulating sheath around nerve cells, has a genetic component. Relatives of people who have the disease have an increased risk of developing it; if a patient with MS has an identical twin, that twin's risk climbs to more than 25%. But when a team of US researchers compared the complete genomes of twin females with each other, they failed to find any genetic differences that might cause MS. Reporting this week in Nature1, the researchers, led by Sergio Baranzini at the University of California, San Francisco, and Stephen Kingsmore of the National Center for Genome Resources in Santa Fe, New Mexico, next looked for a difference in epigenetics — chemical modifications to DNA that affect gene expression but not genetic sequence — in the twins' immune cells and in cells of two other sets of similarly affected twins. But no differences were found in the expression levels of key genes, either. Although they did not sequence the genomes of the other two sets of twins, they did compare 1 million specific 'spelling variations' (known as single nucleotide polymorphisms, or SNPs) in the sequences of twins with and without MS, confirming that their genomes were the same. Because the study examined the genome so comprehensively, "it is an incredibly important negative", says David Hafler, a neurologist at Yale University in New Haven, Connecticut. The results indicate that there is no clear genetic reason to explain why one twin developed MS while the other did not. Disease geneticists often survey large populations of patients to find SNPs that are associated with a disease. But sequencing offers a deeper analysis of the genome that can reveal overlooked differences in sets of twins in which one has a disease but one does not. Identical twins' genomes start off the same, but mutations in early development can occur in one and not the other. Earlier studies had identified a handful of gene variants that are linked to a higher risk of getting MS, and all of the twins in the study had at least some of them. "Both twins came into the world with the same set of high risks for developing MS," says Kingsmore. But those genetic factors seem to have been insufficient to cause disease on their own: "There had to be some trigger that caused one to develop it and the other not," he adds. One possibility, says Baranzini, is that although both twins had the same predisposition for the disease, "one was exposed to the perfect combination of environmental triggers". ADVERTISEMENT Comparing the complete genomes of family members to find the exact mutations responsible for disease is the new frontier, says Daniel Geschwind, a neurogeneticist at the University of California, Los Angeles. A study published earlier this month used complete genome sequences to identify a rare, patient-specific gene variant causing the neurological disorder Charcot–Marie–Tooth disease2; another study narrowed down the genetic cause of two more disorders3. The MS study is the first, however, to integrate studies of epigenetics and gene expression with whole-genome sequencing. "What they've done here is create a very nice template for others to follow," Geschwind says. "It isn't just sequence — they went from sequence to epigenome to expression. That's what really makes [the study] something special." Yet scientists are unlikely to glean much immediate insight about MS from the work. One limitation, notes Geschwind, is that although Baranzini and colleagues examined epigenetics and gene expression in three twin pairs, they obtained the complete genome sequences of just one pair. "If we sequenced another dozen twin pairs we could make this much more definitive," says Kingsmore. And although the group targeted immune cells, "we really ought to look at sequencing of the brain tissue," he adds, as this might be an alternative site of genetic differences between the twins. * References * Baranzini, S. E.et al. Nature464, 1351-1356 (2010). * Lupski, J. R.et al. N. Engl. J. Med.362, 1181-1191 (2010). * Roach, J. C.et al. Science advance online publication doi:10.1126/science.1186802 (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.
• Cybersecurity: How safe are your data?
  - Nature 464(7293):1260 (2010)
  Many scientists want to keep their data and resources free; cybersecurity specialists want them under lock and key. Jeffrey Perkel reports. Download a PDF of this article In 2002, bioinformatician Mark Gerstein and his colleagues set up a server to host some commonly used genomics databases. Operating within this was a free software application called Snort, which actively monitors anomalies in web traffic, surreptitious scans and server nudges that might be attempts to compromise a system's integrity. Then the researchers watched and waited. Seven months later, the picture that emerged was one of a network under siege. "If you put up a server, it just continuously gets barraged," says Gerstein of Yale University in New Haven, Connecticut. Most days, the server was hit ten times or fewer, but on occasion the hit count spiked into the thousands1. Not all of those hits were attacks, Gerstein notes, but many were. On two high-hit days, for example, more than 90% of events attempted to induce a 'buffer overflow', whereby superfluous amounts of data are written into a system's memory in an attempt to make it fail, opening it up to exploitation. In the face of such a relentless onslaught, most ventures onto the World Wide Web should be taken with caution. Having a graduate student with little experience set up a website could be disastrous, Gerstein says. Entering either through poorly written code or open ports — digital entry points into computer hardware and operating systems — hackers could deface the content on the site or, worse, install malicious software on the machine running it. Attacks can run the gamut from the installation of programs intended to co-opt system resources to keystroke loggers and scanning software designed to purloin user information and passwords. Some hackers target university systems to steal computing resources or even intellectual property — proprietary compounds, instrument designs, patient data and personal communications. Hacking is suspected in the November 2009 release of e-mails from the Climatic Research Unit at the University of East Anglia, UK, which resulted in a glob! al crisis of confidence in climate science. "There is no sector that has been able to withstand this onslaught of intrusions," warns Steven Chabinsky, deputy assistant director in the cyber division of the Federal Bureau of Investigation (FBI) in Washington DC. Protecting research data presents particular challenges. Most information-technology (IT) professionals suggest ensuring that large or sensitive data stores are managed by a centralized IT team that can monitor and administer systems, keeping a close watch over traffic and limiting access. But this can conflict with the ethos of researchers who need such systems to be accessed by a wide variety of students, postdocs and collaborators. "Universities tend to be fairly open kinds of environments," says John McCanny, lead scientist at the Centre for Secure Information Technologies at Queen's University Belfast, UK. And some researchers bristle at the idea of losing control. "I'd rather be insecure and free," says Phillip Zamore, a biologist at the University of Massachusetts Medical School in Worcester. Drive-by hacking It is a rough world in which to take such a stance. Michael Corn, chief privacy and security officer at the University of Illinois at Urbana-Champaign, estimates that each day his university's firewalls block some two million to three million scans — essentially Internet drive-bys looking for open communications ports. A "significant percentage" of these, he says, are likely to stem from "professionals in the employ of organized crime or possibly state actors". The network at the San Diego Supercomputer Center of the University of California, San Diego, logged an average of 27,000 intrusion attempts per day during the first three months of 2010, according to Dallas Thornton, division director of the university's cyberinfrastructure services. Thornton says that this number actually underestimates the problem, because many common attacks are simply ignored. "Researchers are the best in the world at basically ignoring the administration." Successful intrusions are rarer. Until recently, the Educational Security Incidents website (http://www.adamdodge.com/esi) reported breaches in cybersecurity for higher education, recording nearly 500 incidents of data theft, loss or exposure between July 2005 and December 2009. Most of these occurred in the United States; just 10 occurred in the United Kingdom, 11 in Canada and 8 in Japan. But that may be just the tip of the iceberg; most incidents go unreported, says Chabinsky. McCanny reports that cybercrime's growth in the United Kingdom has greatly outpaced expectation. "The train is coming down the track much faster than most people would have anticipated even 15 months ago," he says. EDUCAUSE, a non-profit organization of higher-education IT professionals, undertakes annual surveys of academic chief information officers. The 2009 survey ranked security third overall among IT problems facing higher-education institutions today2. Security officers in such institutions face two crucial problems. One is funding, which ranked first in the survey. The chemistry department at the University of Wisconsin-Madison, for instance, has one IT person overseeing 1,300 computers used by 500 staff and several thousand students. In such a climate, says departmental chairman Robert Hamers, "it's just very limiting in terms of what you can actually expect one person to do". Last year, Hamers' department suffered a breach. In the absence of a firewall (now installed), foreign hackers infiltrated 40 computers, installing software that turned those systems into file-sharing servers for copyrighted music, movies and television programmes. The other problem, says Alan Paller, director of research at the cybersecurity-focused SANS Institute in Bethesda, Maryland, is researcher independence. Academic researchers need to be able to install software on demand, to collaborate with colleagues, to develop new tools for public or private consumption, and to cater for an ever-changing and heterogeneous user base. Besides that, "researchers are the best in the world at basically ignoring the administration", says Paller. In 2006, a researcher at Georgetown University in Washington DC independently decided to migrate a server handling confidential patient data from an IT-monitored UNIX system to an unmonitored Windows one. The server was hacked, and the names, birth dates and social-security numbers of some 41,000 individuals may have been accessed. The university was legally obliged to notify each of them. Such incidents, says Brian Voss, chief information officer at Louisiana State University in Baton Rouge, mostly occur when researchers strike out on their own. "It's like herding cats," he says. "The challenge is, how do you get them all under the umbrella?" Generally, universities do that by promoting the benefits of their centralized services. Many academic institutions offer a battery of common but effective defences — everything from pushing operating system and antivirus patches out to users, to remotely monitoring network traffic, to the establishment of secure virtual private networks for encrypted communication and virtual machines. Virtual machines are hardware surrogates: although users can interface as if they are working on physical computers or web servers, they're actually just working through windows running on a centralized host computer. Gerstein says that most of his lab is set up on a framework of virtual machines. This allows him and his colleagues to maintain back-ups for all the resources they put up on the web. "If something gets hacked into, we are not as worried any more," he says, "because we can roll back really easily and then put the thing back up." "The best way to secure a computer is to remove the keyboard, then the human cannot make a mistake." The American University in Washington DC also offers virtual-machine services to its faculty members, says chief information officer David Swartz, who (with Voss) co-chairs the EDUCAUSE Higher Education Information Security Council. "If they need a server I say, 'Come to me, I'll set you up'," Swartz says. The resulting sites are professionally secured, continuously monitored, and easily backed up and restored. And in the event of a breach, that intrusion is often effectively contained by virtue of the virtual machines' isolated architecture. Cybercrime is evolving rapidly. At the University of Nevada in Las Vegas, Lori Temple, vice-provost for information technology, says she is seeing increased intrusion through social-networking sites. Facebook games and images, for example, are particularly problematic, she says. "As much as you try to be ahead, you are almost always one step behind." How much individual researchers need to worry depends on their own cost–benefit analysis, says Chabinsky — a reflection of the value of the data's confidentiality and integrity both to the researcher and his or her competitors. Many will calculate that they have little cause for concern, save the loss or corruption of their own data, which can be mitigated by routine back-ups. But for those who must store personal, confidential or economically valuable information, he says, "they should ask some strong questions of their system security providers". They should enquire, for example, about the confidence they have in the systems in place and what additional measures they can take to mitigate risks. This is especially important as US federal granting agencies are beginning to require certification that sensitive information such as health records will be secured in compliance with the Federal Information Security Management Act of 2002. "An incident at the university could cause more than public embarrassment or a lawsuit," says Swartz, "it might actually cause the loss of federal grants." ADVERTISEMENT Ultimately, preemptive training might be the most cost-effective weapon IT departments have. Knowledge, after all, is power (see 'Ten tips for cybersecure science'). Especially given that no amount of infrastructure can overcome user carelessness. In 2007, the University of Illinois at Urbana-Champaign suffered a breach in which a spreadsheet containing the personal information of 5,247 students was accidentally e-mailed to 700 unauthorized individuals. As Marty Lindner, a principal engineer in the computer emergency response team (CERT) at the Carnegie Mellon Software Engineering Institute programme in Pittsburgh, Pennsylvania, says: "The best way to secure a computer is to remove the keyboard, because then the human cannot make a mistake." Jeffrey Perkel is a freelance writer in Pocatello, Idaho. * References * Smith, A. , Greenbaum, D. , Douglas, S. M. , Long, M. & Gerstein, M.Genome Biol.6, 119 (2005). * Agee, A. S.et al. EDUCASE Rev.44, 44-59 (2009). 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.
• Car industry: Fuel of the Future?
  - Nature 464(7293):1262 (2010)
  Hydrogen fuel-cell vehicles, largely forgotten as attention turned to biofuels and batteries, are staging a comeback. Jeff Tollefson investigates. Download a PDF of this article "The first car driven by a child born today could be powered by hydrogen and pollution-free," declared former US president George W. Bush in 2003, as he announced a US$1.2-billion hydrogen-fuel initiative to develop commercial fuel-cell vehicles by 2020. The idea was appealing. Ties to foreign oil fields would be severed, and nothing but water vapour would emerge from such a vehicle's exhaust pipe. Congress duly approved the money, and the Department of Energy and other research agencies got to work. But then the whole effort faded into obscurity, as attention shifted first to biofuels and then to battery-powered electric vehicles. Both seemed to offer much quicker and cheaper routes to low-carbon transportation. The shift seemed complete when the US Secretary of Energy Steven Chu entered office last year. Chu outlined four primary pitfalls with the hydrogen initiative. Car manufacturers still needed a fuel cell that was sturdy, durable and cheap, as well as a way to store enough hydrogen on board to allow for long-distance travel. Hydrogen also required a new distribution infrastructure, and even then the greenhouse-gas benefits would be marginal until someone worked out a cost-effective way to make hydrogen from low-carbon energy sources rather than natural gas. Last May, four months after being sworn in, Chu announced that the government would cut research into fuel-cell vehicles in his first Department of Energy budget. Biofuels and batteries, he said, are "a much better place to put our money". The move came as a relief to the many critics of hydrogen vehicles, including some environmentalists who had come to see Bush's hydrogen initiative as a cynical ploy to maintain the petrol-based status quo by focusing on an unattainable technology. Click for larger image But the budget proposal served only to energize the supporters of hydrogen vehicles, and it became clear during subsequent months that the debate was far from over. The same car manufacturers who were investing so heavily in biofuels and batteries felt that hydrogen fuel cells had a long-term potential that they could not afford to ignore. The hydrogen lobby was so effective that Congress eventually voted to override Chu and restore the money. Then on 9 September in Stuttgart, Germany, nine major car manufacturers — Daimler, Ford, General Motors, Honda, Hyundai, Kia, Renault, Nissan and Toyota — signed a joint statement suggesting that fuel-cell vehicles could hit dealerships by 2015. In a coordinated announcement the next day in Berlin, a group of energy companies including Shell and the Swedish firm Vattenfall joined Daimler in an agreement to begin setting up the necessary hydrogen infrastructure in Germany. This push for rapid deployment has left many people shaking their heads. "I just don't see it," says Don Hillebrand, director of the Center for Transportation Research at the Argonne National Laboratory in Illinois. "It doesn't make sense." Yet the proponents of hydrogen vehicles are brimming with confidence. "This memorandum of understanding marks the will of the industry to move forward," says Klaus Bonhoff, who heads the National Organisation for Hydrogen and Fuel Cell Technology (NOW), a Berlin-based organization created by the German government in 2008 to spearhead that country's hydrogen programme. Here Nature assesses the four major challenges facing hydrogen fuel-cell vehicles, and finds that both sides have a point: some of the challenges are close to being met — but others have a long way to go. Fuel cell Conceptually, at least, a fuel cell is simply a device that takes in oxygen from the air and hydrogen from a tank, and reacts them in a controlled way to produce water vapour and electric power. In a vehicle, that power can then be directed through an ordinary electric motor to turn the wheels. In practice, fuel cells are anything but simple: controlling the reaction and extracting the electric current requires a sophisticated assembly including nozzles, membranes and catalysts. And therein lies the challenge: how to pack all that complexity into a device that is light, cheap, robust and durable — as well as being powerful enough to provide rapid acceleration, plus drive all the lights, air conditioning, radio and other amenities that consumers have come to expect in a modern vehicle. Ten years ago this goal seemed far off. Car manufacturers didn't even dare to expose their experimental fuel-cell vehicles to cold weather: they worried that when the cells shut down, residual water vapour could freeze and wreak havoc on the delicate insides. Instead, the companies would shuttle the vehicles around in heated trailers. But a decade has brought fuel-cell technology a remarkably long way. "Nobody woke up one morning and said, 'Ah-ha! Here's the salient breakthrough!'" says Byron McCormick, who headed the fuel-cell programme of General Motors until January 2009. "It has really been a whole lot of small steps." For example, General Motors' fuel-cell vehicles eliminate the cold-weather problem in part by continuing to run the cell's exhaust system for a minute or two after the car is shut down, using the cell's residual heat to drive the water out of the system. Toyota says that its experimental, fuel-cell-equipped Highlander sports-utility vehicle will start up at −37 °C. Engineers are also cutting back on the use of expensive catalysts. General Motors' fuel-cell assembly uses roughly 80 grams of platinum to split electrons and protons from hydrogen atoms. At the current platinum price of about US$60 per gram, this totals some $4,800. But General Motors officials say that their next fuel cell will use less than 30 grams of platinum, thanks to using ever thinner coats of the metal. And the company's scientists are continuing to experiment with measures such as increasing the surface area of the catalyst by introducing more texture at the nanoscale. Within a decade, they expect to get platinum use to below 10 grams, which would make the fuel cells competitive with today's catalytic converters in terms of precious-metal use. These and other advances translate into price reductions. The Department of Energy estimates that fuel-cell costs per kilowatt of power dropped by nearly 75% between 2002 and 2008, based on cost projections for high-volume manufacturing. Companies won't discuss retail prices except to say that the vehicles slated to appear by the middle of the decade will be priced competitively. "I've been doing this for 10 years, and the numbers even surprise and shock me," says Craig Scott, manager of Toyota's advanced technologies group in Torrance, California. "It is definitely going to be a car that is in reach of a lot of people." "It is definitely going to be a car that is in reach of a lot of people." On-board storage In June 2009, Toyota engineers and US government monitors hopped into a pair of fuel-cell Highlanders at the company's US headquarters in Torrance and took a 533-kilometre round trip through real-world traffic — without refuelling. Calculations suggest that the vehicles' performances corresponded to a range of 693 kilometres on a single tank of hydrogen, which is on a par with the range of current petrol vehicles. Ten years ago, this feat also would have seemed daunting. Gaseous hydrogen is easy enough to store in a tank. But getting enough of it on board would require either a ridiculously large tank that would eliminate space for people, groceries and camping gear, or an exceptionally strong tank that could safely store compressed hydrogen gas at hundreds of times atmospheric pressure. Liquid hydrogen is much denser, but it would have to be maintained in an insulated tank at −253 °C, which would add to a vehicle's weight, complexity and expense. In the end, the comparative simplicity of compressed hydrogen won out. Most companies have chosen to use modern carbon-fibre tanks, which can store hydrogen at up to 680 atmospheres, while still being relatively lightweight. To improve range further, many companies are also equipping their vehicles with the same 'regenerative braking' technology that allows hybrid petrol and electric cars and all-electric cars to capture energy during braking, store it in auxiliary batteries, and reuse it for later acceleration. Indeed, because hydrogen and battery-powered vehicles both use electric motors, they share many technologies. The only real difference is the power source: fuel cells versus batteries. Scott says that electric vehicles based on the lithium-ion battery chemistry are unlikely to get beyond a range of 150–250 kilometres on a single charge. And although that may be enough to cover urban driving, consumers like having the option to drive cross-country. So in the shift away from petrol, the hydrogen vehicle's greater range could give it an edge in the long term. Scott says that hydrogen and electric vehicles have a space to occupy. "I just think that fuel cells will occupy a bigger space," he says. Distribution infrastructure Regardless of range, every vehicle needs fuel at some point. And here lies hydrogen's chicken-and-egg problem: fuel-cell vehicles will never sell in a big way until there is a viable network of service stations to fuel them. But no one is going to invest the capital required to create such a network until there is a fleet of thirsty hydrogen vehicles to provide a market. Hydrogen pumps can and have been added to existing petrol stations, where at first glance they look much the same as conventional pumps. Because the hydrogen used is a compressed gas, filling the tank is not just a matter of placing a nozzle in the petrol-tank opening and letting gravity take care of the rest. Instead, a tight seal has to be established between the nozzle and car, and high-powered pumps have to force hydrogen through the nozzle until the desired pressure is reached. In practice, the current-generation hydrogen pumps are already easy and safe enough for an average consumer to use. But they do have to work perfectly if tanks are to be filled to full pressure; at present their performance is solid but variable. A larger question facing car manufacturers is how rapidly the network of hydrogen-filling stations will spread. In the United States, for example, the number of hydrogen pumps is at present measured in dozens, and there seems to be little coordinated effort to change the situation. And until recently, things seemed much the same elsewhere. That's why hydrogen proponents see so much significance in last year's agreements in Germany, which promise to break the chicken-and-egg deadlock. The car manufacturers have promised the cars, and NOW is pushing for a network of several hundred pumps throughout Germany within a few years, and as many as 1,000 by the end of the decade. That should be enough to provide broad coverage within the metropolitan areas and regular access along the highways. Bonhoff says that the consortium expects the price to be within the range of what energy companies would normally spend to maintain, upgrade and expand their petrol infrastructure over the same interval. Charlie Freese, who heads the fuel-cell programme at General Motors, says that the hydrogen-infrastructure costs could be similarly manageable even in much larger countries such as the United States. In the early stages of a hydrogen-vehicle rollout, the Los Angeles basin could be well served with 50 hydrogen stations at a cost of roughly $200 million. Further down the line, some 11,000 stations might be needed to provide blanket coverage across the United States. "That's something you could do for roughly the cost of the Alaska pipeline," he says, referring to a proposed $35-billion project intended to carry natural gas from Alaska's North Slope to the North American market. Hydrogen production From a climate perspective, the main question facing hydrogen is where to get the gas in the first place. At present, the cheapest source is via a chemical reaction between steam and natural gas. But this process produces carbon dioxide, which means that the total greenhouse-gas production of a fuel-cell vehicle is not dramatically less than that of a conventional petrol vehicle. So the challenge is to derive hydrogen from carbon-free renewable sources. "The question is whether we can afford not to have hydrogen infrastructure if we want to use renewables." Vattenfall, sees this as an opportunity and is building a facility in Hamburg that will use excess wind power to split water molecules and produce hydrogen for a fleet of 20 fuel-cell buses. Power companies tend to disperse extra wind turbines in various locations to compensate for the fact that wind is inherently unreliable. But those excess turbines will produce more electricity than the grid can handle if the wind blows in too many places at once. When that happens, turbines are shut down. Once the Hamburg facility comes on line, Vattenfall will instead fire up the electrolysis unit, tapping the excess power to make hydrogen and keeping the grid stable. Cost is still an issue, says Oliver Weinmann, head of innovation management for Vattenfall in Germany. He says that the company will be able to produce hydrogen at €3–4 ($4–5.3) per kilogram, compared with €2 per kilogram for hydrogen produced from natural gas. But with Europe looking to expand its use of renewable energy over the coming decade, the growth potential is enormous, says Weinmann. "It is not really a question of whether we can afford the hydrogen infrastructure," says Freese. "The question is whether we can afford not to have hydrogen infrastructure if we want to use renewables." Adoption Not everyone is persuaded by such arguments. Even if car manufacturers do get their fuel-cell vehicles to market by 2015, it will take years to establish a customer base, increase production and bring down costs. Few firms anticipate profitability on these vehicles until 2020 or even 2025. Meanwhile, they and the energy companies are also pushing biofuels and battery-powered electric cars, each of which would require its own distribution system. Building these transportation infrastructures simultaneously might not be possible. These concerns are felt even within the car industry. Ford, for example, is confining its fuel-cell activities to long-term research, and has no current plans to market a commercial hydrogen vehicle. And BMW is hedging its bets with research into an otherwise conventional car whose internal combustion engine can burn petrol or hydrogen. Some hydrogen advocates predict a multiple-niche scenario, in which battery vehicles are used in urban areas, whereas hydrogen pumps proliferate along the highways for long-distance travel. But perhaps the biggest mistake would be to assume that anybody in this game really knows what they are doing, says John Heywood, director of the Sloan Automotive Lab at the Massachusetts Institute of Technology in Cambridge. ADVERTISEMENT Heywood says that the first round of vehicles will not be finished products so much as 'production prototypes' that allow companies to assess their performance — and the consumer response. Toyota followed this approach with its Prius hybrid car in 1997, and there's no reason to think that the process will be any faster for hydrogen or battery-powered vehicles. In either case, it could take three or more decades to revolutionize the global automobile fleet, says Heywood, and that's the kind of time frame that is guiding the car makers today. "There are two paths, and they are going to invest in the electricity and the hydrogen pathway until it becomes clearer that one is significantly better than the other," he says. "Right now, we don't know the answer." 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.
