Hot off the presses! May 20 Nature

The May 20 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:

• Still prime time for primates
  - Nature (London) 465(7296):267 (2010)
  Nature | Editorial Still prime time for primates Journal name:NatureVolume:465,Page:267Date published:(20 May 2010)DOI:doi:10.1038/465267aPublished online19 May 2010 Rats turn out to be surprisingly useful for research on cognition. But if the goal is to understand the human brain and its many disorders, then primate studies remain essential. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Researchers who study cognition in non-human primates have long had to contend with protests from animal-rights activists, who argue that experimenting on such close human relatives is ethically abhorrent. Now a wave of research showing that some cognition experiments can be carried out in rodents (see page 282) has given scientists something else to worry about. Will activists try to exploit these developments to argue that there is no longer a scientific justification for using primates? Even the most enthusiastic proponents of rodent-cognition research share this worry. They have had to argue hard to convince some people within the scientific community that useful work can be done in rats — and some sceptics remain unconvinced. But the rodent researchers have never argued that rats could or should replace primates in research that is ultimately directed at understanding how the human brain works — and thus what goes wrong in neurological and psychiatric conditions. "Non-human primates have a level of social intelligence that is missing in rodents but highly relevant for humans." What these scientists have discovered over the past decade or so is that rats can do simple cognitive tasks that had often been assumed to be beyond them and that, with appropriate training, they can indicate what is going on in their minds by poking their noses in different directions. In retrospect, this is perhaps not so surprising. After all, rodents in the wild have to navigate safely and successfully in constantly changing environments, just as primates do. Because the brain is the organ that has evolved to fulfil this task, the basic mechanisms for cognitive functions such as remembering, paying attention and discriminating certain stimuli are likely to have been conserved across evolution. This approach — combined with the low cost of rearing and keeping rodents and the wide availability of genetic tools for studying them — promises to help scientists to reach these basic cognitive components with unprecedented speed and rigour. Rodent research is also a less ethically sensitive issue than primate research, so the more information that can be wrung out of rats and mice the better. However, scientists will not be able to extrapolate directly from the rodent brain to the human brain to work out what has gone wrong in complex disorders such as schizophrenia. Nor will rodents do much to help scientists develop neuroprosthetics that may one day help to compensate for loss of brain tissue. Structurally, the brains of rodents and humans are just too different. The human organ has a large, highly evolved outer layer — the cortex — that provides a processing power unequalled in the animal world for making sense of external stimuli. Included in this layer, situated right behind the forehead, is a pronounced prefrontal cortex where thoughts are orchestrated and complex plans are formulated. Rodents, by contrast, have a minimal cortex and no prefrontal cortex. Their brains accordingly cannot help to illuminate the additional levels of complexity of functional brain networks in humans. The brains of non-human primates are anatomically closer to those of humans, so their cognitive strategies are more likely to be similar. Non-human primates also have a level of social intelligence that is missing in rodents but is highly relevant for humans. The empathy between primates allows them to form complex social bonds — and perhaps underlies the human instinct to protect monkeys and apes. Rodent studies have the potential to deliver reliable data that can inform human, and primate, cognition research, and allow those experiments to become even more revealing. But, if the goal is to understand the human brain and mind, rodent and primate work will need to be continued in parallel for the foreseeable future. It's a no-brainer. Additional data
• Change of purpose
  - Nature (London) 465(7296):267 (2010)
  Nature | Editorial Change of purpose Journal name:NatureVolume:465,Pages:267–268Date published:(20 May 2010)DOI:doi:10.1038/465267bPublished online19 May 2010 The United States should protect investments used to find new uses for old drugs. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg In 2007, a paper in the journal Cancer Cell announced that the compound dichloroacetate (DCA) had been found to shrink tumours in rats (S. Bonnetet al. Cancer Cell11, 37–51; 2007). That news by itself would not have created much of a stir: many compounds tested in rodents raise hopes of their becoming potential cures, and almost as many go on to fail in human clinical trials. But DCA had already been tested in humans against a condition called lactic acidosis, and so seemed to be relatively safe. Indeed, the authors of the paper argued that DCA could swiftly find its way into late-stage clinical trials against cancer — except for one problem. The drug was no longer protected by patents, and no pharmaceutical company would invest the millions of dollars needed to fund clinical trials. Since then, the researchers have managed to pull together enough funding for preliminary trials, the first of which was published last week (E. D. Michelakis et al. Science Transl. Med.2, 31ra34; 2010). Supported by a mix of Canadian federal grants and donations from philanthropic organizations and individuals, the study showed promising results when DCA was used against a form of brain cancer. But the team was able to test the drug in only five patients. And although the researchers have gathered enough funding for additional small studies, they admit that the prospect of moving into the final phase of clinical testing — which typically involves a much larger trial — is daunting. Over the past few years, as observers have lamented the declining productivity of the pharmaceutical industry, there have been many calls to speed up the process by 'repurposing' or 'repositioning' existing drugs. Unfortunately, that suggestion runs up against the same stumbling block faced by DCA: when drugs have gone off patent, it is difficult for a company to recoup the substantial investment required to test