• French research also being stifled by autocracy
  - Nature 464(7293):1266 (2010)
  Your Editorial 'Scientific glasnost' (Nature 464, 141–142; 2010) highlights parochial anachronisms in the Russian Academy of Sciences that are obstructing the development of a knowledge-based economy.
• Forensics: stronger scientific scrutiny needed in Britain
  - Nature 464(7293):1266 (2010)
  I congratulate Nature for highlighting problems that exist in forensic science, and in low-copy-number DNA profiling in particular (Nature464, 325 and 347–348; 2010).Any move intended to improve matters must, in the first instance, be made within the scientific community.
• Forensics: experts disagree on statistics from DNA trawls
  - Nature 464(7293):1266 (2010)
  Statistical analysis in DNA-fingerprint matching is a case in point of the need for more science in forensics (Nature 464, 325; 2010)In 'confirmatory cases', suspects' DNA is found to match that from the crime scene.
• Statisticians and historians should help improve metrics
  - Nature 464(7293):1267 (2010)
  To develop and apply adequate metrics (Nature 464, 488–489; 2010), a proper understanding of the methodology of measuring and of the phenomenon to be measured is essential.Key contributors to the analysis of scientific metrics may therefore be statisticians and historians of science.
• Nature's readers comment online
  - Nature 464(7293):1267 (2010)
  To capture the essence of good science, stakeholders must combine forces to create an open, sound and consistent system for measuring all the activities that make up academic productivity, says Julia Lane.
• The making of an exceptional scientist
  - Nature 464(7293):1268 (2010)
  Dorothy Hodgkin was born 100 years ago next month. Her biographer, Georgina Ferry, reflects on the factors that propelled the Nobel-prizewinning crystallographer to greatness.
• Forecasts needed for retreating forests
  - Nature 464(7293):1271 (2010)
  As tree habitats shift towards the poles in response to climate change, we must study the neglected, trailing edges of forests, warns Csaba Mátyás — they are economically and ecologically important.
• Two views of our planet's future
  - Nature 464(7293):1273 (2010)
  David Orr explains how two environmentalists' manifestos bracket the debate on climate change — one favouring technological solutions, the other local interventions.
• New in Paperback
  - Nature 464(7293):1273 (2010)
  Formerly head of the Human Genome Project, Francis Collins now directs the US National Institutes of Health. "The Language of Life is timely, current and full of moving stories ... Collins argues convincingly that your DNA can become "your personal textbook" that "could literally save your life".
• Happiness breeds prosperity
  - Nature 464(7293):1275 (2010)
  It has long been assumed that economic prosperity brings happiness. However, the evidence is to the contrary.
• Signatures of life on other worlds
  - Nature 464(7293):1276 (2010)
  In the 15 years since the discovery of the first planet around a star other than our Sun, we have found more than 400 such exoplanets — but there is still no place like home. In How to Find a Habitable Planet, James Kasting extends knowledge of the planets in our Solar System to searches for distant Earth-like exoplanets that could harbour life.
• Education as a global commodity
  - Nature 464(7293):1277 (2010)
  Globalization is rapidly changing both the way universities operate and the idea of what a university is. In particular, there is increasing worldwide competition for the best students and scholars, and an expanding global market for educational credentials.
• Why fairness pays
  - Nature 464(7293):1280 (2010)
  Why would two drivers caught in a snowdrift both shovel snow to clear a route, rather than wait for one to do it? Or, given $10 to split with someone however you like provided they accept your offer, why are you more likely to give them $5 than $1?
• The omnipresent hubbub
  - Nature 464(7293):1281 (2010)
  In The Unwanted Sound of Everything We Want, writer Garret Keizer exposes the history of noise, its opponents and apologists, and recent efforts to measure and curb it. The result is a scattered mosaic that uses the conceit of human clamour to reveal the paradoxes of post-industrial life.
• A hero with a butterfly net
  - Nature 464(7293):1282 (2010)
  Raff is the main character in Anthill, the first novel by the towering entomologist Edward O. Wilson.
• Under the skin of climate change
  - Nature 464(7293):1283 (2010)
  Following his 2005 novel Saturday, in which the central character is a neurosurgeon, in his latest book celebrated British author Ian McEwan explores the personal side of the science and politics of climate change. A sophisticated work of fiction, Solar is littered with references to physics and engineering.
• Immunology: Close encounters of the second type
  - Nature 464(7293):1285 (2010)
  To combat intestinal worms, mammals rely on adaptive immune responses mediated by T cells. However, it seems that, initially, innate immune cells mimic T-cell activity, while T cells get ready for action.
• Asteroids: A frosty finding
  - Nature 464(7293):1286 (2010)
  The asteroid belt is classically considered the domain of rocky bodies, being too close to the Sun for ice to survive. Or so we thought — not only is ice present, but at least one asteroid is covered in it.
• Metabolism: Host and microbes in a pickle
  - Nature 464(7293):1287 (2010)
  Metabolic disorders such as obesity are characterized by long-term, low-grade inflammation. Under certain conditions, the resident microorganisms of the gut might contribute to this inflammation, resulting in disease.
• 50 & 100 years ago
  - Nature 464(7293):1289 (2010)
  'A possible fundamental in the behaviour of young nidifugous birds' — One of the most significant behaviour patterns observed is one which occurs immediately upon hatching. I propose to call this the 'brooding reflex' because it seems to be the mechanism whereby the newly hatched duckling orientates itself to the position of optimum warmth and mechanical protection beneath the female.
• Quantum physics: Atoms in chequerboard order
  - Nature 464(7293):1289 (2010)
  Bose–Einstein condensates are ideal tools with which exotic phenomena can be investigated. The hitherto-unrealized Dicke quantum phase transition has now been observed with one such system in an optical cavity.
• Geochemistry: The mystery of Don Juan Pond
  - Nature 464(7293):1290 (2010)
  Abstract
• Neuroscience: Each synapse to its own
  - Nature 464(7293):1290 (2010)
  A neuron can receive thousands of inputs that, together, tell it when to fire. New techniques can image the activity of many inputs, and shed light on how single neurons perform computations in response.
• Obituary: James Black (1924–2010)
  - Nature 464(7293):1292 (2010)
  Pharmacologist who changed the face of medicine.
• Genetics, pathogenesis and clinical interventions in type 1 diabetes
  - Nature 464(7293):1293 (2010)
  Nature | Review Genetics, pathogenesis and clinical interventions in type 1 diabetes * Jeffrey A. Bluestone1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kevan Herold2 Search for this author in: * NPG journals * PubMed * Google Scholar * George Eisenbarth3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1293–1300Date published:(29 April 2010)DOI:doi:10.1038/nature08933 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 Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Once diagnosed, patients require lifelong insulin treatment and can experience numerous disease-associated complications. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk, timing of disease activation, and disease tempo. Here we describe current progress, the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies. View full text Subject terms: * Immunology * Genetics * Genomics Figures at a glance * Figure 1: Markers of diabetes. , Typical child followed from birth until development of diabetes in the DAISY (Diabetes Auto Immunity Study in the Young; http://www.uchsc.edu/misc/diabetes/Teddy/DAISY/DAISY_home.htm) study (M. Rewers, unpublished work), expressing multiple autoantibodies (GAD, the islet cell antibody ICA512 and low-level insulin autoantibodies). , Islet invasion by lymphocytes of NOD mice is asynchronous during progression to diabetes, often with a mixture of normal islets, peri-insulitis, intra-islet insulitis, and complete β-cell destruction. , Pathology of the pancreas in a long-term type 1 diabetic (the nPOD program, pancreas 6028, see http://www.jdrfnpod.org/). The section shows lobular areas in which all β-cells (insulin-producing) in all islets have been destroyed (pseudoatrophic islets in which only glucagon, somatostatin, and pancreatic polypeptide cells are present) juxtaposed with regions in which all islets contain insulin-containing β-cells. * Figure 2: Immunologic history of type 1 diabetes. An as-yet-undefined immunologic insult occurs in an individual with genetic predisposition and initiates a chronic low-grade immunologic process (priming). The initiating events involve infiltration of innate immune cells (such as monocytes and natural killer cells with autoreactive B cells) (orange ovals) into the pancreatic islets. The principal site of antigen presentation is thought to be the pancreatic lymph node where islet antigens are presented by antigen-presenting cells (white ovals) to T cells (brown dots). Blue ovals are antigen-presenting cells loaded with islet antigens. B cells (green dots) and dendritic cells may be among the early antigen-presenting cells. The cellular infiltration of islets ensues but the insulitis is uneven. Islets with infiltration may be situated near to islets without cells. The process specifically targets insulin-producing β-cells (light blue circles), while other endocrine cells (red circles) within the islet are spared. In the lymp! h nodes, the cycle of antigen presentation, activation of adaptive immune cells, licensing of effector T cells and epitope spreading continues with the loss of β-cells over time. There is evidence for a regenerative attempt of β-cells in the midst of the islet inflammation (dark blue circles). Tertiary lymphoid organs are thought to develop within the islets, which may lead to amplification of the adaptive immune response. Regulatory T cells (yellow dots) may arrest this process in its early and late stages but are not able to contain the amplified process in the late stages despite an increase in their numbers. With continued loss of β-cells, hyperglycaemia can be detected. The loss of metabolic function at presentation may be both functional and anatomic, because immune therapies can restore cells that have lost the capacity to produce insulin but have not been destroyed. Without intervention, however, β-cell loss continues. * Figure 3: Immune system balance is key to disease pathogenesis. This schematic illustrates the fine balance of immune regulation versus pathogenesis, highlighting a number of genes that are likely to influence the balance through effects on central and peripheral tolerance and the environmental factors that control immunity. The key cell types that affect the balance locally during immune responses are listed (with the regulatory cytokines and proteins given in parentheses). iNOS, inducible nitric oxide synthase. IDO, indoleamine-2,3 dioxygenase. * Figure 4: Targets of immune intervention in type 1 diabetes. This schematic provides an overview of the pathogenesis of type 1 diabetes, highlighting a number of key pathways that are being targeted by current therapeutics. Although not exhaustive (see Supplementary Table 1), this figure shows that both non-specific and antigen-specific therapies are being tested, which inhibit effector cells and antigen presentation as well as boost regulatory pathways. Purple and green dotted arrows indicate the therapeutics, black arrows are immune and metabolic pathways; a green dotted arrow indicates a positive effect and a purple dotted arrow indicates a negative effect. In addition, these immunotherapies are being combined with drugs that promote β-cell survival to potentially replenish insulin-producing β-cells. The figure has been redrawn after ref. 87, with permission. Author information * Author information * Supplementary information * Comments Affiliations * Diabetes Center and the Department of Medicine, University of California, San Francisco, San Francisco, California 94143, USA * Jeffrey A. Bluestone * Department of Immunobiology, Yale University, New Haven, Connecticut 06520, USA * Kevan Herold * Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, Colorado 80045-6511, USA * George Eisenbarth Contributions Each co-author (G.E., K.H. and J.A.B.) contributed experimental results, data analysis, writing and creative contributions to this work. Competing financial interests J.A.B. has a financial interest in the commercialization of the anti-CD3 monoclonal antibody. Both J.A.B. and G.E. serve on several boards involved in the development of drugs to treat type 1 diabetes. Corresponding author Correspondence to: * Jeffrey A. Bluestone (jbluest@diabetes.ucsf.edu.) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (138K) This file contains Supplementary Tables 1-2 and Supplementary References. Additional data
• Dicke quantum phase transition with a superfluid gas in an optical cavity
  - Nature 464(7293):1301 (2010)
  Nature | Article Dicke quantum phase transition with a superfluid gas in an optical cavity * Kristian Baumann1 Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Guerlin1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ferdinand Brennecke1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tilman Esslinger1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1301–1306Date published:(29 April 2010)DOI:doi:10.1038/nature09009Received13 December 2009Accepted18 February 2010 Abstract * Abstract * Author 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 A phase transition describes the sudden change of state of a physical system, such as melting or freezing. Quantum gases provide the opportunity to establish a direct link between experiments and generic models that capture the underlying physics. The Dicke model describes a collective matter–light interaction and has been predicted to show an intriguing quantum phase transition. Here we realize the Dicke quantum phase transition in an open system formed by a Bose–Einstein condensate coupled to an optical cavity, and observe the emergence of a self-organized supersolid phase. The phase transition is driven by infinitely long-range interactions between the condensed atoms, induced by two-photon processes involving the cavity mode and a pump field. We show that the phase transition is described by the Dicke Hamiltonian, including counter-rotating coupling terms, and that the supersolid phase is associated with a spontaneously broken spatial symmetry. The boundary of the ph! ase transition is mapped out in quantitative agreement with the Dicke model. Our results should facilitate studies of quantum gases with long-range interactions and provide access to novel quantum phases. View full text Subject terms: * Applied physics * Engineering * Information technology Figures at a glance * Figure 1: Concept of the experiment. A BEC is placed inside an optical cavity and driven using a standing-wave pump laser oriented along the z axis (vertically in the figure). The frequency of the pump laser is far red-detuned with respect to the atomic transition line but close detuned from a particular cavity mode. Correspondingly, the atoms coherently scatter pump light into the cavity mode with a phase depending on their position within the combined pump–cavity mode profile. , For a homogeneous atomic density distribution along the cavity axis, the build-up of a coherent cavity field is suppressed as a result of destructive interference of the individual scatterers. SPCM, single-photon counting module. , Above a critical pump power, Pcr, the atoms self-organize onto either the even or odd sites of a chequerboard pattern, thereby maximizing cooperative scattering into the cavity. This dynamical quantum phase transition is triggered by quantum fluctuations in the condensate density. It is accompanied by spo! ntaneous symmetry breaking both in the atomic density and in the relative phase between the pump and cavity fields. , Geometry of the chequerboard pattern. The intensity maxima of the pump and cavity fields are depicted by the horizontal and vertical lines, respectively; λp, pump wavelength. * Figure 2: Analogy to the Dicke model. In an atomic two-mode picture, the pumped BEC–cavity system is equivalent to the Dicke model including counter-rotating interaction terms. , Light scattering between the pump field and the cavity mode induces two balanced Raman channels between |px, pz = |0, 0, the atomic zero-momentum state, and |± k, ± k, the symmetric superposition of states with an additional unit of photon momentum along the x and z directions. Primes indicate electronically excited momentum states. , The two excitation paths (dashed and solid) corresponding to the two Raman channels are illustrated in a momentum diagram. * Figure 3: Observation of the phase transition. , The pump power (dashed) is gradually increased while the mean intracavity photon number (solid; 20-μs bins) is monitored. After the sudden release of the atomic cloud and its subsequent ballistic expansion for 6 ms, absorption images (clipped equally in atomic density) are made for pump powers corresponding to lattice depths of 2.6Er (), 7.0Er () and 8.8Er (). Self-organization is manifested by an abrupt build-up of the cavity field accompanied by the formation of momentum components at (px, pz) = (± k, ± k) (). The weak momentum components at (0, ±2 k) () result from loading the atoms into the one-dimensional standing-wave potential of the pump laser. The pump–cavity detuning was Δc = -2π × 14.9(2) MHz and the atom number was N = 1.5(3) × 105 (parentheses show uncertainty in last digit). * Figure 4: Steady state in the self-organized phase. , Pump power sequence (dashed) and recorded mean intracavity photon number (solid; 20-μs bins). After crossing the transition point, at 9 ms, the system reaches a steady state within the self-organized phase. The slow decrease in photon number is due to atom loss (see text). The short-time fluctuations are due to detection shot noise. , Absorption images are made at different times in the self-organized phase: after 3 ms (), after 7 ms () and after returning the pump power to zero (). The pump–cavity detuning was Δc = -2π × 6.3(2) MHz and the atom number was N = 0.7(1) × 105. * Figure 5: Phase diagram. , The pump power is increased to 1.3 mW over 10 ms for different values of the pump-cavity detuning, Δc. The recorded mean intracavity photon number, , is displayed (colour scale) as a function of pump power (and corresponding pump lattice depth) and pump–cavity detuning, Δc. A sharp phase boundary is observed over a wide range of Δc values; this boundary is in very good agreement with a theoretical mean-field model (dashed curve). The dispersively shifted cavity resonance for the non-organized atom cloud is marked by the arrow on the vertical axis. , , Typical traces showing the intracavity photon number for different pump–cavity detunings: Δc = -2π × 23.0(2) MHz, 20-μs bins (); Δc = -2π × 4.0(2) MHz, 10-μs bins (). The atom number was N = 1.0(2) × 105. In the detuning range -2π × 7 MHz ≥ Δc ≥ -2π × 21 MHz, the pump power ramp was interrupted at 540 μW. Therefore, no photon data was taken in the area of und! er the insets. Author information * Abstract * Author information * Comments Affiliations * Institute for Quantum Electronics, ETH Zürich, 8093 Zürich, Switzerland * Kristian Baumann, * Christine Guerlin, * Ferdinand Brennecke & * Tilman Esslinger * Present address: Thales Research and Technology, Campus Polytechnique, 1 Avenue Augustin Fresnel, F-91767 Palaiseau, France. * Christine Guerlin Contributions The data was taken and analysed by K.B. and C.G. The theoretical analysis was mainly performed by F.B. and T.E. The relation to the Dicke model was realized by F.B. The experimental concept was developed by T.E. All authors contributed extensively to the discussion of the results as well as to the preparation of the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Tilman Esslinger (esslinger@phys.ethz.ch.) Additional data
• Dendritic organization of sensory input to cortical neurons in vivo
  - Nature 464(7293):1307 (2010)
  Nature | Article Dendritic organization of sensory input to cortical neurons in vivo * Hongbo Jia1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Nathalie L. Rochefort1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaowei Chen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Arthur Konnerth1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1307–1312Date published:(29 April 2010)DOI:doi:10.1038/nature08947Received14 October 2009Accepted24 February 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 In sensory cortex regions, neurons are tuned to specific stimulus features. For example, in the visual cortex, many neurons fire predominantly in response to moving objects of a preferred orientation. However, the characteristics of the synaptic input that cortical neurons receive to generate their output firing pattern remain unclear. Here we report a novel approach for the visualization and functional mapping of sensory inputs to the dendrites of cortical neurons in vivo. By combining high-speed two-photon imaging with electrophysiological recordings, we identify local subthreshold calcium signals that correspond to orientation-specific synaptic inputs. We find that even inputs that share the same orientation preference are widely distributed throughout the dendritic tree. At the same time, inputs of different orientation preference are interspersed, so that adjacent dendritic segments are tuned to distinct orientations. Thus, orientation-tuned neurons can compute their ch! aracteristic firing pattern by integrating spatially distributed synaptic inputs coding for multiple stimulus orientations. View full text Subject terms: * Neuroscience * Physiology Figures at a glance * Figure 1: Visually evoked action potentials, subthreshold depolarizations and global dendritic calcium signals. , Reconstruction of a biocytin-filled layer 2/3 (L2/3) neuron in mouse primary visual cortex (projection along the antero-posterior axis). Data from the same neuron are presented in –. , Microphotograph of a spiny basal dendrite. , Projection along the dorso-ventral axis obtained in vivo from 469 sections (step size 0.5 µm) from Alexa fluorescence. , Whole-cell current-clamp recordings of responses to drifting gratings of different orientations. Three trials were superimposed. Upper red traces, action potential responses at resting potential (indicated on the left); lower blue traces, subthreshold responses obtained after hyperpolarizing the neuron to -70 mV. , Polar plots of visually evoked responses, average of eight trials. Red plot, spike rate; blue plot, amplitude of subthreshold depolarization. , Tuning properties of spiking and subthreshold responses for six orientation-selective neurons, each normalized to their preferred orientation (noted as 0°). Error bars! , +s.d. , , Two-photon imaging of dendritic calcium signals in basal and oblique dendrites of another layer 2/3 neuron during action potential firing (electrical recording lower red trace) evoked by drifting gratings. , Average image of 100 frames recorded at 173 µm below the cortical surface. Yellow dashed lines indicate out-of-focus portions of the dendrites. Green dashed lines indicate the regions of interest (ROIs). , Ca2+-dependent fluorescence changes (black traces) recorded in the soma and in five dendrites (indicated by numbers in ) and the corresponding membrane potential (Vm, red traces) recordings, during two separate trials. Light grey bars indicate the stimulation period with oriented gratings. AP, action potential. * Figure 2: Subthreshold local dendritic calcium signals evoked by drifting grating stimulation. , Two-photon image used for calcium recordings in . The image is an average of 100 frames. Five ROIs are indicated by green dashed rectangles. , Subthreshold Ca2+ transients (black traces) and corresponding depolarization (blue traces) evoked by drifting grating stimulation. Note the prominent Ca2+ signal in dendrite 3. Left traces, single trials; right traces, average (black trace) of five individual trials (grey traces) from various dendritic sites and soma, as indicated. , Upper panel, pseudo-colour image of local dendritic Ca2+ signals. Ratio of the averages of 30 frames before and 30 frames during stimulation. Yellow arrows indicate two sites of local dendritic calcium signals. Lower panel, enlarged view of the dashed box indicated in the upper image, 'super-average' obtained from 500 frames. , Calcium recordings from five neighbouring dendritic regions of 3 µm length (d1–d5, ROIs shown in ), average of five trials. , Calcium signals evoked during five consecut! ive trials within the ROI indicated by the red dashed line in . , Amplitude distribution of calcium signals within dendritic hotspots (n = 50 hotspots, 17 neurons). Grey dashed lines indicate the Gaussian fitting to the amplitude distribution of calcium signals within individual hotspots. Red line indicates the Gaussian fit to all points. Average half-width at half-maximum (HWHM) with standard deviation (±) is indicated. , Left, two-photon image of a neuron (average n = 100 frames) and schematic representation of drug application pipette containing AP5 and Alexa-594. The red dashed lines indicate the approximate area of drug application. The green dashed box is the ROI for calcium monitoring. Right, Ca2+ recordings before, during and after the application of AP5. Average trace (black line) of five individual trials (grey lines). , Amplitude of calcium signals before and during the application of AP5 obtained from n = 9 local calcium signals in four neurons. The amplitude o! f each Ca2+ signal was normalized to the mean amplitude of all! signals in control condition. Paired t-test, ***P < 0.0001. * Figure 3: Heterogeneity and distribution pattern of orientation-tuned dendritic hotspots. , Four two-photon images (each an average of n = 100 frames) of a layer 2/3 neuron obtained at different depths under the cortical surface as indicated. Red dashed boxes indicate hotspots of local dendritic calcium signalling. , Local dendritic calcium signals evoked by drifting gratings of different orientations (average of six trials) at three different dendritic sites indicated in . , Location of each hotspot indicated as a red dot on the Z-projection of the reconstructed dendritic tree. Red dashed lines point to the polar plot obtained for the corresponding local Ca2+ signals. The frame (grey dashed line) indicates the area of imaging. The output signal of the neuron was tuned for the vertical orientation. * Figure 4: Spatial arrangement of dendritic hotspots and input–output relation. , Distribution of dendritic hotspots (red dots) tuned for the orientation preference indicated in the upper left corner, in the dendritic tree of a neuron (left panel). Right panel, summary of the results obtained for the same orientation in eight neurons. Cell bodies are indicated by the grey-filled dashed circles (black), dendrites are indicated by dashed red lines (Z-projections reconstructed from stacks). , Three two-photon images of dendrites (each an average of n = 100 frames) at higher magnification with hotspots as indicated. Yellow arrows indicate the preferred orientation of local calcium signal in the corresponding hotspot. Note that the hotspots in dendrites 2 and 3 as well as the two distal hotspots in dendrite 1 were located in branch point-delimited segments. , Summary graphs. Left panel, the proportion of full dendrites (n = 12) with hotspots coding for multiple orientations versus those with just one and the same orientation (≥3 hotspots per full dendrite)! . Right panel, the proportion of branch segments (between two branching points) with hotspots coding for multiple orientations versus those with the same orientation (≥2 hotspots per branch, n = 10). , Input–output relations in highly tuned (upper) and poorly tuned (lower) neurons. The red and blue histograms show orientation selectivity indices (OSIs as indicated) for the input (Ca2+ signals in dendritic hotspots) and the output (spiking rate) of highly and poorly tuned neurons (n = 6 for each group), respectively. Author information * Abstract * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Hongbo Jia & * Nathalie L. Rochefort Affiliations * Institute of Neuroscience and Center for Integrated Protein Science, Technical University Munich, Biedersteinerstrasse 29, 80802 Munich, Germany * Hongbo Jia, * Nathalie L. Rochefort, * Xiaowei Chen & * Arthur Konnerth Contributions H.J., N.L.R. and X.C. carried out the experiments. H.J., N.L.R. and A.K. performed the analysis. A.K. designed the study and wrote the manuscript with the help of all authors. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Arthur Konnerth (arthur.konnerth@lrz.tum.de.) Supplementary information * Abstract * Author information * Supplementary information * Comments PDF files * Supplementary Information (741K) This file contains Supplementary Methods and References and Supplementary Figures 1-3 with legends. Additional data
• Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1
  Iwabu M Yamauchi T Okada-Iwabu M Sato K Nakagawa T Funata M Yamaguchi M Namiki S Nakayama R Tabata M Ogata H Kubota N Takamoto I Hayashi YK Yamauchi N Waki H Fukayama M Nishino I Tokuyama K Ueki K Oike Y Ishii S Hirose K Shimizu T Touhara K Kadowaki T - Nature 464(7293):1313 (2010)
  Nature | Article Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1 * Masato Iwabu1, 2, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Toshimasa Yamauchi1, 2, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Miki Okada-Iwabu1, 2, 11 Search for this author in: * NPG journals * PubMed * Google Scholar * Koji Sato6 Search for this author in: * NPG journals * PubMed * Google Scholar * Tatsuro Nakagawa7 Search for this author in: * NPG journals * PubMed * Google Scholar * Masaaki Funata1 Search for this author in: * NPG journals * PubMed * Google Scholar * Mamiko Yamaguchi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Shigeyuki Namiki3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ryo Nakayama1 Search for this author in: * NPG journals * PubMed * Google Scholar * Mitsuhisa Tabata8 Search for this author in: * NPG journals * PubMed * Google Scholar * Hitomi Ogata9 Search for this author in: * NPG journals * PubMed * Google Scholar * Naoto Kubota1 Search for this author in: * NPG journals * PubMed * Google Scholar * Iseki Takamoto1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yukiko K. Hayashi10 Search for this author in: * NPG journals * PubMed * Google Scholar * Naoko Yamauchi4 Search for this author in: * NPG journals * PubMed * Google Scholar * Hironori Waki1 Search for this author in: * NPG journals * PubMed * Google Scholar * Masashi Fukayama4 Search for this author in: * NPG journals * PubMed * Google Scholar * Ichizo Nishino10 Search for this author in: * NPG journals * PubMed * Google Scholar * Kumpei Tokuyama9 Search for this author in: * NPG journals * PubMed * Google Scholar * Kohjiro Ueki1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yuichi Oike8 Search for this author in: * NPG journals * PubMed * Google Scholar * Satoshi Ishii5 Search for this author in: * NPG journals * PubMed * Google Scholar * Kenzo Hirose3 Search for this author in: * NPG journals * PubMed * Google Scholar * Takao Shimizu5 Search for this author in: * NPG journals * PubMed * Google Scholar * Kazushige Touhara6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Takashi Kadowaki1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:464,Pages:1313–1319Date published:(29 April 2010)DOI:doi:10.1038/nature08991Received12 August 2009Accepted11 March 2010Published online31 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 Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca2+ influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca2+ concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1α expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased ox! idative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes. View full text Subject terms: * Cell biology * Molecular biology * Biochemistry Figures at a glance * Figure 1: Decreased mitochondria, oxidative type I myofibres and exercise capacity in skeletal muscle of muscle-R1KO mice. –, Phosphorylation and amount of AMPK (), Ppargc1a, Esrra, Nrf1, Tfam, Cycs, mt-Co2, Mef2c, Acadm, Sod2, Cat and Slc2a4 mRNA levels (), PGC-1α protein levels (), mitochondrial content as assessed by mitochondrial DNA copy number (), amounts of troponin I (slow) protein (), ATPase (pH 4.3 for type I fibres) staining of soleus muscles (scale bars, 100 μm) (), quantification of type I fibres () based on fibre-type analyses (), exercise endurance (), β oxidation (), triglyceride content (), and TBARS () in skeletal muscle (–, –) obtained from control or muscle-R1KO after 5 h fasting. All values are presented as mean ± s.e.m. n = 5–12, *P < 0.05 and **P < 0.01 compared to control mice. * Figure 2: Mechanisms of abnormal glucose and insulin homeostasis in muscle-R1KO mice. –, Plasma glucose (, ) and plasma insulin () during an oral glucose tolerance test (OGTT) (1.5 g glucose per kg body weight) (, ) or during an insulin tolerance test (ITT) (0.25 U insulin per kg body weight) (), endogenous glucose production (EGP) (), rates of glucose disposal (Rd) () and glucose infusion rate (GIR) () during a hyperinsulinaemic-euglycaemic clamp study in control and muscle-R1KO mice. –, Phosphorylation of tyrosine (pTyr) (), Ser 302 () and Ser 636/639 () in IRS-1, phosphorylation and amount of Akt (), S6K1 () and JNK () in skeletal muscle treated with or without insulin (0.3 U per kg body weight) for 7.5 min in control and muscle-R1KO mice after 5 h fasting. IB, immunoblot; IP, immunoprecipitate. All values are presented as mean ± s.e.m. n = 6–15 from 3–5 independent experiments, *P < 0.05 and **P < 0.01 compared to control or as indicated. NS, not significant. * Figure 3: Adiponectin/AdipoR1 increase PGC-1α expression and activity, and mitochondrial biogenesis in C2C12 myocytes. –, Mitochondrial content as assessed by mitochondrial DNA copy number (, , ), Ppargc1a mRNA levels (), acetyl-lysine (Ac-Lys) levels checked on PGC-1α or Flag immunoprecipitates (, , ), NAD+/NADH ratio (, ) in C2C12 myocytes treated with adiponectin for the times indicated (), in C2C12 myocytes transfected with the indicated siRNA duplex (–), in C2C12 myocytes transfected with the wild-type or the 2A mutant form of PGC-1α (, ) or the R13 mutant form of PGC-1α () treated with 10 μg ml-1 adiponectin for 48 h (, , ) or for 1.5 h () or 2 h (, ), or in skeletal muscle from control or muscle-R1KO mice treated with or without adiponectin (, ). The supernatant was blotted against GAPDH as an input control (, , ). C2C12 myocytes were used after myogenic differentiation in all experiments. All values are presented as mean ± s.e.m. n = 5–10, *P < 0.05 and **P < 0.01 compared to control or unrelated siRNA or as indicated. * Figure 4: Adiponectin-induced Ca2+ influx by AdipoR1 in C2C12 myocytes and Xenopus oocytes. , Pseudocoloured images of changes in fura-2 before and after 1 min stimulation with adiponectin (30 μg ml-1). Red corresponds to the greatest response. The bottom trace demonstrates the average calcium response of C2C12 myocytes to 1-min stimulation with adiponectin along with application of 5 mM EGTA (black bar). The shaded region around the trace represents s.e.m. –, Adipor1 mRNA levels (), fura-2 calcium response () and their magnitude () of C2C12 myocytes transfected with unrelated siRNA duplex or AdipoR1 siRNA duplex to stimulation with 30 μg ml-1 adiponectin for 1 min. –, The amounts of AdipoR1 protein (), representative Ca2+-activated Cl- current traces () before (left) and after (right) 30-s application of adiponectin, and their magnitude () in Xenopus oocytes injected with or without Adipor1 cRNA in response to adiponectin (30 μg ml-1), and with or without application of 5 mM EGTA with depolarizing pulses of +100 mV. [Ca2+]i and [Ca2+]e! , intracellular and external Ca2+ concentration, respectively. All values are presented as mean ± s.e.m. n = 6–14, *P < 0.05 and **P < 0.01 compared to unrelated siRNA cells or control cells or as indicated. * Figure 5: Adiponectin-induced Ca2+ influx is required for CaMKK and AMPK activation and PGC-1α expression. , , Phosphorylation and amount of AMPK in C2C12 myocytes preincubated for 20 min with or without 5 mM EGTA and then treated for 5 min with adiponectin (30 μg ml-1) or ionomycin (1 μM), or for 1 h with AICAR (1 mM) (), or C2C12 myocytes transfected with the indicated siRNA duplex and then treated with 30 μg ml-1 adiponectin for 5 min (). , Amount of Ppargc1a mRNA in C2C12 myocytes preincubated for 1 h with AraA (0.5 mM) or for 6 h with STO-609 (1 μg ml-1) or for 20 min with EGTA (5 mM), and then treated for 1.5 h with or without adiponectin (10 μg ml-1). , Representative pseudocoloured images of changes in the fura-2 calcium response before and after 5 min stimulation with adiponectin (30 μg ml-1) in a soleus muscle from control mice (top) and muscle-R1KO mice (bottom). Red corresponds to the greatest response. Scale bars, 100 μm. , Trace demonstrates the calcium response of soleus muscle in the fields presented in . Ad! iponectin was applied during the indicated period. , The magnitude of fura-2 calcium response signals by 160-s adiponectin stimulation to soleus muscles. ΔF ratio indicates the change in the fluorescence ratio after adiponectin application. All values are presented as mean ± s.e.m. n = 5–10, *P < 0.05 and **P < 0.01 compared to control or unrelated siRNA cells or as indicated. * Figure 6: The effect of exercise on muscle-R1KO mice. –, The insulin resistance index (), area under the curves (AUC) of plasma glucose levels during the ITT (), mitochondrial content as assessed by mitochondrial DNA copy number (), and citrate synthase (CS) enzyme activity () in skeletal muscle of control and muscle-R1KO mice after 2 weeks exercise. The results are expressed as the percentage of the value in control littermates (, ). , Scheme illustrating the signal transduction of adiponectin/AdipoR1 in muscle cells. Both CaMKKβ and LKB1 are necessary for adiponectin-induced full AMPK activation. AMPK and SIRT1 are required for adiponectin/AdipoR1-induced PGC-1α activation. CaMKKβ activation by adiponectin-induced Ca2+ influx via AdipoR1 is required for adiponectin-induced increased PGC-1α expression. PGC-1α is required for mitochondrial biogenesis stimulated with adiponectin/AdipoR1. From these data, we conclude that adiponectin and AdipoR1 increase PGC-1α expression and activity by Ca2+ signalling and by AMPK and ! SIRT1, leading to increased mitochondrial biogenesis. We focused on the molecules that we have obtained direct evidence by both gain-of-function and loss-of-function experiments in vitro and in vivo, except for CaMK, which has already been reported to increase PGC-1α expression by other researchers39. AC, acetylation. All values are presented as mean ± s.e.m. n = 5–8, *P < 0.05 and **P < 0.01 compared to control mice or as indicated. Author information * Abstract * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Masato Iwabu, * Toshimasa Yamauchi & * Miki Okada-Iwabu Affiliations * Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, * Masato Iwabu, * Toshimasa Yamauchi, * Miki Okada-Iwabu, * Masaaki Funata, * Mamiko Yamaguchi, * Ryo Nakayama, * Naoto Kubota, * Iseki Takamoto, * Hironori Waki, * Kohjiro Ueki & * Takashi Kadowaki * Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center * Masato Iwabu, * Toshimasa Yamauchi & * Miki Okada-Iwabu * Department of Neurobiology, Graduate School of Medicine, * Shigeyuki Namiki & * Kenzo Hirose * Department of Pathology, Graduate School of Medicine, * Naoko Yamauchi & * Masashi Fukayama * Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan * Satoshi Ishii & * Takao Shimizu * Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan * Koji Sato & * Kazushige Touhara * Department of Integrated Biosciences, The University of Tokyo, Chiba 277-8562, Japan * Tatsuro Nakagawa & * Kazushige Touhara * Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan * Mitsuhisa Tabata & * Yuichi Oike * Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8577, Japan * Hitomi Ogata & * Kumpei Tokuyama * Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan * Yukiko K. Hayashi & * Ichizo Nishino Contributions M.I., M.O.-I., T.Y., K.S., T.N., M.F., M.Y., S.N., R.N., M.T., H.O., N.K., I.T., Y.K.H. and N.Y. performed experiments. T.K. and T.Y. conceived and supervised the study. K.T., T.S. and K.H. supervised the study. T.Y., T.K., M.I. and M.O-I. wrote the paper. All authors interpreted data. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Takashi Kadowaki (kadowaki-3im@h.u-tokyo.ac.jp) or * Toshimasa Yamauchi (tyamau-tky@umin.net) Supplementary information * Abstract * Author information * Supplementary information * Comments PDF files * Supplementary Information (1.4M) This file contains Supplementary Results, Supplementary Methods, Supplementary References and Supplementary Figures 1-20 with legends. Additional data
• Water ice and organics on the surface of the asteroid 24 Themis
  - Nature 464(7293):1320 (2010)