the drug in a new population of patients. Large pharmaceutical companies have expressed little interest in repurposing drugs — and at least two of the small companies that have tried have gone bankrupt. The fundamental difficulty is that patent systems generally reward innovation, not development. Although it is possible to file a new 'method of use' patent to cover a repurposed drug, such patents are difficult, if not impossible, to enforce if a generic copy of the drug is already on the market. Several solutions have been proposed, none of them perfect. One would be for the federal government to pay for clinical trials of repurposed drugs that — like DCA — lack intellectual-property protection. This is an expensive proposition, however, and taxpayers might chafe at the notion of paying for trials that were previously the responsibility of the private sector. Another possibility is to follow the path taken by the European Union, which allows an extra year of patent exclusivity if new uses are found for an approved drug. In the United States, a similar approach is already being used to encourage the testing of drugs for treating children: drug manufacturers get an extra six months of protection if they find a new paediatric use for their product. But this programme, although successful, comes with a trade-off: the drugs will remain free from generic competition, and therefore more expensive, for longer. It is a difficult conundrum, but one that warrants serious thought and creativity from researchers, agencies and policy-makers alike. This is especially true as the US National Institutes of Health designs its Cures Acceleration Network, which was mandated in the recent health-care reform bill. Funds permitting, the network will try to repurpose drugs that pharmaceutical companies have abandoned. Such an initiative could cut down the time and expense needed to find new therapies, and those who would take up the effort deserve support. Additional data
• Singular vision
  - Nature (London) 465(7296):268 (2010)
  Nature | Editorial Singular vision Journal name:NatureVolume:465,Page:268Date published:(20 May 2010)DOI:doi:10.1038/465268aPublished online19 May 2010 Reforms that could harmonize and enhance European research deserve support. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg If the plan set out on 11 May by Máire Geoghegan-Quinn, Europe's research commissioner, comes to fruition, the continent may finally realize its long-standing goal of a single market for science and technology. Her proposals aim to break down barriers to the transfer of knowledge and researchers, as well as to reform regulations that hamper high-tech businesses. The plan has three key elements. It would create a single patent system that would grant companies protection for their inventions across all the European Union (EU) member states at once, removing the need to file separate patents in multiple countries. It would also set up an EU-wide pension scheme to make it easier for researchers to move around the continent. At present, pensions are not transferable from one member state to the next, which discourages movement. Finally, it would increase public procurement: directing the money that EU agencies spend on areas such as telecommunications, energy-efficient buildings and computer software towards EU businesses, thereby spurring home-grown innovation rather than going after the cheapest price abroad. None of these ideas is new, although in the past they have struggled to gain traction. The EU patent, for example, has previously proved too controversial in too many countries to make much headway, and the others have never had a sufficiently vigorous political champion. "The goal is to create a smooth flow from research discoveries to products and services on the market." This time things may be different. Geoghegan-Quinn was an experienced politician in her native Ireland before assuming her current post, and she has quickly earned a reputation for being no-nonsense, hard-driving and determined. And, for the first time, she is pushing an integrated plan. Instead of treating research (primarily in academic institutions) and innovation (primarily in the business world) in a piecemeal fashion, as the commission has done in the past, her plan treats them as an organic whole. The goal is to create a smooth flow from research discoveries to products and services on the market. Geoghegan-Quinn says that the plan will refocus Europe's research efforts on a series of grand challenges facing the continent as a whole, such as climate change and an ageing population. New partnerships would bring together the EU, member states and public and private researchers to work on specific aspects of these grand challenges. For example, for the ageing-population challenge, these partnerships could work on tackling chronic diseases or on developing technologies to allow older people to stay in their homes for longer. Existing initiatives, such as Europe's multibillion-euro Framework programme for research, and the Joint Technology Initiative's public–private research partnerships, will also be integrated with the plan to avoid overlap. Although there are some potential pitfalls in the plan — the pursuit of direct societal benefits and high-tech industrial growth cannot be allowed to undermine basic research, for example — it is on the right track. Geoghegan-Quinn's vision will come under scrutiny this autumn, when EU heads of state meet to discuss it in detail. The task now is to sustain political momentum, and to ensure that the necessary decisions are taken at that autumn summit. European research minsters should explicitly give their endorsement for moving this agenda forward when they next meet on 25 May. Geoghegan-Quinn's reforms are especially important given Europe's current financial crisis. Budgetary pain is looming for everyone, so the kind of integration and coherence that Geoghegan-Quinn has outlined is essential for making the most effective use of the research money that scientists do have. Additional data
• Nanotechnology: Bacterial power
  - Nature (London) 465(7296):270 (2010)
  
• Neuroscience: Instant learning
  - Nature (London) 465(7296):270 (2010)
  
• Organic chemistry: Biofuel boost
  - Nature (London) 465(7296):270 (2010)
  
• Cancer: Melanoma's moving target
  - Nature (London) 465(7296):270 (2010)
  
• Ecology: No farm is an island
  - Nature (London) 465(7296):270 (2010)
  
• Cell biology: Viral vote
  - Nature (London) 465(7296):271 (2010)
  
• Neuroscience: Bright eyed
  - Nature (London) 465(7296):271 (2010)
  
• Physics: Not a WISP of evidence
  - Nature (London) 465(7296):271 (2010)
  