  Nature | Letter Water ice and organics on the surface of the asteroid 24 Themis * Humberto Campins1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kelsey Hargrove1 Search for this author in: * NPG journals * PubMed * Google Scholar * Noemi Pinilla-Alonso2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ellen S. Howell3 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael S. Kelley4 Search for this author in: * NPG journals * PubMed * Google Scholar * Javier Licandro5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * T. Mothé-Diniz7 Search for this author in: * NPG journals * PubMed * Google Scholar * Y. Fernández1 Search for this author in: * NPG journals * PubMed * Google Scholar * Julie Ziffer8 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1320–1321Date published:(29 April 2010)DOI:doi:10.1038/nature09029Received21 September 2009Accepted24 February 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 It has been suggested1, 2, 3 that Earth's current supply of water was delivered by asteroids, some time after the collision that produced the Moon (which would have vaporized any of the pre-existing water). So far, no measurements of water ice on asteroids4, 5 have been made, but its presence has been inferred from the comet-like activity of several small asteroids, including two members of the Themis dynamical family6. Here we report infrared spectra of the asteroid 24 Themis which show that ice and organic compounds are not only present on its surface but also prevalent. Infrared spectral differences between it and other asteroids make 24 Themis unique so far, and our identification of ice and organics agrees with independent results7 that rule out other compounds as possible sources of the observed spectral structure. The widespread presence of surface ice on 24 Themis is somewhat unexpected because of the relatively short lifetime of exposed ice at this distance (~3.2�! ��au) from the Sun. Nevertheless, there are several plausible sources, such as a subsurface reservoir that brings water to the surface through 'impact gardening' and/or sublimation. View full text Subject terms: * Astronomy * Astrophysics * Planetary sciences Author information * Author information * Supplementary information * Comments Affiliations * University of Central Florida, PO Box 162385, Orlando, Florida 32816-2385, USA * Humberto Campins, * Kelsey Hargrove & * Y. Fernández * NASA-Ames Research Center, Moffett Field, California 94035, USA * Noemi Pinilla-Alonso * NAIC-Arecibo Observatory, Arecibo, Puerto Rico 00612 * Ellen S. Howell * University of Maryland, College Park, Maryland 20742, USA * Michael S. Kelley * Instituto de Astrofísica de Canarias, Calle Vía Láctea s/n, E-38200 La Laguna, Spain * Javier Licandro * Department of Astrophysics, University of La Laguna, E-38205 La Laguna, Spain * Javier Licandro * Universidade Federal Do Rio De Janeiro, RJ 20080-090, Brazil * T. Mothé-Diniz * University of Southern Maine, Department of Physics, Portland, Maine 04104, USA * Julie Ziffer Contributions H.C. and K.H. carried out the observations, the data reduction and the interpretation of the results. N.P.-A. carried out the spectral modelling and interpretation. E.S.H. provided software and participated extensively in the data reduction. M.S.K. and Y.F. provided software and participated extensively in the thermal modelling of the asteroid. T.M.-D. carried out the spectral comparison with meteorites and mineral samples. J.L. and J.Z. contributed to the interpretation of the spectroscopic results. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Humberto Campins (campins@physics.ucf.edu.) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (219K) This file contains Supplementary Information comprising: Observations and Data Reduction; Spectral Modelling; Supplementary Table 1; Supplementary References and Supplementary Figures S1-S2 with legends. Additional data
• Detection of ice and organics on an asteroidal surface
  - Nature 464(7293):1322 (2010)
  Nature | Letter Detection of ice and organics on an asteroidal surface * Andrew S. Rivkin1 Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua P. Emery2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1322–1323Date published:(29 April 2010)DOI:doi:10.1038/nature09028Received22 September 2009Accepted24 February 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 observations, including the discovery1 in typical asteroidal orbits of objects with cometary characteristics (main-belt comets, or MBCs), have blurred the line between comets and asteroids, although so far neither ice nor organic material has been detected on the surface of an asteroid or directly proven to be an asteroidal constituent. Here we report the spectroscopic detection of water ice and organic material on the asteroid 24 Themis, a detection that has been independently confirmed2. 24 Themis belongs to the same dynamical family as three of the five known MBCs, and the presence of ice on 24 Themis is strong evidence that it also is present in the MBCs. We conclude that water ice is more common on asteroids than was previously thought and may be widespread in asteroidal interiors at much smaller heliocentric distances than was previously expected. View full text Subject terms: * Planetary sciences Figures at a glance * Figure 1: The reflectance spectra of 24 Themis are well fitted by a mixture of ice-coated pyroxene grains and amorphous carbon. The spectrum of 24 Themis from 2008 (filled symbols) is plotted (binned ×6) along with an example spectral model that includes a thin coating of water ice on surface grains (grey line). The 24 Themis data are binned to lower spectral resolution and plotted as geometric albedo. The model is an intimate mixture containing 29% pyroxene coated with a 0.045-μm-thick layer of water ice and 71% amorphous carbon6, 14. All grains have a diameter of 30 μm. Error bars, 1 sample s.d. * Figure 2: Organic material is present on the surface of 24 Themis. The spectrum of 24 Themis from 2008 has been divided by the model shown in Fig. 1 to identify residual absorptions (open symbols). A residual absorption band centred near 3.4 μm and with a width of ~0.2 μm is well matched by complex organic materials. The thick black line is ice tholin (the residual of an irradiated mixture of water ice and ethane; calculated from optical constants; ref. 9). Offset from the ice tholin and the spectrum/model data by 0.1 units, the dashed line is asphaltite15, the heavy grey line is the carbonaceous meteorite Cold Bokkeveld (a slope from hydrated silicates has been removed; ref. 11) and the thin black line is an average of six polycyclic aromatic hydrocarbons (ref. 10). Absorption features in organic materials near 3.4 and 3.5 μm are typically –CH2 and –CH3 stretch bands, whereas those near 3.3 μm in the polycyclic aromatic hydrocarbons are aromatic stretch bands. Error bars, 1 sample s.d. Author information * Author information * Supplementary information * Comments Affiliations * Johns Hopkins University Applied Physics Laboratory, Laurel, Maryland 20723, USA * Andrew S. Rivkin * Earth and Planetary Science Department, University of Tennessee, Knoxville, Tennessee 37996, USA * Joshua P. Emery Contributions A.S.R. performed all of the telescopic observations and reduced all of the data, including the thermal flux removal. J.P.E. performed the spectral modelling of the ice and organics and performed spectral library searches. The authors contributed equally to interpretation and analysis. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Andrew S. Rivkin (andy.rivkin@jhuapl.edu.) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (2.4M) This file contains Supplementary Information and Data comprising: Consideration of alternate explanations for 3.1-µm absorption, Supplementary References, Supplementary Table S1 and Supplementary Figures S1-S4 with legends. Additional data
• Dipolar collisions of polar molecules in the quantum regime
  - Nature 464(7293):1324 (2010)
  Nature | Letter Dipolar collisions of polar molecules in the quantum regime * K.-K. Ni1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * S. Ospelkaus1, 3, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * D. Wang1 Search for this author in: * NPG journals * PubMed * Google Scholar * G. Quéméner1 Search for this author in: * NPG journals * PubMed * Google Scholar * B. Neyenhuis1 Search for this author in: * NPG journals * PubMed * Google Scholar * M. H. G. de Miranda1 Search for this author in: * NPG journals * PubMed * Google Scholar * J. L. Bohn1 Search for this author in: * NPG journals * PubMed * Google Scholar * J. Ye1 Search for this author in: * NPG journals * PubMed * Google Scholar * D. S. Jin1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:464,Pages:1324–1328Date published:(29 April 2010)DOI:doi:10.1038/nature08953Received15 January 2010Accepted23 February 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 Ultracold polar molecules offer the possibility of exploring quantum gases with interparticle interactions that are strong, long-range and spatially anisotropic. This is in stark contrast to the much studied dilute gases of ultracold atoms, which have isotropic and extremely short-range (or 'contact') interactions. Furthermore, the large electric dipole moment of polar molecules can be tuned using an external electric field; this has a range of applications such as the control of ultracold chemical reactions1, the design of a platform for quantum information processing2, 3, 4 and the realization of novel quantum many-body systems5, 6, 7, 8. Despite intense experimental efforts aimed at observing the influence of dipoles on ultracold molecules9, only recently have sufficiently high densities been achieved10. Here we report the experimental observation of dipolar collisions in an ultracold molecular gas prepared close to quantum degeneracy. For modest values of an applied ! electric field, we observe a pronounced increase in the loss rate of fermionic potassium–rubidium molecules due to ultracold chemical reactions. We find that the loss rate has a steep power-law dependence on the induced electric dipole moment, and we show that this dependence can be understood in a relatively simple model based on quantum threshold laws for the scattering of fermionic polar molecules. In addition, we directly observe the spatial anisotropy of the dipolar interaction through measurements of the thermodynamics of the dipolar gas. These results demonstrate how the long-range dipolar interaction can be used for electric-field control of chemical reaction rates in an ultracold gas of polar molecules. Furthermore, the large loss rates in an applied electric field suggest that creating a long-lived ensemble of ultracold polar molecules may require confinement in a two-dimensional trap geometry to suppress the influence of the attractive, 'head-to-tail', dipo! lar interactions11, 12, 13, 14. View full text Subject terms: * Applied physics * Engineering Figures at a glance * Figure 1: Two-body inelastic loss for fermionic polar molecules. , We extract the inelastic loss rate coefficient, β, from a fit (solid lines) to the measured time evolution of the trapped molecular gas density. Data are shown here for induced dipole moments of d = 0.08 D (open triangles) and d = 0.19 D (filled circles), and T0 = 300 nK. , Data points show β/T0 plotted as a function of d. The dashed line shows a fit to a simple model based on the quantum threshold behaviour for tunnelling through a dipolar-interaction-modified p-wave barrier (see text). The solid line shows the result of a more complete quantum scattering calculation. Inset, the calculated dependence of d on the applied electric field, E. Error bars, 1 s.d. * Figure 2: A p-wave centrifugal barrier for dipolar collisions between fermionic polar molecules. , The effective intermolecular potential for fermionic molecules at zero electric field. At intermediate intermolecular separation, two colliding molecules are repelled by a large centrifugal barrier for p-wave collisions. , For a relatively small applied electric field, the spatially anisotropic dipolar interactions reduce the barrier for head-to-tail collisions and increase the barrier for side-by-side collisions. , Height of the p-wave barrier as a function of dipole moment. Dipolar interactions lower the centrifugal barrier for ml = 0 collisions (V0) and raise the barrier for ml = ±1 collisions (V1). The lowering of the ml = ±1 barrier at very large dipole moments is due to mixing with higher-l partial waves (l = 3, 5, 7, …). * Figure 3: Normalized fractional heating rate, /n, as a function of dipole moment. The heating rate is extracted using a linear fit to the initial temperature increase and is then normalized by the initial density and temperature of the ensemble. The solid line is the expected heating rate, given by / n = (β/T0)/12 (see text). Typical initial conditions for these data are n = 0.3 × 1012 cm-3 and T0 = 0.5 μK, and the absolute heating rate ranges from 0.1 μK s-1 at zero electric field to 2 μK s-1 at our highest electric fields. Error bars, 1 s.d. * Figure 4: Apparent cross-dimensional rethermalization in the polar molecule gas. Shown as a function of dipole moment, d, for Tz > Tx (–) and Tz < Tx (–). The experimental data reveal a striking difference between heating the gas in the vertical direction (–) and heating it in the horizontal directions (–), and thus provide evidence for the strong anisotropic characteristic of dipolar interactions (see text). The electric field is applied along the z direction. Error bars show 1-s.d. uncertainties for a few example points. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * K.-K. Ni & * S. Ospelkaus Affiliations * JILA, NIST and University of Colorado, Department of Physics, University of Colorado, Boulder, Colorado 80309-0440, USA * K.-K. Ni, * S. Ospelkaus, * D. Wang, * G. Quéméner, * B. Neyenhuis, * M. H. G. de Miranda, * J. L. Bohn, * J. Ye & * D. S. Jin * Present address: Max Planck Institute for Quantum Optics, D-85748 Garching, Germany. * S. Ospelkaus Contributions The experimental work and data analysis were done by K.-K.N., S.O., D.W., B.N., M.H.G.M., J.Y. and D.S.J. Theoretical calculations of the inelastic loss rates were done by G.Q. and J.L.B. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * D. S. Jin (jin@jilau1.colorado.edu) or * J. Ye (ye@jila.colorado.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (82K) This file contains Supplementary Information and Data comprising: Heating due to two-body inelastic p-wave collisions. Additional data
• A molecular molybdenum-oxo catalyst for generating hydrogen from water
  - Nature 464(7293):1329 (2010)
  Nature | Letter A molecular molybdenum-oxo catalyst for generating hydrogen from water * Hemamala I. Karunadasa1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher J. Chang1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey R. Long1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:464,Pages:1329–1333Date published:(29 April 2010)DOI:doi:10.1038/nature08969Received17 November 2009Accepted26 February 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 A growing awareness of issues related to anthropogenic climate change and an increase in global energy demand have made the search for viable carbon-neutral sources of renewable energy one of the most important challenges in science today1. The chemical community is therefore seeking efficient and inexpensive catalysts that can produce large quantities of hydrogen gas from water1, 2, 3, 4, 5, 6, 7. Here we identify a molybdenum-oxo complex that can catalytically generate gaseous hydrogen either from water at neutral pH or from sea water. This work shows that high-valency metal-oxo species can be used to create reduction catalysts that are robust and functional in water, a concept that has broad implications for the design of 'green' and sustainable chemistry cycles. View full text Subject terms: * Environmental science Figures at a glance * Figure 1: Reaction of [(PY5Me2)Mo(CF3SO3)]1+ with water to form [(PY5Me2)MoO]2+ and release H2. The generation of H2 was confirmed by mass spectrometry, and the oxo ligand was shown to originate from water through observation of the expected isotopic shift for νMo = O in the infrared spectrum, using H218O. The structures depicted are the results of single-crystal X-ray analyses of compounds and , with green, yellow, light blue, red, blue and grey spheres representing Mo, S, F, O, N and C atoms, respectively; H atoms are omitted for clarity. Selected interatomic distances and angles for compounds and are as follows. Mo–O: 2.117(9) Å, 1.685(9) Å; mean Mo–Nequatorial: 2.14(2) Å, 2.154(3) Å; Mo–Naxial: 2.097(9) Å, 2.297(8) Å; mean O–Mo–Nequatorial: 93(3)°, 98(1)°; O–Mo–Naxial: 176.2(4)°, 179(1)°; mean Nequatorial–Mo–Nequatorial: 90(10)°, 89(8)°. * Figure 2: Cyclic voltammograms of compounds 2 and 7. , A 5 mM acetonitrile solution of . , A 2 mM acetonitrile solution of compound . , A 4.2 µM aqueous solution of compound . Measurements in and were performed using 0.1 M (Bu4N)PF6 as the electrolyte with a scan rate of 100 mV s-1, whereas the measurement in was performed in 1 M KCl with a scan rate of 100 mV s-1. In and , red lines indicate the initial scans and black lines indicate subsequent scans. * Figure 3: Electrochemical data for a 7.7 µM solution of [(PY5Me2)MoO](PF6)2 (7) in a 0.6 M phosphate buffer at pH 7. , Cyclic voltammograms of the buffer with (red line) and without (blue line) compound at a scan rate of 50 mV s-1. , Charge build-up versus time at various overpotentials. , Turnover frequency versus overpotential. The background solvent activity has been subtracted from the plots in and . Overpotential = |applied potential minus E(pH 7)|. Turnover frequency calculations assume (see Supplementary Fig. 6) that every electron is used for the generation of hydrogen, and provide only a lower bound, given that not all catalyst molecules are in proximity to the electrode surface at a given time. * Figure 4: Extended electrolysis. Electrolysis data for a 2 μM solution of [(PY5Me2)MoO](PF6)2 (compound ) in a 3 M pH 7 phosphate buffer, showing charge build-up and turnover number versus time (red circles), and data for the buffer solution alone showing charge build-up versus time (blue circles) with the cell operating at a potential of -1.40 V versus SHE. * Figure 5: Speculative electrocatalytic cycle for the reduction of water to release hydrogen and hydroxide anions. Although formal metal oxidation states are given for electron counting purposes, it should be recognized that there is probably significant delocalization of the added electrons onto the PY5Me2 ligand. An alternative cycle, in which each reduction step is immediately followed by or even coupled to a proton transfer, is depicted in Supplementary Fig. 7. Author information * Author information * Supplementary information * Comments Affiliations * Department of Chemistry, University of California, Berkeley, California 94720, USA * Hemamala I. Karunadasa, * Christopher J. Chang & * Jeffrey R. Long * Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA * Hemamala I. Karunadasa, * Christopher J. Chang & * Jeffrey R. Long * Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA * Christopher J. Chang Contributions H.I.K., C.J.C. and J.R.L. planned the research, and H.I.K. performed the experiments. H.I.K., C.J.C. and J.R.L. prepared the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Christopher J. Chang (chrischang@berkeley.edu) or * Jeffrey R. Long (jrlong@berkeley.edu) X-ray coordinates from the crystal structure determinations have been deposited with the Cambridge Crystallographic Data Centre with reference codes 720362 (compound ), 720363 (compound ), 753993 (compound ), 753992 (compound ) and 720364 (compound ). Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (742K) This file contains Supplementary Methods, a Supplementary Discussion, Supplementary Tables S1-S2, Supplementary Figures S1-S9 with legends and References. Additional data
• The central role of diminishing sea ice in recent Arctic temperature amplification
  - Nature 464(7293):1334 (2010)