• Microbial genomics: A happy marriage
  - Nature (London) 465(7296):271 (2010)
  
• Journal club
  - Nature (London) 465(7296):271 (2010)
  
• News briefing: 20 May 2010
  - Nature (London) 465(7296):272 (2010)
  The week in science. This article is best viewed as a PDF. Policy|Research|Business|Business watch|People|The week ahead|News maker|Number crunch The oil spewing into the Gulf of Mexico was partially stemmed this week, after BP managed to force a siphon tube into the leaking wellhead pipe. But the political fallout intensified as Congress sought answers about the explosion of the Deepwater Horizon rig. US interior secretary Ken Salazar said on 11 May that the Minerals Management Service would be split up, separating safety and environmental operations from its oil-leasing arm. For more on the spill, see pages 274–275. NASA's ageing research labs are in dire need of an overhaul, according to a report released on 11 May by the National Academies. Some 80% of the agency's research facilities are more than 40 years old, and its deferred-maintenance bill has risen from US$1.77 billion in 2004 to $2.46 billion in 2009. US President Barack Obama's proposed 2011 budget for the agency would rectify some problems by transferring money from the cancelled Constellation moon-rocket programme to long-term technology-development and research. But legislators in Congress have so far fought the President's budget plan. The House of Representatives unexpectedly shot down science and education legislation on 13 May after Republicans raised concerns about the federal budget deficit and about government employees, including some at the National Science Foundation, viewing Internet pornography sites. The legislation would have authorized future spending under the 2007 America COMPETES Act, which called for a doubling of research funding in the physical sciences. See go.nature.com/aSMYlX for more. The Indian government on 15 May took over the Medical Council of India (MCI), three weeks after its president, Ketan Desai, was arrested on corruption charges (see Nature 464, 1251; 2010). An ordinance signed by Indian President Pratibha Devisingh Patil establishes a board of governors to run the council for one year. During that year, the government may also dissolve the MCI, which sets and maintains standards of medical education and accredits Indian medical schools. H. HAMBURG/AP US senators John Kerry (Democrat, Massachusetts; pictured centre) and Joseph Lieberman (Independent, Connecticut; pictured right) released their much-anticipated climate legislation on 12 May, setting the stage for one last attempt at getting climate legislation through the current Congress before the midterm elections in November. The bill would use a cap-and-trade scheme to curb emissions by 17% by 2020, and by some 80% by 2050 (relative to 2005 levels). It contains mechanisms intended to stabilize carbon prices and make costs predictable for industry (see go.nature.com/2mpfSN). A day later, the Environmental Protection Agency turned up the pressure on Congress by releasing a rule clarifying how greenhouse-gas emission restrictions would be phased in for major industrial polluters beginning next year — if Congress fails to enact climate legislation. On 14 May, the US National Institutes of Health doled out the final big chunk of new awards to be funded from its US$10.4-billion 2009 economic stimulus package: $1 billion to construct, repair and renovate research labs at extramural institutions in 44 states, Puerto Rico and the District of Columbia. The 146 individual grants include $7.4 million to the University of Alaska in Fairbanks for building clinical-trial facilities to study health disparities in Native Americans, and $15 million to the University of Colorado at Boulder for a new biotechnology facility housing 60 faculty members and more than 500 graduate students, researchers and support staff. A fire at a research centre in São Paulo, Brazil, has destroyed a leading collection of dead snakes. The state-funded Butantan Institute, which was nearly 100 years old, contained around 80,000 preserved snakes and thousands of spiders and scorpions that were used for biomedical research. The curator Franciso Franco has told press agencies that its destruction on 15 May was a "loss to humanity". The cause of the fire is being investigated. There is no clear link between mobile-phone use and the risk of brain cancer, according to a major study published this week (The INTERPHONE Study Group Int. J. Epidemiol. doi:10.1093/ije/dyq079; 2010). The study, run by the World Health Organization's International Agency for Research on Cancer in Lyon, France, interviewed thousands of adults with and without cancer in 13 countries about their mobile-phone usage. See go.nature.com/uZph7a for more. India's largest military technology research body is set for a management revamp under government measures announced on 13 May. The 52-year-old state-owned Defence Research & Development Organisation currently employs more than 5,000 scientists in 51 laboratories. It will be split into seven separately directed centres, such as life sciences and materials science, and projects will be monitored by a new oversight committee. A 2007 review had recommended restructuring the organization after criticisms that projects such as combat aircraft and guided missiles encountered huge time and cost overruns. The US pharmacy chain Walgreens postponed plans to start selling a personal genome-testing kit in thousands of its shops last week, after the Food and Drug Administration began an investigation into whether the kits require regulatory approval. The $30 saliva-collection kit is manufactured by Pathway Genomics, a direct-to-consumer genetic-testing company based in San Diego, California. Shoppers would have to send their DNA sample to the company's laboratory for a customized genetic report costing $79–249. The kit is already available to order online. Jinko Solar, one of several Chinese firms hoping to dominate the crowded silicon photovoltaic market, received a cautious welcome at its 14 May initial public offering on the New York Stock Exchange. The company, based in Shanghai, raised some US$64 million at $11 per share — a price at the lower end of its predicted range, and which stayed at that level throughout the day. It will use the money to expand manufacturing capacity. Astellas Pharma, headquartered in Tokyo, Japan, said on 16 May that it had agreed to pay US$4 billion to purchase OSI Pharmaceuticals, based in New York. The US firm is best known for its anticancer drug erlotinib (Tarceva). SOURCE: NEW YORK STOCK EXCHANGE Investors are losing confidence in Monsanto, the agricultural biotech giant based in St Louis, Missouri (see chart). Some farmers aren't seeing big yield increases with the company's new herbicide-tolerant soya bean line, Roundup Ready 2 Yield. They are also hesitant about buying its forthcoming SmartStax maize (corn), which incorporates eight genes conferring herbicide tolerance and insect protection. If farmers don't switch to Roundup Ready 2, the company's profits may suffer, as the original Roundup Ready trait goes off patent in 2014. According to Laurence Alexander, an analyst at investment bank Jefferies, headquartered in New York City, Monsanto is being squeezed in the North American soya and maize market by the world's number-two seed company DuPont, which owns plant-genetics firm Pioneer Hi-Bred International, based in Johnston, Iowa. Alexander worries that Monsanto will cut prices to protect its share, which could potentially hurt its research budget. But on 5 May, Carl Casale, Monsanto's executive vice-president and chief financial officer, said research spending was not in jeopardy. Meanwhile, Swiss firm Syngenta, based in Basel, is flexing its muscles with the imminent release of its herbicide-tolerant, insect-resistant Viptera maize. In the longer term, the three firms will also be vying to offer farmers drought-tolerant maize. David Willetts has been named as Britain's minister for universities and science. He was appointed on 12 May, after a coalition government had been formed between the Conservative and Liberal Democrat parties. Willetts, 54, studied philosophy, politics and economics at the University of Oxford, and has been a Member of Parliament since 1992. He was the Conservative Party's shadow minister for innovation, universities and skills for the three years leading up to the 6 May general election. Nobel laureate Harold Varmus is to be the next director of the US National Cancer Institute at the National Institutes of Health (NIH), replacing John Niederhuber. The $5.1-billion cancer institute is the largest of the NIH's 27 institutes and centres. Varmus, whose appointment was announced on 18 May, headed the NIH during the Clinton administration, between 1993 and 1999, and then became president of the Memorial Sloan-Kettering Cancer Center in New York, before advising Barack Obama during his run for the presidency. Mouse models of autism are one of the items on the agenda at the international meeting for autism research, which convenes in Philadelphia, Pennsylvania. → www.autism-insar.org This year's International Day for Biological Diversity (as proclaimed by the United Nations) has been allotted the theme of poverty and development. → www.cbd.int/idb The American Astronomical Society holds its 216th meeting in Miami, Florida. → aas.org/meetings/aas216 E. DEBEBE/UN PHOTO The Costa Rican diplomat, 53, is the new head of the United Nations Framework Convention on Climate Change, succeeding Yvo de Boer. April's combined land and sea surface temperature: the hottest April on record, at 0.76 °C above the average for the twentieth century. Source: NOAA 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.
• Oil cruise finds deep-sea plume
  - Nature (London) 465(7296):274 (2010)
  Nature reports from the research ship Pelican as scientists map the hidden extent of the Deepwater disaster. Researchers including (left to right) Matt Lowe, Vernon Asper and Andy Gossett have been studying the impact of the oil spill on ocean chemistry.M. Schrope The first oceanographic research expedition into the Deepwater Horizon oil-spill zone has uncovered evidence that a deep-sea plume — probably made of oil, and not visible on the surface — seems to be spreading from the ruptured wellhead. Environmental concerns following the oil-well blowout on 20 April initially focused on the effects of spilled oil on the Gulf of Mexico shoreline, which hosts many fishing communities and wildlife reserves. The discovery of the plume suggests that much of the oil may instead be lurking deep below the sea surface, with potentially dire consequences for marine organisms. The find is already raising questions about the possible impact of the widespread use of oil dispersants to tackle the spill, and comes amid growing dissatisfaction among researchers about the limited efforts that have been made so far to study the spill and accurately gauge its size. The team that found the plume is from the National Institute for Undersea Science and Technology (NIUST), a cooperative effort between the University of Mississippi in Oxford and the University of Southern Mississippi in Hattiesburg, funded by the National Oceanic and Atmospheric Administration (NOAA) in Silver Spring, Maryland. The researchers had originally been scheduled to map sea-floor formations in the Gulf of Mexico, just 15 kilometres from the Deepwater Horizon platform, and to survey historically significant shipwrecks using autonomous underwater vehicles launched from the Louisiana Universities Marine Consortium's 35-metre-long research vessel Pelican. But when the oil-well blowout happened, just days before the ship was scheduled to depart, team leaders decided that the group should divert to oil studies and set about getting approval from NOAA, which is funding the expedition through a competitively awarded grant. "We felt that the mapping that we wanted to do could wait and that it would be an inappropriate use of this valuable ship time to do something that was not as urgent as the oil study," says NIUST oceanographer Vernon Asper. For the first week of the cruise, much of the NIUST work focused on taking samples of sediment cores throughout the region, to develop a reliable baseline for future studies of oil that may settle to the sea floor. After a week of establishing a series of study sites, the team returned to port briefly to take on additional equipment — and a Nature journalist. "We've certainly put a kink in the efficiency of the system out there, but how much effect that will have and for how long, we don't know." On their fourth day back at sea, on 12 May, the scientists made an astonishing find. "You've got to see this," said Arne Diercks, rushing into the ship's main lab. As those aboard gathered in the control room where data from a lowered sampling system come through in real time, Diercks, NIUST's chief scientist for the cruise, pointed out the telltale instrument readings. At a depth of around 1,000 metres, the team seemed to have struck oil. The team's hypothesis was based on three key readings. The transmissometer, which measures the blocking of light by particles or opaque dissolved matter in the water, showed a serious hike in murkiness. The