  Nature | Letter The central role of diminishing sea ice in recent Arctic temperature amplification * James A. Screen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ian Simmonds1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1334–1337Date published:(29 April 2010)DOI:doi:10.1038/nature09051Received10 November 2009Accepted12 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 rise in Arctic near-surface air temperatures has been almost twice as large as the global average in recent decades1, 2, 3—a feature known as 'Arctic amplification'. Increased concentrations of atmospheric greenhouse gases have driven Arctic and global average warming1, 4; however, the underlying causes of Arctic amplification remain uncertain. The roles of reductions in snow and sea ice cover5, 6, 7 and changes in atmospheric and oceanic circulation8, 9, 10, cloud cover and water vapour11, 12 are still matters of debate. A better understanding of the processes responsible for the recent amplified warming is essential for assessing the likelihood, and impacts, of future rapid Arctic warming and sea ice loss13, 14. Here we show that the Arctic warming is strongest at the surface during most of the year and is primarily consistent with reductions in sea ice cover. Changes in cloud cover, in contrast, have not contributed strongly to recent warming. Increases in atmos! pheric water vapour content, partly in response to reduced sea ice cover, may have enhanced warming in the lower part of the atmosphere during summer and early autumn. We conclude that diminishing sea ice has had a leading role in recent Arctic temperature amplification. The findings reinforce suggestions that strong positive ice–temperature feedbacks have emerged in the Arctic15, increasing the chances of further rapid warming and sea ice loss, and will probably affect polar ecosystems, ice-sheet mass balance and human activities in the Arctic2. View full text Subject terms: * Climate science * Environmental science Figures at a glance * Figure 1: Surface amplification of temperature trends, 1989–2008. Temperature trends averaged around circles of latitude for winter (December–February; ), spring (March–May; ), summer (June–August; ) and autumn (September–November; ). The black contours indicate where trends differ significantly from zero at the 99% (solid lines) and 95% (dotted lines) confidence levels. The line graphs show trends (same units as in colour plots) averaged over the lower part of the atmosphere (950–1,000 hPa; solid lines) and over the entire atmospheric column (300–1,000 hPa; dotted lines). Red shading indicates that the lower atmosphere has warmed faster than the atmospheric column as whole. Blue shading indicates that the lower atmosphere has warmed slower than the atmospheric column as a whole. * Figure 2: Temperature trends linked to changes in sea ice. Temperature trends over the 1989–2008 period averaged around circles of latitude for winter (), spring (), summer () and autumn (). The trends are derived from projections of the temperature field on the sea ice time series (Methods Summary). The black contours indicate where the ice–temperature regressions differ significantly from zero at the 99% (solid lines) and 95% (dotted lines) uncertainty levels. * Figure 3: Impacts of cloud-cover changes on the net surface radiation. Mean net surface radiation (short-wave plus long-wave) over the 1989–2008 period under cloudy-sky (solid lines) and clear-sky (dotted lines) conditions. Means are averaged around circles of latitude for winter (), spring (), summer () and autumn (). The fluxes are defined as positive in the downward direction. Red shading indicates that the presence of cloud has a net warming effect at the surface. Blue shading indicates that the presence of cloud has a net cooling effect at the surface. The dashed lines show the approximate edge of the Arctic basin. Symbols show latitudes where increases (triangles) and decreases (crosses) in total cloud cover significant at the 99% uncertainty level are found. * Figure 4: Atmospheric moisture trends, 1989–2008. Specific humidity trends averaged around circles of latitude for June–October: total trends (); trends that are linked to changes in sea ice (). The black contours indicate where trends () or humidity–ice regressions () differ significantly from zero at the 99% (solid lines) and 95% (dotted lines) uncertainty levels. In , triangles show latitudes where increases in the surface latent-heat flux significant at the 99% uncertainty level are found. Author information * Author information * Supplementary information * Comments Affiliations * School of Earth Sciences, University of Melbourne, Melbourne, Victoria 3010, Australia * James A. Screen & * Ian Simmonds Contributions The analysis was performed and the manuscript written by J.A.S. Both authors contributed with ideas and discussions. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * James A. Screen (screenj@unimelb.edu.au.) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (249K) This file contains a Supplementary Discussion, Supplementary Figures 1-2 with legends, Supplementary Table 1 and References. Additional data
• Exceptional dinosaur fossils show ontogenetic development of early feathers
  - Nature 464(7293):1338 (2010)
  Nature | Letter Exceptional dinosaur fossils show ontogenetic development of early feathers * Xing Xu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaoting Zheng2 Search for this author in: * NPG journals * PubMed * Google Scholar * Hailu You3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:464,Pages:1338–1341Date published:(29 April 2010)DOI:doi:10.1038/nature08965Received18 December 2009Accepted24 February 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 discoveries of feathered dinosaur specimens have greatly improved our understanding of the origin and early evolution of feathers, but little information is available on the ontogenetic development of early feathers1, 2, 3, 4, 5, 6, 7. Here we describe an early-juvenile specimen and a late-juvenile specimen, both referable to the oviraptorosaur Similicaudipteryx8, recovered from the Lower Cretaceous Yixian Formation of western Liaoning, China9. The two specimens have strikingly different remiges and rectrices, suggesting that a radical morphological change occurred during feather development, as is the case for modern feathers10. However, both the remiges and the rectrices are proximally ribbon-like in the younger specimen but fully pennaceous in the older specimen, a pattern not known in any modern bird10. In combination with the wide distribution of proximally ribbon-like pennaceous feathers and elongate broad filamentous feathers among extinct theropods, this find ! suggests that early feathers were developmentally more diverse than modern ones and that some developmental features, and the resultant morphotypes, have been lost in feather evolution. View full text Subject terms: * Evolution * Developmental biology * Palaeontology * Zoology Figures at a glance * Figure 1: Feathers of two Similicaudipteryx specimens. , Slab of specimen STM4-1; , rectrices of STM4-1 (slab); , primary remiges of STM4-1 (counterslab). , Similicaudipteryx specimen STM22-6; , rectrices of STM22-6; , remiges of STM22-6. * Figure 2: Elongate broad filamentous feathers in selected non-avian theropods. , Series of posterior caudal vertebrae and associated integumentary structures in a specimen of the therizinosauroid Beipiaosaurus (IVPP V11559); , close-up of elongate broad filamentous feathers in IVPP V11559; , series of posterior caudal vertebrae and associated integumentary structures in a large specimen that may represent a tyrannosauroid (STM1-5); , close-up of EBFFs in STM1-5. * Figure 3: Known feather morphotypes across a simplified dinosaurian phylogeny. Many dinosaurian groups, such as most ornithischians, the sauropodomorphs and the basal theropods, are not included in this simplified dinosaurian cladogram. The available specimens suggest that members of these groups have scaly skin, but the possibility that they are partially covered by filamentous integumentary structures cannot be completely excluded. Preservational factors make it difficult to observe the detailed structure of the filamentous feathers in available specimens of compsognathids, tyrannosauroids, and therizinosauroids, and thus we use a '?' to indicate uncertainty regarding the presence of morphotypes 1, 3, 4 and 5 in these groups. On the basis of the anatomical, ontogenetic and phylogenetic distribution patterns of known feather morphotypes among non-avian dinosaurs and early birds, morphotypes 1, 2 and 7 are inferred to have been lost in feather evolution, along with their associated developmental mechanisms. (For a more detailed interpretation, see ! Supplementary Information.) Author information * Author information * Supplementary information * Comments Affiliations * Key Laboratory of Evolutionary Systematics of Vertebrates, Institute of Vertebrate Paleontology & Paleoanthropology, Chinese Academy of Sciences, 142 Xiwai Street, Beijing 100044, China * Xing Xu * Shandong Tianyu Museum of Nature, Pingyi, Shandong 273300, China * Xiaoting Zheng * Institute of Geology, Chinese Academy of Geological Sciences, 26 Baiwanzhuang Road, Beijing 100037, China * Hailu You Contributions X.X. and X.Z. designed the project, X.X., X.Z. and H.Y. performed the research, and X.X. wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Xing Xu (xingxu@vip.sina.com) or * Xiaoting Zheng (ty4291666@163.com) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (544K) This file contains Supplementary Information comprising: Preservation of STM4-1 and STM22-6; Identification of STM4-1 and STM22-6; Additional description of PRPFs (proximal ribbon-like pennaceous feathers) and EBFFs (elongated broad filament feathers); Homologies of EBFFs and other primitive feathers; Major feather morphotypes documented in non-avian theropods; Supplementary Table 1; Supplementary Figures 1-3 with legends and References. Additional data
• Evolution of self-compatibility in Arabidopsis by a mutation in the male specificity gene
  - Nature 464(7293):1342 (2010)
  Nature | Letter Evolution of self-compatibility in Arabidopsis by a mutation in the male specificity gene * Takashi Tsuchimatsu1, 2, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Keita Suwabe3, 4, 10 Search for this author in: * NPG journals * PubMed * Google Scholar * Rie Shimizu-Inatsugi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sachiyo Isokawa3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Pavlos Pavlidis6 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Städler7 Search for this author in: * NPG journals * PubMed * Google Scholar * Go Suzuki8 Search for this author in: * NPG journals * PubMed * Google Scholar * Seiji Takayama9 Search for this author in: * NPG journals * PubMed * Google Scholar * Masao Watanabe3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Kentaro K. Shimizu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:464,Pages:1342–1346Date published:(29 April 2010)DOI:doi:10.1038/nature08927Received03 August 2009Accepted17 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 Ever since Darwin's pioneering research, the evolution of self-fertilisation (selfing) has been regarded as one of the most prevalent evolutionary transitions in flowering plants1, 2. A major mechanism to prevent selfing is the self-incompatibility (SI) recognition system, which consists of male and female specificity genes at the S-locus and SI modifier genes2, 3, 4. Under conditions that favour selfing, mutations disabling the male recognition component are predicted to enjoy a relative advantage over those disabling the female component, because male mutations would increase through both pollen and seeds whereas female mutations would increase only through seeds5, 6. Despite many studies on the genetic basis of loss of SI in the predominantly selfing plant Arabidopsis thaliana7, 8, 9, 10, 11, 12, 13, 14, 15, it remains unknown whether selfing arose through mutations in the female specificity gene (S-receptor kinase, SRK), male specificity gene (S-locus cysteine-rich pro! tein, SCR; also known as S-locus protein 11, SP11) or modifier genes, and whether any of them rose to high frequency across large geographic regions. Here we report that a disruptive 213-base-pair (bp) inversion in the SCR gene (or its derivative haplotypes with deletions encompassing the entire SCR-A and a large portion of SRK-A) is found in 95% of European accessions, which contrasts with the genome-wide pattern of polymorphism in European A. thaliana16, 17. Importantly, interspecific crossings using Arabidopsis halleri as a pollen donor reveal that some A. thaliana accessions, including Wei-1, retain the female SI reaction, suggesting that all female components including SRK are still functional. Moreover, when the 213-bp inversion in SCR was inverted and expressed in transgenic Wei-1 plants, the functional SCR restored the SI reaction. The inversion within SCR is the first mutation disrupting SI shown to be nearly fixed in geographically wide samples, and its prevalence! is consistent with theoretical predictions regarding the evol! utionary advantage of mutations in male components. View full text Subject terms: * Evolution * Genomics * Genetics * Plant sciences Figures at a glance * Figure 1: The relationship between population structure and haplogroup frequencies of the S-locus and flanking genes, PUB8 and ARK3. In European A. thaliana, there are two distinct haplogroups at the S-locus (A and C) and two distinct haplogroups for both ARK3 and PUB8 (named E and W). Four clusters in Europe are based on ref. 17 ('Western', 'Contact zone', 'Eastern' and 'Northern'; Supplementary Note 1 and Supplementary Table 1). The schematic genomic structure depicted along the top of the figure is based on the genomic sequence of Col-0 (GenBank accession number NC_003075). The correlation between haplogroup and population structure is statistically significant for ARK3 and PUB8, but not for the S-locus (see text). * Figure 2: Disrupted SCR-A in A. thaliana. , Schematic genomic structures of SCR-A of A. halleri and A. thaliana (Col-0). For the Col-0 structure, grey triangles denote the locations of deletions and white triangles denote the locations of insertions. All of these indels (insertions and deletions) are located in the intron and there are no disruptive mutations in the exons, except for a 213-bp inversion and a 14-bp duplication. The 14-bp duplication was found in several accessions, including Col-0, but not in others (Nok-0 and Pog-0; see also Supplementary Note 1). , Alignment of predicted amino acid sequences of SCR-A of A. halleri and Col-0, SCR-B of Cvi-0, two SCR sequences of A. lyrata7 and SCR-A-Col-0-restored, which is the full-length ORF reconstructed by inverting the 213-bp inversion and deleting the 14-bp duplication. The eight conserved cysteine residues are depicted in red; asterisks denote stop codons. * Figure 3: Interspecific crosses between A. halleri and A. thaliana. , Incompatible and compatible reactions on the stigma. Crosses were carried out between A. halleri bearing haplogroup A and A. thaliana bearing an intact SRK-A of haplogroup A (Wei-1); between A. halleri bearing a non-A haplogroup and A. thaliana with intact SRK-A (Wei-1); and between A. halleri bearing haplogroup A and A. thaliana with degenerated SRK-A (Sha; see text). A bundle of pollen tubes indicate a compatible reaction (arrow), whereas no or few pollen tubes indicate incompatible reactions. Scale bars, 0.1 mm. , Dependence of the incompatible phenotype on developmental stage in Old-1 and Wei-1. We confirmed that pistil length (treated as a continuous variable; Supplementary Note 2) was significantly influenced by developmental stage, that is, the time after the beginning of stage 13 (P < 2.0 × 10-16, by Generalized Linear Model (GLM); Supplementary Fig. 8). At this stage, flowers start to open and their stamens were removed experimentally. Red lines indicat! e the number of samples plotted at the same position (sunflower-plot). Binomial regressions based on GLM are shown as black lines (Old-1: P = 0.0001, Wei-1: P = 0.001). The light blue area indicates the mean length of pistils (± s.d.) when anthers would touch the stigma autonomously, which was observed using unmanipulated flowers with intact stamens (Old-1: n = 6; Wei-1: n = 8). * Figure 4: Restoration of functional SCR-A results in self-incompatibility and the prevention of selfing. , Inhibited growth of pollen tubes on the stigma of a selfed pistil of Wei-1-SI-2. , Growth of pollen tubes in the stigma of a pistil of Wei-1-SI-2 pollinated with pollen from Wei-1 (wild-type, non-functional SCR-A). An arrow indicates a bundle of pollen tubes. , , Scale bars, 0.1 mm. , Inflorescences of the transgenic Wei-1-SI-2 plant and a wild-type Wei-1 plant (WT). Scale bar, 1 cm. , Comparison of number of seeds per silique resulting from selfing of the transgenic Wei-1-SI-2 plant and a wild-type Wei-1 plant. The number of seeds was significantly reduced in the transgenic plant (Mann–Whitney U test, nwild-type = 30, nWei-1-SI-2 = 30, P = 3.57 × 10-11). , Comparison of silique length resulting from selfing of the transgenic Wei-1-SI-2 plant and a wild-type Wei-1 plant. Silique length was significantly reduced in the transgenic plant (Mann–Whitney U test, nwild-type = 30, nWei-1-SI-2 = 30, P = 1.91 × 10-11). , , Bars represent the median, boxes the inter! quartile range and whiskers extend out to 1.5 times the interquartile range. Accession codes * Accession codes * Author information * Supplementary information * Comments Primary accessions GenBank * NC_003075 * GU723782 * GU723953 Author information * Accession codes * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Takashi Tsuchimatsu & * Keita Suwabe Affiliations * Institute of Plant Biology, University Research Priority Program in Systems Biology/Functional Genomics & Zürich-Basel Plant Science Center, University of Zurich, Zollikerstrasse 107, CH-8008 Zurich, Switzerland * Takashi Tsuchimatsu, * Rie Shimizu-Inatsugi & * Kentaro K. Shimizu * Department of General Systems Studies, University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo 153-8902, Japan * Takashi Tsuchimatsu * Graduate School of Life Sciences, Tohoku University, Katahira, Sendai 980-8577, Japan * Keita Suwabe, * Sachiyo Isokawa & * Masao Watanabe * Graduate School of Bioresources, Mie University, Tsu 514-8507, Japan * Keita Suwabe * Faculty of Science, Tohoku University, Aoba, Sendai 980-8578, Japan * Sachiyo Isokawa & * Masao Watanabe * Section of Evolutionary Biology, BioCenter, University of Munich (LMU), Grosshaderner Strasse 2, D-82152 Planegg-Martinsried, Germany * Pavlos Pavlidis * Plant Ecological Genetics, Institute of Integrative Biology, ETH Zurich, Universitätstrasse 16, CH-8092 Zurich, Switzerland * Thomas Städler * Division of Natural Science, Osaka Kyoiku University, Kashiwara 582-8582, Japan * Go Suzuki * Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma 630-0101, Japan * Seiji Takayama Contributions T.T., K.S., M.W. and K.K.S. conceived and designed the study; T.T., R.S.-I. and K.K.S. performed sequencing, genotyping and crossing experiments; T.T., P.P., T.S. and K.K.S. conducted molecular population genetic analysis; K.S., S.I., S.T. and M.W. conducted transgenic analysis; T.T., K.S., G.S., T.S., M.W. and K.K.S. wrote the paper. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Kentaro K. Shimizu (shimizu@botinst.uzh.ch) or * Masao Watanabe (nabe@ige.tohoku.ac.jp) Sequence data have been deposited to GenBank under accession numbers GU723782–GU723953. Supplementary information * Accession codes * Author information * Supplementary information * Comments PDF files * Supplementary Information (1.6M) This file contains Supplementary Notes 1-4, Supplementary Tables 1-5 and Supplementary Figures 1-11 with legends. Additional data
• A role for host–parasite interactions in the horizontal transfer of transposons across phyla
  - Nature 464(7293):1347 (2010)
  Nature | Letter A role for host–parasite interactions in the horizontal transfer of transposons across phyla * Clément Gilbert1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah Schaack1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * John K. Pace II1 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul J. Brindley2 Search for this author in: * NPG journals * PubMed * Google Scholar * Cédric Feschotte1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1347–1350Date published:(29 April 2010)DOI:doi:10.1038/nature08939Received26 November 2009Accepted18 February 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 Horizontal transfer (HT), or the passage of genetic material between non-mating species, is increasingly recognized as an important force in the evolution of eukaryotic genomes1, 2. Transposons, with their inherent ability to mobilize and amplify within genomes, may be especially prone to HT3, 4, 5, 6, 7. However, the means by which transposons can spread across widely diverged species remain elusive. Here we present evidence that host–parasite interactions have promoted the HT of four transposon families between invertebrates and vertebrates. We found that Rhodnius prolixus, a triatomine bug feeding on the blood of various tetrapods and vector of Chagas' disease in humans, carries in its genome four distinct transposon families that also invaded the genomes of a diverse, but overlapping, set of tetrapods. The bug transposons are ~98% identical and cluster phylogenetically with those of the opossum and squirrel monkey, two of its preferred mammalian hosts in South Americ! a. We also identified one of these transposon families in the pond snail Lymnaea stagnalis, a cosmopolitan vector of trematodes infecting diverse vertebrates, whose ancestral sequence is nearly identical and clusters with those found in Old World mammals. Together these data provide evidence for a previously hypothesized role of host–parasite interactions in facilitating HT among animals3, 7. Furthermore, the large amount of DNA generated by the amplification of the horizontally transferred transposons supports the idea that the exchange of genetic material between hosts and parasites influences their genomic evolution. View full text Subject terms: * Evolution * Genetics * Genomics Figures at a glance * Figure 1: Taxonomic distribution and age of SPIN, OC1, ET and hAT1. , Distribution of the elements among 102 animal genomes for which whole genome sequences are available. Branch lengths of the tree are proportional to time and tick marks illustrate the timing of amplification for each element. The period 60–20 Myr ago is shaded in grey in mammals (dashed line at 40 Myr ago) to facilitate the comparison of the amplification times between species. , Venn diagram illustrating the overlap in taxonomic distribution of the four elements relative to all species for which whole genome sequence data are publicly available. * Figure 2: Biogeographic and phylogenetic evidence supporting horizontal transfers of SPIN and OC1 transposons on multiple continents. , Map showing the likely geographic distribution of the taxa that contain these elements at the time of the transfers (Methods). , , Maximum-likelihood phylogenies of SPIN and OC1 consensuses, respectively; bootstrap values above 70 are shown. , Alignment of representative autonomous (Auto) and non-autonomous (NA) OC1 consensus sequences, showing portions of the highly conserved 5′ and 3′ termini (black) and the 5′ subterminal region in Old World (light grey) and New World (dark grey) species. All nucleotide positions are with reference to the bushbaby consensus. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Clément Gilbert & * Sarah Schaack Affiliations * Department of Biology, University of Texas, Arlington, Texas 76019, USA * Clément Gilbert, * Sarah Schaack, * John K. Pace II & * Cédric Feschotte * Department of Microbiology, Immunology & Tropical Medicine, George Washington University Medical Center, Washington DC 20037, USA * Paul J. Brindley Contributions C.G., S.S. and C.F. designed research, performed research, and analysed data. J.K.P. contributed data and perl scripts. P.J.B. contributed reagents and materials. C.G., S.S. and C.F. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Cédric Feschotte (cedric@uta.edu.) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (1.9M) This file contains Supplementary Tables 1-5 and Supplementary Figures 1-6 with legends and references. * Supplementary Data (761K) This file contains Supplementary Datasets 1-3. Additional data
• Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis
  - Nature 464(7293):1351 (2010)
  Nature | Letter Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis * Sergio E. Baranzini1 Search for this author in: * NPG journals * PubMed * Google Scholar * Joann Mudge2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jennifer C. van Velkinburgh2 Search for this author in: * NPG journals * PubMed * Google Scholar * Pouya Khankhanian1 Search for this author in: * NPG journals * PubMed * Google Scholar * Irina Khrebtukova3 Search for this author in: * NPG journals * PubMed * Google Scholar * Neil A. Miller2 Search for this author in: * NPG journals * PubMed * Google Scholar * Lu Zhang3 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew D. Farmer2 Search for this author in: * NPG journals * PubMed * Google Scholar * Callum J. Bell2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ryan W. Kim2 Search for this author in: * NPG journals * PubMed * Google Scholar * Gregory D. May2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jimmy E. Woodward2 Search for this author in: * NPG journals * PubMed * Google Scholar * Stacy J. Caillier1 Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph P. McElroy1 Search for this author in: * NPG journals * PubMed * Google Scholar * Refujia Gomez1 Search for this author in: * NPG journals * PubMed * Google Scholar * Marcelo J. Pando4 Search for this author in: * NPG journals * PubMed * Google Scholar * Leonda E. Clendenen2 Search for this author in: * NPG journals * PubMed * Google Scholar * Elena E. Ganusova2 Search for this author in: * NPG journals * PubMed * Google Scholar * Faye D. Schilkey2 Search for this author in: * NPG journals * PubMed * Google Scholar * Thiruvarangan Ramaraj2 Search for this author in: * NPG journals * PubMed * Google Scholar * Omar A. Khan5 Search for this author in: * NPG journals * PubMed * Google Scholar * Jim J. Huntley3 Search for this author in: * NPG journals * PubMed * Google Scholar * Shujun Luo3 Search for this author in: * NPG journals * PubMed * Google Scholar * Pui-yan Kwok6, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas D. Wu8 Search for this author in: * NPG journals * PubMed * Google Scholar * Gary P. Schroth3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jorge R. Oksenberg1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen L. Hauser1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen F. Kingsmore2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:464,Pages:1351–1356Date published:(29 April 2010)DOI:doi:10.1038/nature08990Received25 July 2009Accepted11 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 Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis1, 2, 3, 4, 5, 6, 7, 8. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture9, 10, 11, 12. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4+ lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among ~3.6 million single nucleotide polymorphisms (SNPs) or ~0.2 million insertion-deletion polymor! phisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of ~19,000 genes in CD4+ T cells. Only 2 to 176 differences in the methylation of ~2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to ~800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported. View full text Subject terms: * Genomics * Neuroscience * Genetics Figures at a glance * Figure 1: Comparison of the genomic locations of heterozygous cSNPs exhibiting imbalanced allelic expression in mRNA of twins 041896-001 and -101. , , Allelic imbalance for 041896-001 () and 041896-101 () was detected in cSNPs called by ≥10 gDNA reads with Q ≥ 20 and where 20–80% of uniquely aligning gDNA reads called the SNP, together with detection in ≥10 mRNA reads with Q ≥ 20. Out of 14,461 heterozygous cSNPs, 268 (1.9%) showed significant allelic imbalance in expression (P < 10-7), of which 153 (57%) were of the same magnitude and direction in both subjects. TCRVB is the T cell receptor beta locus, V (variable) segment, locus symbol TRB@. WDR40B is also known as DCAF12L1. * Figure 2: Comparisons of methylation of genomic CpG sites in CD4+ lymphocytes and breast and lung tissue samples. , Frequency distribution of CpG site methylation in 041896-001 (blue) and -101 (red) using ELAND-extended. –, Pairwise comparisons of CpG site methylation using ELAND-extended in CD4+ lymphocytes from monozygotic twin siblings 041896-001 and -101 (), 230178-001 and -101 () and 041907-001 and -101 (); inter-individual differences between CD4+ lymphocytes from 041896-001 and 041907-001 () and 041896-001 and 230178-101 (); neoplastic differences between breast tissue and breast cancer () and between normal lung tissue and lung cancer (); and between-tissue differences between CD4+ lymphocytes and breast tissue () and lung tissue (). Author information * Author information * Supplementary information * Comments Affiliations * Department of Neurology, University of California at San Francisco, San Francisco, California 94143, USA * Sergio E. Baranzini, * Pouya Khankhanian, * Stacy J. Caillier, * Joseph P. McElroy, * Refujia Gomez, * Jorge R. Oksenberg & * Stephen L. Hauser * National Center for Genome Resources, Santa Fe, New Mexico 87505, USA * Joann Mudge, * Jennifer C. van Velkinburgh, * Neil A. Miller, * Andrew D. Farmer, * Callum J. Bell, * Ryan W. Kim, * Gregory D. May, * Jimmy E. Woodward, * Leonda E. Clendenen, * Elena E. Ganusova, * Faye D. Schilkey, * Thiruvarangan Ramaraj & * Stephen F. Kingsmore * Illumina Inc., Hayward, California 94545, USA * Irina Khrebtukova, * Lu Zhang, * Jim J. Huntley, * Shujun Luo & * Gary P. Schroth * Stanford Medical School Blood Center, Palo Alto, California 94303, USA * Marcelo J. Pando * Department of Neurology, Wayne State Medical School, Detroit, Michigan 48201, USA * Omar A. Khan * Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California 94143, USA * Pui-yan Kwok * Institute for Human Genetics, University of California at San Francisco, San Francisco, California 94143, USA * Pui-yan Kwok, * Jorge R. Oksenberg & * Stephen L. Hauser * Department of Bioinformatics, Genentech Inc., South San Francisco, California 94080, USA * Thomas D. Wu Contributions S.E.B., G.P.S., J.R.O., S.L.H. and S.F.K. designed the project. S.F.K., S.E.B., J.M. and J.R.O. wrote the paper with input from the other authors. S.E.B., J.M., J.C.v.V., L.Z., R.W.K., G.D.M., J.E.W., S.J.C., J.P.M., R.G., M.J.P., L.E.C., E.E.G., F.D.S., J.J.H. and S.L. performed the experiments. S.E.B., J.M., J.C.v.V., P.K., I.K., N.A.M., L.Z., A.D.F., C.J.B., T.R., S.L., P.K., T.D.W., G.P.S., J.R.O., S.L.H. and S.F.K. analysed the data. S.L.H., J.R.O. and O.A.K. supervised patient recruitment. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Sergio E. Baranzini (sebaran@cgl.ucsf.edu) or * Stephen F. Kingsmore (sfk@ncgr.org) Data is deposited at dbGaP under accession phs000239.v1.p1. Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (21.9M) This file contains Supplementary Tables 1-16 and Supplementary Figures 1-18 with legends. Additional data
• NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
  - Nature 464(7293):1357 (2010)
  Nature | Letter NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals * Peter Duewell1, 3, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Hajime Kono2, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Katey J. Rayner4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Cherilyn M. Sirois1 Search for this author in: * NPG journals * PubMed * Google Scholar * Gregory Vladimer1 Search for this author in: * NPG journals * PubMed * Google Scholar * Franz G. Bauernfeind6 Search for this author in: * NPG journals * PubMed * Google Scholar * George S. Abela8 Search for this author in: * NPG journals * PubMed * Google Scholar * Luigi Franchi9 Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriel Nuñez9 Search for this author in: * NPG journals * PubMed * Google Scholar * Max Schnurr3 Search for this author in: * NPG journals * PubMed * Google Scholar * Terje Espevik10 Search for this author in: * NPG journals * PubMed * Google Scholar * Egil Lien1 Search for this author in: * NPG journals * PubMed * Google Scholar * Katherine A. Fitzgerald1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kenneth L. Rock2 Search for this author in: * NPG journals * PubMed * Google Scholar * Kathryn J. Moore4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Samuel D. Wright11 Search for this author in: * NPG journals * PubMed * Google Scholar * Veit Hornung5, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Eicke Latz1, 7, 10, 12 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1357–1361Date published:(29 April 2010)DOI:doi:10.1038/nature08938Received25 June 2009Accepted18 February 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 inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation1. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome2, 3, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activa! te the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1α/β-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries ! or elsewhere is an early cause rather than a late consequence ! of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease. View full text Subject terms: * Immunology * Medical research * Cell biology Figures at a glance * Figure 1: Cholesterol crystals appear in early atherosclerotic lesions. , , Haematoxylin/eosin staining () and confocal fluorescence and reflection microscopy () of adjacent aortic sinus sections of Apo-E knockout mice fed on a high-cholesterol diet as indicated or on a normal diet (bottom panels). Areas in white or black boxes are shown enlarged; the crystal reflection signal is colour-coded green. –, Quantification of lesion size (), amount of crystal or macrophage marker MoMa-2 staining presented as absolute values () or as a percentage of lesion size (). ND, not detected. In and sections representative of three mice from each group are shown. Means and s.e.m. are shown in , and . * Figure 2: Cholesterol crystals activate the NLRP3 inflammasome. , , Resting or LPS-primed human PBMCs were treated with cholesterol crystals as indicated, monosodium urate (MSU) crystals (250 μg ml-1) or ATP in the absence () or presence () of the caspase-1 inhibitor zYVAD-fmk (10 μM). ELISA and immunoblotting (IB) were performed for IL-1β. , , IB for caspase-1 in supernatants and cell lysates () or ELISA for IL-1β in supernatants () from LPS-primed wild-type, NLRP3-deficient (KO) or ASC-deficient macrophages stimulated with cholesterol crystals, transfected double-stranded DNA (poly(dA-dT)·poly(dT-dA)), nigericin or ATP. Means and s.e.m. for four donors are shown in and ; one out of three independent experiments is shown in each of and . * Figure 3: Cholesterol crystals activate the NLRP3 inflammasome by inducing lysosomal damage. , IL-1β ELISA of supernatants from LPS-primed mouse macrophages stimulated with cholesterol crystals or nigericin in the presence or absence of cytochalasin D. , , Combined confocal fluorescence and reflection microscopy of mouse macrophages incubated with DQ ovalbumin alone (, left) or together with cholesterol crystals (125 μg ml-1) (, right; ) for 2 h; plasma membrane was stained with Alexa647-conjugated choleratoxin B (, ). , Cells were fixed and permeabilized (0.05% saponin) and internal membranes were additionally stained with Alexa555-conjugated choleratoxin B. Nuclei were stained with Hoechst dye. , IL-1β ELISA of supernatants from LPS-primed mouse macrophages stimulated with cholesterol crystals. , , Mouse macrophages stimulated with oxidized LDL for the indicated durations and fluorescent dextran (, 20 h) were imaged by combined confocal fluorescence and reflection microscopy. , Unprimed mouse macrophages were incubated for 24 h with oxidized LDL as in! dicated, and IL-1β in supernatants was measured by ELISA. In each of , and , one of three independent experiments is shown (means and s.d.). Representative images of five (, ) and two (, ) independent experiments are shown. * Figure 4: The NLRP3 inflammasome mediates crystal-induced peritoneal inflammation and atherosclerosis in vivo. , C57BL/6 (n = 23), B6-129 (n = 13) or mice deficient in genes encoding IL-1R (n = 11), IL-1α/β (double knockout, dKO; n = 11), IL-1α (n = 4), IL-1β (n = 4), caspase-1 (n = 7), ASC (n = 15), cathepsin B (n = 10), cathepsin L (n = 5) or NLRP3 (n = 10) were injected peritoneally with cholesterol crystals in PBS or with PBS alone (C57BL/6, n = 14; B6-129, n = 4). Peritoneal lavage cells were analysed for neutrophils after 15 h. Results are shown as means and s.e.m. for pooled groups of mice from experiments repeated two to four times. –, Female LDLR-KO mice reconstituted with C57BL/6 (n = 7), NLRP3-KO (n = 9), ASC-KO (n = 8) or IL-1α/β-dKO (n = 7) bone marrow were fed a high fat diet for 8 weeks and analysed for serum IL-18 concentration () and average aortic sinus lesion size (, ). BMT, bone marrow transplantation. () Each dot represents the mean lesion size of serial cross-sections from individual mice. () Representative photographs of the aortic sinus stained with ! Giemsa. Insets show twofold magnified portions of the boxed images; arrows indicate atherosclerotic lesions. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Peter Duewell, * Hajime Kono, * Veit Hornung & * Eicke Latz Affiliations * Department of Infectious Diseases and Immunology and, * Peter Duewell, * Cherilyn M. Sirois, * Gregory Vladimer, * Egil Lien, * Katherine A. Fitzgerald & * Eicke Latz * Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA * Hajime Kono & * Kenneth L. Rock * Department of Medicine, Division of Gastroenterology, University of Munich, 80336 Munich, Germany * Peter Duewell & * Max Schnurr * Leon H. Charney Division of Cardiology, New York University, New York, New York 10016, USA * Katey J. Rayner & * Kathryn J. Moore * Harvard Medical School, Lipid Metabolism Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA * Katey J. Rayner, * Kathryn J. Moore & * Veit Hornung * Institute of Clinical Chemistry and Pharmacology and, * Franz G. Bauernfeind * Institute of Innate Immunology, University Hospitals, University of Bonn, 53127 Bonn, Germany * Eicke Latz * Department of Medicine, Division of Cardiology, Michigan State University, East Lansing, Michigan 48824, USA * George S. Abela * Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA * Luigi Franchi & * Gabriel Nuñez * Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, 7491, Norway * Terje Espevik & * Eicke Latz * Cardiovascular Therapeutics, CSL Limited, Parkville, Victoria 3052, Australia * Samuel D. Wright Contributions P.D., H.K., K.J.R, C.M.S., G.V., F.G.B, V.H., L.F. and E. Latz designed and performed experiments and analysed data. G.S.A. collected and prepared human samples. T.E., G.N., M.S., K.J.M., G.S.A., K.A.F. and E. Lien provided critical suggestions and discussions throughout the study. P.D., H.K., K.L.R., S.D.W., V.H. and E. Latz wrote the paper. E. Latz conceived and supervised the study. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Eicke Latz (eicke.latz@umassmed.edu; eicke.latz@uni-bonn.de.) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Figures (3M) This file contains Supplementary Figures 1-6 with legends. Additional data
• IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses
  Saenz SA Siracusa MC Perrigoue JG Spencer SP Urban Jr JF Tocker JE Budelsky AL Kleinschek MA Kastelein RA Kambayashi T Bhandoola A Artis D - Nature 464(7293):1362 (2010)
  Nature | Letter IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses * Steven A. Saenz1 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark C. Siracusa1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jacqueline G. Perrigoue1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sean P. Spencer1 Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph F. Urban Jr3 Search for this author in: * NPG journals * PubMed * Google Scholar * Joel E. Tocker4 Search for this author in: * NPG journals * PubMed * Google Scholar * Alison L. Budelsky4 Search for this author in: * NPG journals * PubMed * Google Scholar * Melanie A. Kleinschek5 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert A. Kastelein5 Search for this author in: * NPG journals * PubMed * Google Scholar * Taku Kambayashi2 Search for this author in: * NPG journals * PubMed * Google Scholar * Avinash Bhandoola2 Search for this author in: * NPG journals * PubMed * Google Scholar * David Artis1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1362–1366Date published:(29 April 2010)DOI:doi:10.1038/nature08901Received27 August 2009Accepted12 February 2010Published online03 March 2010Corrected online07 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 CD4+ T helper 2 (TH2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections1. However, TH2 cells also promote chronic inflammation associated with asthma and allergic disorders2. The non-haematopoietic-cell-derived cytokines thymic stromal lymphopoietin, IL33 and IL25 (also known as IL17E) have been implicated in inducing TH2 cell-dependent inflammation at mucosal sites3, 4, 5, 6, but how these cytokines influence innate immune responses remains poorly defined. Here we show that IL25, a member of the IL17 cytokine family, promotes the accumulation of a lineage-negative (Lin-) multipotent progenitor (MPP) cell population in the gut-associated lymphoid tissue that promotes TH2 cytokine responses. The IL25-elicited cell population, termed MPPtype2 cells, was defined by the expression of Sca-1 (also known as Ly6a) and intermediate expression of c-Kit (c-Kitint), and exhibited multipotent capacity, giving rise to cell! s of monocyte/macrophage and granulocyte lineages both in vitro and in vivo. Progeny of MPPtype2 cells were competent antigen presenting cells, and adoptive transfer of MPPtype2 cells could promote TH2 cytokine responses and confer protective immunity to helminth infection in normally susceptible Il25-/- mice. The ability of IL25 to induce the emergence of an MPPtype2 cell population identifies a link between the IL17 cytokine family and extramedullary haematopoiesis, and suggests a previously unrecognized innate immune pathway that promotes TH2 cytokine responses at mucosal sites. View full text Subject terms: * Immunology Figures at a glance * Figure 1: IL25 elicits a c-Kitint-GFP- and c-Kitint-GFP+ cell population in the GALT. , , Cell numbers from IL25-treated IL4-eGFP reporter mice. Numbers of total MLN cells or of T cells (CD4+ or CD8+), B cells (CD19+) and macrophages (MP; CD11b+ MHC class II+) () and total numbers of NBNT c-Kit+ cells () are shown. –, The frequency of c-Kitint cells in MLNs (), Peyer's patches (PP) () and caecal patch (CP) () was assessed by flow cytometry. SSC-A, side scatter area. , , Frequencies () and total numbers () of c-Kitint cells in control (Ctrl) or N. brasiliensis-infected (INF) mice. Plots shown are gated on live, CD4- CD8- CD11b- (also known as Itgam or Mac1) CD11c- (Itgax) and B220- (Ptprc) cells or as indicated. *P < 0.05. Error bars indicate s.e.m. Data in – are representative of more than five independent experiments (control, n = 16; IL25-treated, n = 34). Data in and are representative of at least two independent experiments (control, n = 2; infected, n = 6). * Figure 2: IL25-elicited c-Kitint cells promote TH2 cytokine-dependent responses in vivo. –, CFSE-labelled CD45.2 OVA-specific CD4+ T cells were adoptively transferred by intravenous (i.v.) injection into CD45.1 congenic recipients, and mice were immunized by intraperitoneal (i.p.) injection with OVA/IFA in the presence or absence of IL25-elicited c-Kitint cells. , Proliferation of donor CD45.2 cells in recipient mice receiving T cells alone (red shaded histogram) or T cells and OVA/IFA immunization ± c-Kitint cells (black histograms) was measured by flow cytometry. , The frequency of donor OVA-specific CD4+ cells per total CD4+ T cells isolated from the peritoneum. PECs, peritoneal exudate cells. , IL13 production from anti-CD3/CD28-stimulated MLN cells was measured by ELISA. Data in – are representative of two independent experiments (n = 7). *P < 0.05, **P < 0.01. –, Adoptive transfer of IL25-elicited c-Kitint cells protects T. muris-infected Il25-/- mice. Cytokine production by anti-CD3/CD28-stimulated MLN cells (), T. muris-specific serum ! IgG1 antibody titres (), intestinal mucin responses (), and number of worms from T. muris-infected mice () were assessed at day 20 after infection. Scale bars, 50 μm. Data in – and are mean ± s.e.m.; horizontal bars in denote the mean. * Figure 3: IL25-elicited c-Kitint cells show multipotent capacity. , , Frequencies of c-Kitint cells in the MLNs of IL25-treated IL4-eGFP reporter mice () and expression of HSC markers by c-Kitint-GFP- (blue histograms) or c-Kitint-GFP+ (green histograms) cells from IL25-treated IL4-eGFP reporter mice (). Number indicates