fluorometer, tuned to measure fluorescence given off by dissolved oil, was also giving readings many times higher than normal. And oxygen levels had dropped, suggesting heightened activity by microbes as they consume the oil and associated organic material. "We've got to home in on this," Asper said excitedly. "You never see signals like that in the open ocean." The team spent much of the remaining time at sea mapping the boundaries of a plume that extends about 45 kilometres southwest from the wellhead and roughly 10 kilometres wide at depths of 1,000–1,400 metres (see 'Oil zone'). On returning to previously sampled sites, the team showed that the plume was shifting, but that it generally remained at least 100 metres above the sea floor. Dispersant debate Data received from NOAA while the researchers were still at sea confirmed that deep-water currents at the time were flowing southwest, further suggesting that the plume they were measuring was oil emanating from the well. However, the group will not be able to confirm the plume's composition until tests on collected water samples are performed this week. Aboard the Pelican, the NIUST team watched as news of the plume spread, and eventually began getting satellite calls from journalists. On 16 May, at a daily press briefing, officials from energy company BP, which operates the well, skipped over an initial request for comment on the plume. In response to a second question, BP spokesman Andrew Gowers said: "We have no confirmation of that, but my observation as a layman is that oil is lighter than water and it tends to go up." Many scientists had also assumed that this was the case, although others had predicted that because of the depth of the leak, certain components of the oil would separate out as they rose to the surface and settle into a subsurface layer. Still, the magnitude of the plume was an unpleasant surprise. Experts including Jeffrey Short, an environmental chemist with the conservation advocacy group Oceana, based in Washington DC, have suggested that oil coming straight from the well could naturally break into small, less-buoyant droplets that would be capable of forming such a plume below the surface. But underwater use of dispersants, a previously untried technique that was approved by the Environmental Protection Agency (EPA) on 15 May, may also play a part by shaping the oil into smaller droplets. For several days before that announcement, and while the NIUST team was studying the plume, BP applied more than 100,000 litres of dispersant at the sea floor during EPA-sanctioned tests. Biogeochemist Samantha Joye at the University of Georgia in Athens, who works with the NIUST team and will be analysing the plume water samples, says that either possibility or a combination of both could explain the plume. But "it doesn't matter if it's dispersed oil or natural crude, it's going to have a huge impact", she says. Thomas Shirley, a marine biologist at Texas A&M University in Corpus Christi, says that although little oil has washed ashore and the harm to coastal ecosystems has so far been minimal, offshore species may be at greater risk. Toxic compounds from the floating oil could threaten species living near the surface, including commercially important fish and their prey, he says. Meanwhile, toxins from the under­water plume could affect deep corals and other species, a problem that could be exacerbated by dispersant use, which breaks up the oil into smaller particles and makes it easier for animals to take in. Shirley suggests that deep-dwelling organisms such as zooplankton might be hit by the low oxygen levels in the plume, which could take months or years to recover because oxygen is slow to diffuse into the deep. The plume could form a barrier that blocks the normal up-and-down daily migration of numerous organisms, and could block the flow of particles of organic debris from ! the surface to the deep where they are a critical food source. "We've certainly put a kink in the efficiency of the system out there," says Shirley, "but how much effect that will have and for how long, we don't know." Shirley says that as the effects of the deeper oil come to the fore, accurately assessing how much oil is gushing from the wellhead will be even more important. The official US Coast Guard estimate is 795,000 litres per day. However, a number of groups have questioned the figure, and Short says that the underwater plume could be further evidence that the true flow rate is much higher than the official figure. Whereas NOAA administrator Jane Lubchenco has argued that the estimate is reasonable and that having a more accurate rate would not change the response strategy, some researchers feel that knowing the spill's true size is essential to understanding its full biological impacts, and deciding whether massive deployment of dispersants is the best option. "I think that knowing the volume of oil is very important," says Shirley, "and I would urge BP to make all the video they have available and work with people to provide all the data possible." BP's ultimate legal liability for damages could be directly tied to the size of the spill, adds Short: "That is a long-standing principle in these sorts of cases." Last week, the administration of President Barack Obama sent a letter to BP asking for clarification on the company's financial redress plans and reiterating the position that BP is responsible for all clean-up costs and economic damage. A BP spokesman declined to comment on the potential implications of the plume. For now, both the gushing oil and the US political debate over drilling continue. On 16 May, BP reported that it had managed to insert a tube into the pipe coming out of the well, which it says is capturing about 320,000 litres of oil per day. And the company is pursuing several other options to capture leaking oil or close off the well before it can finish drilling a separate relief well, a process that could take months. On 14 May, the team aboard the Pelican all gathered in the galley to watch a press conference in which President Obama said that offshore drilling remains an important part of the overall US energy policy, although any movement towards expanding it is on hold. Short says that the drilling debate centres in part on weighing the benefits of oil against the environmental impact. "If the environmental impacts are an order of magnitude larger than anyone dreamed of, that's probably going to be a factor in the debate," he says, "I suspect BP has its eye on that too." * Read the full account of the Pelican's mission at http://go.nature.com/TBKWnY 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.
• Space-science hopes rest on rocket test
  - Nature (London) 465(7296):276 (2010)
  New launch vehicle could carry next generation of NASA's research probes. SpaceX When the Falcon 9 rocket makes its inaugural test flight, expected later this month, it will carry with it NASA's hopes for a new generation of low-cost rockets to ferry cargo and people into space. The rocket — touted as a possible saviour of human spaceflight — could also solve a serious problem facing the next generation of space probes. Satellites that observe Earth and nearby planets, as well as space telescopes able to look deep into the cosmos, are about to be hit by the retirement of the Delta II rocket, a workhorse that has launched 60% of NASA's science missions during the past decade. Among NASA's stable of rockets, the Delta II is the right size for all but the most ambitious science missions, and at about $50 million per rocket the price was right too — ten years ago. But since then, the cost of a Delta II launch has roughly doubled, making it unaffordable. The last science launch scheduled for the Delta II is in 2011, for GRAIL (Gravity Recovery and Interior Laboratory), a mission to study the Moon's core by mapping tiny variations in its weak gravitational field. "We're almost reaching the stage of desperation for launch vehicles," says Jack Burns, a space scientist at the University of Colorado at Boulder and a member of NASA's science advisory committee. NASA science chief Edward Weiler adds, "If there is no replacement ever for the Delta II, that would take away a critical capability." He hopes that in three or four years the Falcon 9, developed by SpaceX of Hawthorne, California, will emerge as a low-cost replacement. "Very much hoping, I might add." SpaceX unveiled its plans for Falcon 9 in 2005, and a year later won NASA contracts worth $278 million to develop rockets that could carry supplies and science experiments to the International Space Station (ISS). In December 2008, SpaceX won a $1.6-billion contract for 12 ISS resupply flights, up until the end of 2015. The rocket's potential role expanded in February, when President Barack Obama proposed axing the suite of NASA rockets intended to replace the Space Shuttle and once again send humans to the Moon. Some $6 billion over 5 years — money that would have gone to the Constellation rockets — would instead be ploughed into commercial providers such as SpaceX, in the hope that they could transport not only cargo, but people as well (see Nature 463, 716–717; 2010). This radical transition is still very much in doubt, as legislators in Congress fight to protect space-industry jobs (see Nature doi:10.1038/news.2010.189; 2010). Yet even the most ardent critics of Obama's new space vision are eager to see whether Falcon 9 can help to keep NASA astronauts in space. "The more the launch vehicle costs, the less science mission you get for your money." In the obsession over human space flight, many are overlooking the role that the Falcon 9 could have in replacing the Delta II, which came to prominence during a golden era in the 1990s when rockets were plentiful and relatively inexpensive. The rocket's biggest buyer, the US Air Force, had to launch a constellation of global positioning satellites, and private satellite-communication companies such as Iridium were also snapping up the rockets by the handful. But then the communications satellite market dried up, and the Air Force said it no longer had an essential need for the Delta II, conducting its final launch with one last year. Instead, the Air Force has committed to sustaining the very large Delta IV and Atlas V rockets in the Evolved Expendable Launch Vehicle programme. Price hikes As buyers have bailed, the price of a Delta II, including launch, has shot up. A decade ago, they were a relative bargain, ranging from $50 million to $80 million apiece. Now, each one costs about $120 million — almost as expensive as the much bigger Atlas V — with further hikes expected. United Launch Alliance, the joint venture of Lockheed Martin and Boeing that makes the Delta II, would be happy to continue selling it to NASA. The components for five rockets are waiting to be assembled, says William Wrobel, who directs NASA's launch services programme. The problem is that, without the additional buyers and bigger market, NASA cannot afford to pay for the upkeep of the launch-pad infrastructure that the Air Force had paid for. "NASA can't go it alone," says Wrobel. Wrobel says that most imminent mission launches, such as the 2011 launch of the heavy Mars Science Laboratory and Juno, a mission to Jupiter, needed the extra thrust of an Atlas V anyway. But if NASA officials are forced to buy more Atlas Vs in the future, they will be paying extra for unused launch capacity. "The more that the launch vehicle costs, the less science mission you get for your money. Or fewer missions," says Alan Stern, a planetary scientist at Southwest Research Institute in Boulder, NASA's former science chief and an advocate of commercial space flight. Several missions could take advantage of Falcon 9's leaner launch capability and lower price of about $50 million per launch. These include the Soil Moisture Active and Passive mission, an Earth-observing satellite due for launch in 2015; the International Lunar Network, a system of landers designed to measure the Moon's seismic activity, among other things; and modest-sized astrophysics and planetary-science missions that would launch in 2016. ADVERTISEMENT All bets are not riding on the Falcon 9, however, which will launch from Cape Canaveral, Florida, and carry a prototype of its cargo capsule Dragon. Orbital Sciences, headquartered in Dulles, Virginia, and another winner of ISS cargo-transport money, is developing the Taurus II, another medium-sized launcher that is scheduled for first test flights in 2011 (see Mid-sized rockets need a boost). For the planned 2012 launch of the Lunar Atmosphere and Dust Environment Explorer (LADEE), Orbital is putting together stockpiled ballistic missiles into the Minotaur 5, which costs less than $50 million and is just the right size for the small Moon mission. If Falcon 9's test launch is successful, it should be carrying cargo to the ISS within a few months. But scientists will have to wait a while longer — before a new rocket can carry a scientific payload, NASA requires three successful launches and a technical certification that takes about three years. NASA hopes to certify Falcon 9 or one of its competitors by the end of 2013. 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.