the mean fluorescent intensity. Plots shown are gated on live, lineage- cells (CD3ε, CD8α, CD8β, TCRβ, TCRγδ, B220, CD19, CD11b, CD11c, Gr-1 (also known as Ly6g), NK1.1 (Kl1rb1c) and Ter119 (Ly76)) or as indicated. FSC-A, forward scatter area. Data in and are representative of two independent experiments (control, n = 4; IL25-treated, n = 7). , , Flow cytometric analysis of myeloid cell and granulocyte differentiation of FACS-purified Lin-/lo c-Kitint-GFP+ () or c-Kitint-GFP- () cells from IL25-treated IL4-eGFP reporter mice after in vitro culture in SCF and IL3. , , Cytospin preparation of progeny derived from IL25-elicited c-Kitint-GFP+ cells () or c-Kitint-GFP- cells (). MP, macrophage. Scale bars, 10 μm. Data ! in – are representative of at least three independent experiments. * Figure 4: Progeny from IL25-elicited c-Kitint-GFP- cells promote TH2 cell differentiation. , FACS-purified IL25-elicited c-Kitint cells were cultured for 8 days in SCF and IL3 and the resulting progeny from c-Kitint-GFP+ (black histogram) or c-Kitint-GFP- (grey shaded histogram) cells were assessed for expression of IL4-eGFP and MHC class II. Results in are representative of three independent experiments. , CFSE-dilution by OVA-specific CD4+ CD62Lhi CD44lo T cells after 4 days co-culture with progeny from FACS-purified IL25-elicited c-Kitint-GFP- cells in the presence of OVA peptide with or without addition of monoclonal antibody against MHC class II or IL4Rα. Grey histogram indicates CFSE-dilution by OVA-specific CD4+ T cells cultured in medium alone. , IL4 and IL13 protein levels in cell-free supernatants from were assayed by ELISA. Results in and are representative of at least two independent experiments. Change history * Change history * Author information * Supplementary information * CommentsCorrected online 07 March 2010The X-axis label for Fig. 1b was moved to horizontal and an extra line was removed from Fig. 4b on 7 March 2010. Author information * Change history * Author information * Supplementary information * Comments Affiliations * Department of Pathobiology, * Steven A. Saenz, * Mark C. Siracusa, * Jacqueline G. Perrigoue, * Sean P. Spencer & * David Artis * Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA * Taku Kambayashi & * Avinash Bhandoola * Diet, Genomics, & Immunology Lab, Beltsville Human Nutrition Research Center, US Department of Agriculture, Beltsville, Maryland 20705, USA * Joseph F. Urban Jr * Department of Inflammation Research, Amgen, Seattle, Washington 98119, USA * Joel E. Tocker & * Alison L. Budelsky * Discovery Research, Schering-Plough Biopharma, Palo Alto, California 94304, USA * Melanie A. Kleinschek & * Robert A. Kastelein Contributions S.A.S., M.C.S., J.G.P., S.P.S., T.K., A.B. and D.A. designed and performed the research. J.F.U., J.E.T., A.L.B., M.A.K. and R.A.K. provided new reagents. S.A.S., M.C.S., J.G.P. and D.A. analysed the data. S.A.S. and D.A. wrote the paper. Competing financial interests J.E.T. and A.L.B. are stockholding employees of Amgen. M.A.K. and R.A.K. are employees of SPB, a subsidiary of Merck&Co. Corresponding author Correspondence to: * David Artis (dartis@vet.upenn.edu.) Supplementary information * Change history * Author information * Supplementary information * Comments PDF files * Supplementary Figures (3.3M) This file contains Supplementary Figures 1-13 with legends. Additional data
• Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity
  Neill DR Wong SH Bellosi A Flynn RJ Daly M Langford TK Bucks C Kane CM Fallon PG Pannell R Jolin HE McKenzie AN - Nature 464(7293):1367 (2010)
  Nature | Letter Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity * Daniel R. Neill1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * See Heng Wong1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Agustin Bellosi1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Robin J. Flynn1 Search for this author in: * NPG journals * PubMed * Google Scholar * Maria Daly1 Search for this author in: * NPG journals * PubMed * Google Scholar * Theresa K. A. Langford1 Search for this author in: * NPG journals * PubMed * Google Scholar * Christine Bucks2 Search for this author in: * NPG journals * PubMed * Google Scholar * Colleen M. Kane2 Search for this author in: * NPG journals * PubMed * Google Scholar * Padraic G. Fallon3 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard Pannell1 Search for this author in: * NPG journals * PubMed * Google Scholar * Helen E. Jolin1 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew N. J. McKenzie1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1367–1370Date published:(29 April 2010)DOI:doi:10.1038/nature08900Received01 December 2009Accepted12 February 2010Published online03 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 Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity—responsible for protective immune responses to helminth parasites1, 2 and the underlying cause of the pathogenesis of allergic asthma3, 4—consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively determined. Here, through the use of novel Il13-eGFP reporter mice, we present the identification and functional characterization of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL25 and IL33, and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25! and IL33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity. View full text Subject terms: * Immunology * Parasitology Figures at a glance * Figure 1: IL25 and IL33 induce IL13-producing nuocytes. , Detection of Il13-eGFP+ non-B, non-T (NBNT) cells in MLNs of IL25- or IL33-treated mice. , Cell surface marker expression of Il13-eGFP+ NBNT cells in MLNs after IL25 administration. , Immunofluorescence detection of IL13-eGFP+ cells in the small intestine of mice treated with IL25 and IL33. 7-AAD, 7-amino-actinomycin. Data in – are representative of five experiments with >3 mice per group. , Nuocyte number. Data are representative of two independent experiments with >4 mice per group. Data in bar charts are the mean and s.e.m. , Cluster analysis for freshly isolated nuocytes (ex vivo) or day 9 in vitro expanded nuocytes (single data sets are shown for clarity). DC, dendritic cell; pDC, plasmacytoid dendritic cell. * Figure 2: IL25 and IL33 have partially redundant roles for nuocyte induction and worm expulsion. , Quantification of Il13-eGFP+ cells 5 d.p.i. with N. brasiliensis. Data are representative of two independent experiments with >5 mice per group. iNKT cells, invariant NKT cells. , Intestinal worm burden of N. brasiliensis-infected mice. D, day; ND, none detected. , Quantification of Il13-eGFP+ cells in N. brasiliensis (Nb)-infected mice at 5 d.p.i. Data are representative of two independent experiments with >5 mice per group. , Quantification of nuocytes in N. brasiliensis-infected mice. *P < 0.05, **P < 0.01. Data are representative of two independent experiments with >5 mice per group. Data in bar charts are mean and s.e.m. * Figure 3: Adoptive transfer of cultured nuocytes into Il17br-/- mice restores an IL25-responsive phenotype. , Morphology of Giemsa-stained nuocytes. , Quantification of nuocyte growth in vitro. CC, cytokine cocktail. , Flow cytometric analysis of interferon (IFN)-γ, IL4, IL5 and IL13 intracellular staining of nuocytes after 7 days culture with IL7 and IL33. Data in – are representative of three independent experiments. , Quantification of eosinophil infiltration of the peritoneal cavity after nuocyte (nuo) transfer. WT, wild type. Data in bar charts are mean and s.e.m. , Transverse histological jejunum sections stained with periodic acid–Schiff (PAS) for goblet cells. Data are representative of two independent experiments with >5 mice per group. Original magnifications, ×100 () and ×40 (). * Figure 4: Adoptive transfer of wild-type nuocytes, but not IL13-deficient nuocytes, restores rapid worm expulsion in N. brasiliensis-infected Il17br-/- mice. , Intestinal worm burdens. , Quantification of nuocyte numbers in tissues. Data are representative of three independent experiments with >6 mice per group. , , Intestinal worm burdens. Data are from single experiments with 6–7 mice per group. , Intestinal worm burdens. , N. brasiliensis antigen-specific IL13 production. , Intestinal worm burden. , Quantification of nuocyte numbers. –, Data are representative of two independent experiments with >6 mice per group. *P < 0.05, **P < 0.01, ***P < 0.005. Data in bar charts are mean and s.e.m. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Daniel R. Neill, * See Heng Wong & * Agustin Bellosi Affiliations * MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK * Daniel R. Neill, * See Heng Wong, * Agustin Bellosi, * Robin J. Flynn, * Maria Daly, * Theresa K. A. Langford, * Richard Pannell, * Helen E. Jolin & * Andrew N. J. McKenzie * Immunology Discovery Research, Centocor R&D Inc., 145 King of Prussia Road, Radnor, Pennsylvania 19087, USA * Christine Bucks & * Colleen M. Kane * Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland * Padraic G. Fallon Contributions D.R.N., S.H.W. and A.B. performed experiments, interpreted data, provided intellectual input and wrote the paper; R.J.F. and T.K.A.L. performed the infection studies; M.D. performed cell isolation studies; C.B. and C.M.K. performed microarray studies and Luminex; P.G.F. provided reagents and intellectual input; R.P. and H.E.J. provided reagents and experimental assistance; A.N.J.M. conceived the study and wrote the paper. Competing financial interests S.H.W. and A.N.J.M. were supported by a grant from Centocor. Corresponding author Correspondence to: * Andrew N. J. McKenzie (anm@mrc-lmb.cam.ac.uk.) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (754K) This file contains Supplementary Figures S1-S9 with legends and Supplementary Table 1. Additional data
• Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology
  Buonocore S Ahern PP Uhlig HH Ivanov II Littman DR Maloy KJ Powrie F - Nature 464(7293):1371 (2010)
  Nature | Letter Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology * Sofia Buonocore1 Search for this author in: * NPG journals * PubMed * Google Scholar * Philip P. Ahern1 Search for this author in: * NPG journals * PubMed * Google Scholar * Holm H. Uhlig3 Search for this author in: * NPG journals * PubMed * Google Scholar * Ivaylo I. Ivanov4 Search for this author in: * NPG journals * PubMed * Google Scholar * Dan R. Littman4 Search for this author in: * NPG journals * PubMed * Google Scholar * Kevin J. Maloy1 Search for this author in: * NPG journals * PubMed * Google Scholar * Fiona Powrie1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:464,Pages:1371–1375Date published:(29 April 2010)DOI:doi:10.1038/nature08949Received07 October 2009Accepted19 February 2010Published online14 April 2010Corrected online29 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 key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (TH17) cells1. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells2 and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-γ in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-γ exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (R! OR)-γt and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-γt, which controls IL-23R expression, has a functional role, because Rag-/-Rorc-/- mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease. View full text Subject terms: * Immunology * Medical research Figures at a glance * Figure 1: IL-23-induced IL-17 and IFN-γ are required for H. hepaticus-mediated innate colitis. , Cytokine secretion after overnight culture of splenocytes (left) or cLP cells (right) from control or H. hepaticus-infected 129SvEvRag-/- mice (n = 6 per group). , Cytokine secretion by cLP cells from control 129SvEvRag-/- mice after overnight culture with IL-12 or IL-23 (n = 6). Data are shown as means and s.e.m. –, Colitis scores (), splenomegaly () and representative colon photomicrographs (magnification × 50) () from H. hepaticus-infected 129SvEvRag-/- mice treated with blocking anti-IL-17 and/or anti-IFN-γ or isotype control mAbs. Data represent two pooled experiments (n = 5–12 per group). Asterisk, P < 0.05; two asterisks, P < 0.01; three asterisks, P < 0.001. * Figure 2: IL-23-responsive innate lymphoid cells in inflamed colon are Thy1highSCA-1+ROR-γt+. , , IL-17 and IFN-γ () and Thy1 and IL-17 () expression in Lin- cLP cells from H. hepaticus-infected 129SvEvRag-/- mice after overnight culture with or without IL-23. , Phenotypic analysis of Lin-IL-17+ cLP cells from H. hepaticus-infected 129SvEvRag-/- mice, using specific antibodies (black line) and isotype controls (grey line). , Cytokine secretion by sorted Thy1highSCA-1+ or the remaining cLP cells (remainder) isolated from H. hepaticus-infected 129SvEvRag-/- mice after overnight culture with or without IL-23. , IL-23R, ROR-γt, AHR and Tbx21 mRNA expression by unstimulated cells isolated as in . Data are shown as means and s.e.m. Results are representative of at least two independent experiments. * Figure 3: Thy1high innate lymphoid cells drive H. hepaticus-induced innate intestinal inflammation. , , Frequency of Thy1highSCA-1+ cells (n = 3–6) () and IL-17 expression among Thy1high cells () after culture with or without IL-23 in cLP cells from control or H. hepaticus-infected 129SvEvRag-/- (Hh Rag-/-) mice. Data are representative of two independent experiments. –, Colitis (, left) and typhlitis (, right) scores, splenomegaly (), and representative photomicrographs (magnification ×50; scale bars, 200 μm) () from H. hepaticus-infected mice treated with anti-Thy1 or isotype control mAbs (n = 6 per group). , IL-17 and IFN-γ secretion by cLP cells from the mice described above, following stimulation with or without IL-23. Data are shown as means and s.e.m. (n = 6). Asterisk, P < 0.05; two asterisks, P < 0.01. * Figure 4: ROR-γt-expressing Thy1high innate lymphoid cells are required for anti-CD40-induced innate intestinal inflammation. –, Proximal colitis scores (), colon photomicrographs (magnification ×50) (), weight loss () and cLP cytokine secretion after overnight culture () in anti-CD40-treated C57BL/6 Rag-/- mice injected with or without anti-Thy1 or isotype control mAb. , ROR-γt mRNA expression by sorted Thy1highSCA-1+ cells or the remaining cLP cells from anti-CD40-treated mice. Results are representative of two independent experiments. , , Proximal colitis scores () and photomicrographs (magnification ×50) () from anti-CD40-treated C57BL/6 Rag-/- or C57BL/6 Rag-/-Rorc-/- mice. Data represent pooled results from two experiments (–, n = 6–10; , n = 11–13). In –, data are shown as means and s.e.m. (n = 5). Two asterisks, P < 0.01; three asterisks, P < 0.001. Change history * Change history * Author information * Supplementary information * CommentsCorrected online 29 April 2010Small changes were made to the labelling of Figs 2b, 3b and 4d. Author information * Change history * Author information * Supplementary information * Comments Affiliations * Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK * Sofia Buonocore, * Philip P. Ahern, * Kevin J. Maloy & * Fiona Powrie * Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK * Fiona Powrie * University Children's Hospital, 04317 Leipzig, Germany * Holm H. Uhlig * Molecular Pathogenesis Program, Howard Hughes Medical Institute, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA * Ivaylo I. Ivanov & * Dan R. Littman Contributions S.B. and P.A. designed and performed the experiments. H.U. performed histology. I.I.I. and D.R.L. provided Rag-/-Rorc-/- mice and were involved in the experiments with this strain. S.B. wrote the manuscript with K.J.M. and F.P., and K.J.M. and F.P. directed the research. Competing financial interests Competing interests: Collaboration with Celltech. Corresponding authors Correspondence to: * Fiona Powrie (fiona.powrie@path.ox.ac.uk) or * Kevin J. Maloy (kevin.maloy@path.ox.ac.uk) Supplementary information * Change history * Author information * Supplementary information * Comments PDF files * Supplementary Information (1.4M) This file contains Supplementary Methods and References and Supplementary Figures 1-12 with legends. Please note that the Supplementary Methods and References were added on April 18, 2010. Additional data
• Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling
  Fazzari P Paternain AV Valiente M Pla R Luján R Lloyd K Lerma J Marín O Rico B - Nature 464(7293):1376 (2010)
  Nature | Letter Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling * Pietro Fazzari1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ana V. Paternain1 Search for this author in: * NPG journals * PubMed * Google Scholar * Manuel Valiente1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ramón Pla1 Search for this author in: * NPG journals * PubMed * Google Scholar * Rafael Luján2 Search for this author in: * NPG journals * PubMed * Google Scholar * Kent Lloyd3 Search for this author in: * NPG journals * PubMed * Google Scholar * Juan Lerma1 Search for this author in: * NPG journals * PubMed * Google Scholar * Oscar Marín1 Search for this author in: * NPG journals * PubMed * Google Scholar * Beatriz Rico1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:464,Pages:1376–1380Date published:(29 April 2010)DOI:doi:10.1038/nature08928Received07 August 2009Accepted16 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 Schizophrenia is a complex disorder that interferes with the function of several brain systems required for cognition and normal social behaviour. Although the most notable clinical aspects of the disease only become apparent during late adolescence or early adulthood, many lines of evidence suggest that schizophrenia is a neurodevelopmental disorder with a strong genetic component1, 2. Several independent studies have identified neuregulin 1 (NRG1) and its receptor ERBB4 as important risk genes for schizophrenia3, 4, although their precise role in the disease process remains unknown. Here we show that Nrg1 and ErbB4 signalling controls the development of inhibitory circuitries in the mammalian cerebral cortex by cell-autonomously regulating the connectivity of specific GABA (γ-aminobutyric acid)-containing interneurons. In contrast to the prevalent view, which supports a role for these genes in the formation and function of excitatory synapses between pyramidal cells, we f! ound that ErbB4 expression in the mouse neocortex and hippocampus is largely confined to certain classes of interneurons. In particular, ErbB4 is expressed by many parvalbumin-expressing chandelier and basket cells, where it localizes to axon terminals and postsynaptic densities receiving glutamatergic input. Gain- and loss-of-function experiments, both in vitro and in vivo, demonstrate that ErbB4 cell-autonomously promotes the formation of axo-axonic inhibitory synapses over pyramidal cells, and that this function is probably mediated by Nrg1. In addition, ErbB4 expression in GABA-containing interneurons regulates the formation of excitatory synapses onto the dendrites of these cells. By contrast, ErbB4 is dispensable for excitatory transmission between pyramidal neurons. Altogether, our results indicate that Nrg1 and ErbB4 signalling is required for the wiring of GABA-mediated circuits in the postnatal cortex, providing a new perspective to the involvement of these genes ! in the aetiology of schizophrenia. View full text Subject terms: * Neuroscience * Physiology * Developmental biology Figures at a glance * Figure 1: ErbB4 is expressed by many interneurons in the postnatal neocortex and hippocampus, but not in pyramidal cells at P30. , ErbB4 (filled and open arrowheads) and GFP (arrows and filled arrowheads) immunohistochemistry in the somatosensory cortex (SSCx) of a P30 Dlx5/6-Cre mouse. , Percentage of interneurons among all ErbB4-expressing cortical cells. ECx, entorhinal cortex; HCso, hippocampus stratum oriens; HCsr, hippocampus stratum radiatum; MCx, motor cortex; VCx, visual cortex. , Immunoblots of ErbB4 protein in the brains of control, IN-Erbb4 and PN-Erbb4 mutants (fold to control: IN-Erbb4, 8.6 ± 1.7%, n = 3; PN-Erbb4, 85.9 ± 1.3%, n = 2). Asterisk points to a non-specific band. Tub, tubulin loading control. , Double immunohistochemistry for ErbB4 (filled arrowheads) and parvalbumin (PV; filled and open arrowheads) in the somatosensory cortex of a wild-type mouse. , Percentage of ErbB4-expressing cells among all cortical interneurons. , Percentage of ErbB4-expressing cells among different classes of cortical interneurons. Parvalbumin: prefrontal cortex (PF), 85 ± 5% (mean ±!  s.e.m.); SSCx, 86 ± 2%; hippocampus (HC), 88 ± 4%. Calretinin (CR): PF, 10 ± 4%; SSCx, 10 ± 5%; HC, 10 ± 7%. Somatostatin (SST): PF, 16 ± 4%; SSCx, 18 ± 5%; HC, 27 ± 6%; n = 3. , , Expression of ErbB4 in a chandelier () and basket () cell. I, layer I; II–III; layers II–III. , , Immunogold labelling (arrows) localizes ErbB4 to inhibitory boutons (ib) contacting the AIS of pyramidal neurons, and postsynaptic to excitatory boutons (eb) contacting the dendrites of interneurons (id) in hippocampus. Histograms show mean and s.e.m. Scale bars, 50 μm (, ), 150 μm (, ), 0.3 μm (), 0.2 μm () and 0.05 μm (inset in ). * Figure 2: Nrg1 promotes GABAergic differentiation and synaptogenesis. , , Hippocampal interneurons from primary cultures treated with control medium or Nrg1-β1 at 5 days in vitro (DIV). , Fold change in total axonal length and number of branches in hippocampal interneurons treated with Nrg1-β1 compared to controls. Control, n = 78; Nrg1-β1, n = 92, three cultures; ***P < 0.001, Mann–Whitney test. –, Distribution of GAD65-positive boutons contacting the soma of transfected hippocampal pyramidal neurons. , Number of GAD65 boutons per axonal length; n = 50 neurons, five cultures; *P < 0.05, t-test. , Experimental model. , , , , Single confocal images showing GAD65 boutons apposed to the soma and AIS of transfected pyramidal neurons. ImageJ software was used to process AIS images for counting ( (right) and (right)). , Density of GAD65 boutons. Perisomatic: GFP, n = 24; CRD-Nrg1, n = 35 neurons, four brains. AIS: GFP, n = 26; CRD-Nrg1, n = 30 neurons, four brains. *P < 0.05, ***P < 0.001, t-test. Scale bars, 50 μm (, ), 25!  