• Neglected diseases fund touted
  - Nature (London) 465(7296):277 (2010)
  Initiative seeks billions of dollars to develop promising drugs and vaccines. Despite decades of research into drugs and vaccines for neglected diseases such as tuberculosis and dengue fever, few products have made it through clinical development and into the hands of the millions who desperately need them. One of the biggest hurdles is the sheer expense of running clinical trials, compared with the small profits that commercial companies can expect to make from treatments for diseases that disproportionately affect poor and marginalized populations. This week, alongside the World Health Organization's (WHO's) annual assembly of health ministers in Geneva, Switzerland, a consortium of industry and non-governmental organizations proposed a scheme to help address the problem: a global fund that would channel billions of dollars a year into product development. Plans for the fund were put forward by the International AIDS Vaccine Initiative (IAVI), the pharmaceutical giant Novartis and the George Institute for International Health in Sydney, Australia. It would channel money from donors towards product-development partnerships (PDPs) — collaborative efforts between research agencies, donors and biotech and pharmaceutical companies to develop drugs, diagnostics and vaccines for the developing world. The fund aims to encourage contributions from donors who lack the resources or expertise to assess the quality and progress of the various PDP offerings. Dozens of not-for-profit PDPs, including the IAVI, the Medicines for Malaria Venture, the Global Alliance for TB Drug Development, and the Drugs for Neglected Diseases initiative (DNDi), have been set up during the past 15 years. Their aim is to bridge the gap between basic research and product development, and to prevent promising research leads for neglected diseases from languishing on the shelf. They are run like businesses, but are supported by donor funding, and have generous intellectual-property rules to make any products affordable to poor countries, allowing generic manufacturers to make cheap versions freely. PDPs have become an attractive choice for neglected-disease donors — of the estimated US$3 billion spent on such research in 2008, about one-fifth was channelled through PDPs. Although only 13 of more than 1,000 drugs developed between 1975 and 1997 were for neglected diseases, PDPs created over the past decade already have 143 candidate products in development, and have rolled out 11 products for malaria, leishmaniasis and meningitis. But many PDPs need a fresh cash injection as more of their product candidates begin to enter clinical development, the most expensive phase of drug and vaccine discovery. Without substantial new funding, projects will stall and waste much of the earlier development work and investments, says Paul Herrling, head of the Novartis Institutes for Developing World Medical Research. The proposed PDP+ Fund would seek to raise funds from governments and other donors, and through bond financing and innovative taxation schemes. It would act as a one-stop-shop for donors, coordinating funding of projects to many different PDPs. ADVERTISEMENT "Do we need a super-PDP fund? Without a doubt," says Jean-François Alesandrini, a spokesman for the DNDi. However, he cautions that the details of the scheme still need fleshing out, particularly on the issue of attracting new donor funding. Many questions remain as to how the PDP+ Fund would work, adds Alesandrini, in particular its governance structure, and how its expert committees would choose which projects to fund. Herrling says that informal discussions he has had with donors, including the US government, have been positive, as have those with other companies and groups that will be invited to come on board. The PDP+ Fund resembles the idea for a global research fund that was floated by a WHO expert panel in 2002 to complement the multibillion-dollar Global Fund to Fight AIDS, Tuberculosis and Malaria. This was created in the same year, but funds only disease-control measures, not research. The global research fund proposal never gained traction because governments considered it a risky venture, says Mary Moran, director of health policy at the George Institute. The difference now, says Herrling, is that PDPs are widely recognized to produce drug leads. "We have a state-of-the-art pipeline that now needs investment to take forward," 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.
• Pact protects Canadian forests
  - Nature (London) 465(7296):279 (2010)
  Huge conservation deal will benefit caribou and maybe climate. G. Lenz An unlikely coalition of logging companies and environmental groups has reached an agreement to protect more than 300,000 square kilometres of Canadian boreal forest — an area larger than the United Kingdom — the biggest forest-conservation deal in history. An additional 385,000 square kilometres will fall under strict guidelines that will promote sustainable logging and protect ecologically and culturally sensitive sites. Under the agreement, unveiled on 18 May in Toronto, Ontario, 21 members of the Forest Products Association of Canada, which represents the majority of companies in the Canadian logging industry, will set aside slightly less than half of the land for which they hold leases across seven provinces. In exchange, nine environmental groups, including Greenpeace and the Nature Conservancy, have pledged to suspend do-not-buy campaigns against the loggers' products, which range from construction lumber to toilet paper, and to actively endorse them. "We strongly believe that every improvement in environmental quality can translate into market value for our products," says Avrim Lazar, president of the Forest Products Association. Crucial habitats The finer details of areas to be preserved (see 'Protection plan') will be chosen by biologists and logging companies. Their choices will have to be approved by the provincial governments and Native Canadians. "This will allow us to protect the most intact parts of the boreal forest that are critical habitat for the caribou and other species," says Steve Kallick, director of the Pew Environment Group's International Boreal Conservation Campaign, based in Seattle, Washington, which brokered the deal it hails as "radically pragmatic". When added to earlier commitments by Ontario, Quebec, Manitoba and the Northwest Territories as well as the federal government, this week's agreement means that 1.6 million square kilometres of Canada's boreal forest will be off-limits to logging, which will make it the largest area of protected forest in the world. This is good news for caribou, whose numbers in Canada have been in steep decline. But