μm (, ), and 5 μm (, , , , , ). Histograms show mean and s.e.m. * Figure 3: Nrg1 and ErbB4 signalling is necessary for inhibitory synapse formation in vivo. , Experimental model. , , Representative wild-type and Erbb4 mutant chandelier cells in the somatosensory cortex. , , Representative candlesticks. Arrows point to axonal boutons. , , Drawings from representative candlesticks from ten wild-type () and Erbb4 mutant () chandelier cells. , Length of candlestick (P = 0.90), distance to the closest candlestick (P = 0.81), and density of boutons (0.1840 ± 0.0052 and 0.1440 ± 0.0079 boutons per μm for wild-type and Erbb4 mutant cells, respectively). ***P < 0.001, t-test. NS, not significant. Control: n = 11 neurons, 374 candlesticks; Erbb4 mutant: n = 10 neurons, 276 candlesticks, four brains. , Experimental model. sc, Schaffer collaterals; sp, stratum pyramidale. –, Representative traces (), cumulative plot () and measurements of mIPSC frequencies () and mIPSC amplitudes (). Control: n = 50 neurons, three brains; Erbb4 mutant: n = 71 neurons, four brains. ***P < 0.001 (), P = 0.70 (), t-test. Scale bars, 100 ! μm (, ), 10 μm (), and 2 μm (, ). Histograms show mean and s.e.m. * Figure 4: Conditional deletion of Erbb4 disrupts excitatory input to hippocampal interneurons. , Experimental model. –, Representative traces (), cumulative plot () and measurements of mEPSC frequencies () and mEPSC amplitudes (). Control: n = 48 neurons, five brains; Erbb4 mutant: n = 38 neurons, four brains. **P < 0.01 (), P = 0.07 (), t-test. , Analysis of the distribution of mEPSC frequencies recorded from hippocampal interneurons in control and IN-Erbb4 mutants. P < 0.01, Welch test for the entire distribution. 0–5 Hz: P < 0.05; 5–16 Hz: P < 0.01, χ2 test. , , Single confocal images showing VGlut-1 boutons apposed to parvalbumin-expressing hippocampal interneurons. ImageJ software was used to process images for counting (, , bottom). , Density of VGlut-1 boutons. Control: n = 17, three brains; IN-Erbb4 mutant: n = 21 neurons, three brains. *P < 0.05, t-test. Scale bar, 1 μm (, ). Histograms show mean and s.e.m. Author information * Author information * Supplementary information * Comments Affiliations * Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain * Pietro Fazzari, * Ana V. Paternain, * Manuel Valiente, * Ramón Pla, * Juan Lerma, * Oscar Marín & * Beatriz Rico * Departamento Ciencias Médicas, Facultad de Medicina, Universidad de Castilla-La Mancha, 02006 Albacete, Spain * Rafael Luján * Department of Internal Medicine, California National Primate Research Center, University of California, Davis, California 95616, USA * Kent Lloyd Contributions P.F., O.M. and B.R. planned the experiments, and P.F. analysed the results. A.V.P. and J.L. performed the electrophysiological experiments and analysed the results. R.L. performed the ultrastructural analysis. M.V. and R.P. carried out in utero electroporation and in utero viral injections, respectively. K.L., R.L., J.L., O.M. and B.R. provided reagents, materials and analysis tools. P.F., O.M. and B.R. discussed the results and wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Oscar Marín (o.marin@umh.es) or * Beatriz Rico (brico@umh.es) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Figures (21.9M) This file contains Supplementary Figures 1-17 with legends. Additional data
• IκBζ regulates TH17 development by cooperating with ROR nuclear receptors
  Okamoto K Iwai Y Oh-Hora M Yamamoto M Morio T Aoki K Ohya K Jetten AM Akira S Muta T Takayanagi H - Nature 464(7293):1381 (2010)
  Nature | Letter IκBζ regulates TH17 development by cooperating with ROR nuclear receptors * Kazuo Okamoto1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Yoshiko Iwai4 Search for this author in: * NPG journals * PubMed * Google Scholar * Masatsugu Oh-hora1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Masahiro Yamamoto5 Search for this author in: * NPG journals * PubMed * Google Scholar * Tomohiro Morio6 Search for this author in: * NPG journals * PubMed * Google Scholar * Kazuhiro Aoki7 Search for this author in: * NPG journals * PubMed * Google Scholar * Keiichi Ohya7 Search for this author in: * NPG journals * PubMed * Google Scholar * Anton M. Jetten8 Search for this author in: * NPG journals * PubMed * Google Scholar * Shizuo Akira9 Search for this author in: * NPG journals * PubMed * Google Scholar * Tatsushi Muta10 Search for this author in: * NPG journals * PubMed * Google Scholar * Hiroshi Takayanagi1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:464,Pages:1381–1385Date published:(29 April 2010)DOI:doi:10.1038/nature08922Received12 August 2009Accepted10 February 2010Published online11 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 Interleukin (IL)-17-producing helper T (TH17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases1, 2, 3. IL-6 and transforming growth factor-β (TGF-β) induce TH17 development, in which the orphan nuclear receptors, RORγt and RORα, have an indispensable role4, 5, 6. However, in the absence of IL-6 and TGF-β, the ectopic expression of RORγt or RORα leads to only a modest IL-17 production5, 7, 8. Here we identify a nuclear IκB family member, IκBζ (encoded by the Nfkbiz gene), as a transcription factor required for TH17 development in mice. The ectopic expression of IκBζ in naive CD4+ T cells together with RORγt or RORα potently induces TH17 development, even in the absence of IL-6 and TGF-β. Notably, Nfkbiz-/- mice have a defect in TH17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IκBζ was clearly demonstrated by the resistance to EAE of the Rag2-/! - mice into which Nfkbiz-/- CD4+ T cells were transferred. In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying TH17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease. View full text Subject terms: * Immunology * Cell biology Figures at a glance * Figure 1: Nfkbiz-/- mice are resistant to EAE owing to a CD4+ T-cell-intrinsic defect in TH17 development. , Nfkbiz mRNA expression in TH-cell subsets, inducible Treg (iTreg) cells, naive CD4+ T cells (Naive), conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs). , Disease course of EAE in wild-type (WT; n = 5) or Nfkbiz-/- mice (n = 5). , Pathology analysis of the spinal cord sections. Arrowheads indicate inflammatory cellular infiltrate (haematoxylin and eosin, HE) and demyelinated areas (Luxol fast blue, LFB). , IFN-γ and IL-17 production in splenocytes and lymph node cells after restimulation with MOG peptide. ND, not detected. , , TLR-induced IL-17 production in CD4+ T cells in co-culture with cDCs () or pDCs () isolated from WT or Nfkbiz-/- mice. , Disease course of EAE in Rag2-/- mice reconstituted with WT (n = 8) or Nfkbiz-/- (n = 5) CD4+ T cells. , Pathology analysis of the spinal cord sections from the reconstituted mice. , Frequency of IFN-γ+IL-17+, IFN-γ-IL-17+ and IFN-γ+IL-17- CD4+ T cells in the reconstituted mice. Error bars (, , , and ), mean ±�! �s.e.m.; *P < 0.05; **P < 0.01; ***P < 0.005; NS, not significant. * Figure 2: Targeted disruption of the Nfkbiz gene results in impaired TH17 development. , IFN-γ, IL-4 and IL-17 production in WT or Nfkbiz-/- CD4+ T cells activated under TH0-, TH1-, TH2- or TH17-polarizing conditions. , Intracellular expression of IFN-γ and IL-17 in WT or Nfkbiz-/- CD4+ T cells activated under TH0- or TH17-polarizing conditions. , Il17f, Il21, Il23r and Il22 mRNA expression in WT or Nfkbiz-/- CD4+ T cells. , Rorc and Rora mRNA expression in WT or Nfkbiz-/- CD4+ T cells cultured for 1, 2 or 3 days. , Protein expression level of the IκBζ splicing variants IκBζ (L) (79 kDa), IκBζ (S) (69 kDa) and IκBζ (D) (57 kDa) in TH0 or TH17 cells. ns, non-specific band. , Effects of the cytokines on Nfkbiz mRNA expression in CD4+ T cells. , Nfkbiz mRNA expression in CD4+ T cells derived from Myd88-/-, Il17a-/-, Stat3flox/- Lck-Cre or Rorc-/- mice. Error bars ( and –), mean ± s.e.m.; *P < 0.05; **P < 0.01; ***P < 0.005. * Figure 3: Ectopic expression of IκBζ facilitates TH17 development. , Effects of retroviral expression of IκBζ (L) on IL-17 production. , Effects of retroviral expression of IκBζ (L) on Il17f, Il21 and Il23r mRNA expression in CD4+ T cells activated in the presence of IL-6 and TGF-β. Error bars, mean ± s.e.m. , Schematic of IκBζ variants and truncated mutants of IκBζ (L). , Effects of retroviral expression of the Myc-tagged IκBζ variants and mutants on TH17 development (right). Immunoblot analysis of IκBζ protein levels in Myc-tagged IκBζ variants-expressing CD4+ T cells (left). IκBζ (L) 153–728 and IκBζ (L) 188–728 had a more potent activity to induce IL-17 production than IκBζ (L), which may be correlated to their high expression levels. * Figure 4: IκBζ and ROR nuclear receptors cooperatively activate the Il17a promoter and facilitate TH17 development. , IL-17 production in CD4+ T cells transduced with IκBζ (IRES–hCD2) and RORγt or RORα (IRES–EGFP) after activation under TH0- or TH17-polarizing conditions. FSC, forward scatter. , Effects of retroviral expression of RORγt or RORα on IL-17 production in WT or Nfkbiz-/- CD4+ T cells. , Effects of retroviral expression of IκBζ on IL-17 production in WT, Rorc-/- or Rorasg/sg CD4+ T cells. , Putative IκBζ and ROR response elements5, 17, 21 in the mouse Il17a promoter and the Il17-Luc construct. Three IκBζ response elements were located in the CNS2 region (ISE1, -6350 to -6339; ISE2, -4795 to -4786; ISE3, -4454 to -4445). The transcriptional initiation site was designated as +1. , Effects of IκBζ on RORγt and/or RORα-mediated activation of the Il17a promoter. , Recruitment of IκBζ to the ISE1 region or the region outside CNS2 (-3978 to -3969) in WT, Rorc-/-, Nfkbiz-/- CD4+ T cells. Error bars ( and ), mean ± s.e.m. ***P < 0.005. Author information * Author information * Supplementary information * Comments Affiliations * Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, * Kazuo Okamoto, * Masatsugu Oh-hora & * Hiroshi Takayanagi * Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases, * Kazuo Okamoto, * Masatsugu Oh-hora & * Hiroshi Takayanagi * Japan Science and Technology Agency (JST), ERATO, Takayanagi Osteonetwork Project, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan * Kazuo Okamoto & * Hiroshi Takayanagi * Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan * Yoshiko Iwai * Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, and WPI Immunology Frontier Research Center, Osaka University, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan * Masahiro Yamamoto * Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan * Tomohiro Morio * Department of Hard Tissue Engineering (Pharmacology), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan * Kazuhiro Aoki & * Keiichi Ohya * Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive Research Triangle Park, North Carolina 27709, USA * Anton M. Jetten * Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Yamada-oka 3-1, Suita, Osaka 565-0871, Japan * Shizuo Akira * Laboratory of Cell Recognition and Response, Graduate School of Life Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan * Tatsushi Muta Contributions Ka.O. performed all of the experiments, interpreted the results and prepared the manuscript. Y.I. contributed to dendritic cells experiments and T-cell transfer experiments. M.O. contributed to study design and manuscript preparation. M.Y., A.M.J. and S.A. provided genetically modified mice and advice on data analysis. To.M. provided advice on project planning and data interpretation. K.A. and Ke.O. supported the experiments using Nfkb1-/- mice. Ta.M. provided genetically modified mice and the plasmids, and advised on project planning. H.T. directed the project and wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Hiroshi Takayanagi (taka.csi@tmd.ac.jp.) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (2.5M) This file contains Supplementary Figures 1-19 with legends, Supplementary Tables 1-2 and Supplementary References. Additional data
• Tracking G-protein-coupled receptor activation using genetically encoded infrared probes
  Ye S Zaitseva E Caltabiano G Schertler GF Sakmar TP Deupi X Vogel R - Nature 464(7293):1386 (2010)
  Nature | Letter Tracking G-protein-coupled receptor activation using genetically encoded infrared probes * Shixin Ye1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ekaterina Zaitseva2 Search for this author in: * NPG journals * PubMed * Google Scholar * Gianluigi Caltabiano3 Search for this author in: * NPG journals * PubMed * Google Scholar * Gebhard F. X. Schertler4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas P. Sakmar1 Search for this author in: * NPG journals * PubMed * Google Scholar * Xavier Deupi3 Search for this author in: * NPG journals * PubMed * Google Scholar * Reiner Vogel2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:464,Pages:1386–1389Date published:(29 April 2010)DOI:doi:10.1038/nature08948Received17 December 2009Accepted23 February 2010Published online11 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 Rhodopsin is a prototypical heptahelical family A G-protein-coupled receptor (GPCR) responsible for dim-light vision1, 2. Light isomerizes rhodopsin's retinal chromophore and triggers concerted movements of transmembrane helices, including an outward tilting of helix 6 (H6) and a smaller movement of H5, to create a site for G-protein binding and activation3, 4. However, the precise temporal sequence and mechanism underlying these helix rearrangements is unclear. We used site-directed non-natural amino acid mutagenesis to engineer rhodopsin with p-azido-l-phenylalanine residues incorporated at selected sites5, and monitored the azido vibrational signatures using infrared spectroscopy as rhodopsin proceeded along its activation pathway. Here we report significant changes in electrostatic environments of the azido probes even in the inactive photoproduct Meta I, well before the active receptor state was formed. These early changes suggest a significant rotation of H6 and moveme! nt of the cytoplasmic part of H5 away from H3. Subsequently, a large outward tilt of H6 leads to opening of the cytoplasmic surface to form the active receptor photoproduct Meta II3. Thus, our results reveal early conformational changes that precede larger rigid-body helix movements, and provide a basis to interpret recent GPCR crystal structures6, 7 and to understand conformational sub-states observed during the activation of other GPCRs8. View full text Subject terms: * Biophysics * Chemical biology * Structural biology Figures at a glance * Figure 1: Sites of azF labelling and electrostatic potential around azF250. , , The single azF mutations used in this study are shown simultaneously in models based on the structures of the rhodopsin inactive dark state (Protein Data Bank (PDB) accession 1GZM22; ) and of opsin in its G-protein-interacting conformation (PDB accession 3DQB3; , viewed from the cytoplasmic side). , , The electrostatic potential on the surface of residues around the azF250 label was calculated for both structures. In the inactive dark state (), a cluster of polar residues in H2 (T70 and N73) and H7 (N310 and Q312) creates a local positive electrostatic potential (blue surface) near the azido group of azF250, which is translocated to the hydrophobic interface between H3 (V139) and H5 (L226 and V230) of the G-protein-binding pocket in the opsin structure (). * Figure 2: Sequence of photointermediates of V2506.33azF rhodopsin. Light-induced FTIR difference spectra — photoproduct minus dark state — of the V2506.33azF rhodopsin mutant (coloured spectra) and of wild-type rhodopsin (grey spectra) were measured under conditions that stabilize the active Meta II state or the inactive precursor states Meta I and Lumi. In this representation, bands are positive for the photoproduct and negative for the dark state. The spectral range between 1,900 and 900 cm-1 contains vibrational modes of the protein and the chromophore and allows positive correlation between the photoproduct states of V2506.33azF with those of wild-type rhodopsin. Insets show close-ups in the range of the azido stretch vibration; they reveal no significant shift of the vibration in Lumi and a pronounced downshift in Meta I and Meta II, indicating a decreased polarity of the environment of the label in these photoproduct states. OD, optical density units. * Figure 3: Vibrational shifts of the azido label. FTIR difference spectra as in Fig. 2 are shown in the range of the azido stretch vibration for the transitions from the dark state to the Meta II (left column) and Meta I (right column) photoproduct states for a series of azF rhodopsin mutants. Corresponding spectra of wild-type rhodopsin are shown in grey. Spectra of Y1363.51azF and of V2275.62azF are averages of three independent experiments to increase the signal-to-noise ratio and are shown in an enlarged (3×) scale. * Figure 4: Sequence of helix movements in rhodopsin activation. , In the inactive dark state, 11-cis retinal is wrapped around W2656.48 and E2476.30 interacts with E1343.49/R1353.50, stabilizing H6. , In the model (see Methods) of Meta I, retinal isomerization frees W2656.48 and weakens the H3/H5 interaction (see text), resulting in small tilt/rotation of H5 and H6. The close-up (top) shows a superimposition of Meta I (solid cylinders, orange sticks) with the inactive dark state (translucent cylinders, white sticks). , The model of the active Meta II state shows that the G-protein-binding site opens by subsequent larger movements of H5 and H6. The interaction of E2476.30 with E1343.49/R1353.50 is broken, and a new H5/H6 interaction mediated by K2315.66 and E2476.30 is created. The close-up (top) shows the superimposition of the Meta II model (solid cylinders, red sticks) with that of Meta I. All structures are viewed from the cytoplasmic side. Author information * Author information * Supplementary information * Comments Affiliations * Laboratory of Molecular Biology and Biochemistry, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA * Shixin Ye & * Thomas P. Sakmar * Biophysics Section, Institute of Molecular Medicine and Cell Research, University of Freiburg, Hermann Herder Str. 9, D-79104 Freiburg, Germany * Ekaterina Zaitseva & * Reiner Vogel * Laboratori de Medicina Computacional, Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalunya, Spain * Gianluigi Caltabiano & * Xavier Deupi * MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK * Gebhard F. X. Schertler * Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen, Switzerland * Gebhard F. X. Schertler Contributions S.Y., T.P.S., X.D. and R.V. designed experiments and wrote the paper, S.Y. expressed and purified mutant pigments, E.Z. and R.V. lipid-reconstituted pigments, performed FTIR experiments and analysed data, and G.C., G.F.X.S. and X.D. developed and analysed structural models. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Reiner Vogel (reiner.vogel@biophysik.uni-freiburg.de) or * Xavier Deupi (xavier.deupi@uab.cat) or * Thomas P. Sakmar (sakmar@mail.rockefeller.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Figures (848K) This file contains Supplementary Figures 1-2 with legends. Additional data
• Enzyme-inhibitor-like tuning of Ca2+ channel connectivity with calmodulin
  - Nature 464(7293):1390 (2010)
  Nature | Corrigendum Enzyme-inhibitor-like tuning of Ca2+ channel connectivity with calmodulin * Xiaodong Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Philemon S. Yang Search for this author in: * NPG journals * PubMed * Google Scholar * Wanjun Yang Search for this author in: * NPG journals * PubMed * Google Scholar * David T. Yue Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:464,Page:1390Date published:(29 April 2010)DOI:doi:10.1038/nature09034 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nature463, 968–972 (2010) In the Acknowledgements section of this Letter, the work was incorrectly listed as being funded in part by the US National Institute of Neurological Disorders and Stroke. This work was in fact funded by the US National Institute on Deafness and Other Communication Disorders. Additional data
• Lessons on longevity from budding yeast
  - Nature 464(7293):1390 (2010)
  Nature | Erratum Lessons on longevity from budding yeast * Matt Kaeberlein Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:464,Page:1390Date published:(29 April 2010)DOI:doi:10.1038/nature09046 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Nature464, 513–519 (2010) Figure 3 of this Review contained a minor error. The correct figure is shown below. Figure 1 * Full size image (63 KB) * Download PowerPoint slide (428K) Slides may be downloaded for educational use, according to the terms described in Nature Publishing Group's licensing policy. Additional data
• Grandfather paradox
  - Nature 464(7293):1398 (2010)
  A question of time.