it may also slow down global warming, given mounting evidence that boreal forests are important carbon stores. "Protecting these forests and their soil, which has enormous amounts of carbon, is a hugely important step forward," says Stuart Pimm, a conservation ecologist at Duke University in Durham, North Carolina, who advises Pew. Unlike tropical forests, which constantly recycle atmospheric carbon through phases of growth and decay, boreal forests experience less decay and instead tend to pool carbon in soil and peat. A recent study led by Sebastiaan Luyssaert, a biologist at the University of Antwerp, Belgium, found that mature boreal forests remain active carbon sinks rather than becoming carbon-neutral ecosystems as they mature (S. Luyssaert et al. Nature 455, 213–215; 2008). "As long as they're alive, they keep accumulating carbon," says Luyssaert. The northern circumpolar permafrost region, which includes most of the boreal forests earmarked for protection, contains "approximately 50% of the estimated global belowground organic carbon pool", according to a study co-authored by Josep Canadell, director of the Global Carbon Project in Canberra, Australia (C. Tarnocai et al. Global Biogeochem. Cy. 23, GB2023; 2009). Canadell says that cutting down forests sometimes results in the drying out of wetlands and peat bogs and the release of their huge carbon stores — which hold an average of 7,800 tonnes of carbon per hectare, far more than any other ecosystem. But Werner Kurz, a senior researcher at the Canadian Forest Service in Victoria, British Columbia, isn't sure that forest conservation is going to slow down warming. Given the speed of climate change, it's not clear that intact forests will necessarily be more resilient than well-managed ones, he says. For instance, harvesting old-growth trees and replacing them with seeds obtained from warmer climes can produce trees that will better withstand temperature increases, he says, and as such would be more likely to thrive and sequester carbon. "We're still not sure exactly how useful these forests are going to be in mitigating global warming," says Hank Margolis, a forest ecosystem scientist at Laval University in Quebec City, who heads the Canadian Carbon Program. "That's why it makes sense to keep them intact until we figure it out. And to do that, we're going to need to do a lot of science." The forests may fare better than the research programmes. For years, the Canadian government has declined to renew funding for the Canadian Foundation for Climate and Atmospheric Sciences — its granting agency dedicated to climate research in universities. "I'm afraid most of our research will die out by the end of the year," says Dawn Conway, the foundation's executive director. 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.
• Malaria may not rise as world warms
  - Nature (London) 465(7296):280 (2010)
  Studies suggest that strategies to combat the disease are offsetting the impact of climate change. Preventative measures such as the widespread use of bed nets have outweighed the effects of climate warming on malaria.W. DANIELS/PANOS Of the many climate-change catastrophes facing humankind, the anticipated spread of infectious tropical diseases is one of the most frequently cited — and most alarming. But a paper in this week's Nature adds to the growing voice of dissent from epidemiologists who challenge the prediction that global warming will fuel a worldwide increase in malaria. On the surface, the connection between malaria and climate change is intuitive: higher temperatures are known to boost mosquito populations and the frequency with which they bite. And more mosquito bites mean more malaria. Yet when epidemiologists Peter Gething and Simon Hay of the Malaria Atlas Project at the University of Oxford, UK, and their colleagues compiled data on the incidence of malaria in 1900 and 2007 (see page 342), they found the opposite: despite rising temperatures during the twentieth century, malaria has lost ground. According to the models the researchers used to tease out the factors affecting the incidence of malaria, the impact of public-health measures such as improved medications, widespread insecticide use and bed nets have overwhelmed the influence of climate change. "Malaria is still a huge problem," says Gething. "But climate change per se is not something that should be central to the discussion. The risks have been overstated." Some earlier analyses painted a dire picture of a malaria-ridden future, but these models often exclusively evaluated the impact of warmer temperatures without taking other factors into consideration, says Paul Reiter, an entomologist at the Pasteur Institute in Paris. The latest assessment of the Intergovernmental Panel on Climate Change noted these concerns: "Despite the known causal links between climate and malaria transmission dynamics, there is still much uncertainty about the potential impact of climate change on malaria at local and global scales." Gething and colleagues' study is the first of its kind to provide a detailed statistical model of global trends over the twentieth century, but it does have limitations. For instance, the data used to generate a global map of malaria in 1900 sum up all malarial infections, including those by a malaria parasite named Plasmodium vivax, whereas the data in the 2007 map track infections by just one malaria parasite, P. falciparum, which carries the highest disease burden. And the analysis does not take into account some parameters that are likely to change as a result of global warming, such as rainfall patterns and human migrations. Nevertheless, the results largely match those of several other recent studies, including one published last year by Kevin Lafferty of the US Geological Survey in Santa Barbara, California, which also concluded that rising temperatures over the last century had no net impact on the incidence of malaria (K. D. Lafferty Ecology 90, 888–900; 2009). In 2000, models designed by David Rogers and Sarah Randolph at the University of Oxford predicted that although some parts of the world would gain malaria because of climate change, large areas would see a drop in disease due to reductions in rainfall and humidity (D. J. Rogers and S. E. Randolph Science 289, 1763–1766; 2000). The result: no net difference. "The complexity of malaria and the other vector-borne diseases is astonishing," says Reiter. "To bring it down to just one factor — climate change — is totally unjustifiable." The same could hold true for other diseases that rely on intermediate vectors like mosquitoes. Dengue fever, for example, has also been touted as an infectious disease that could get a boost from climate change. The virus, which is carried by mosquitoes, is already on the march, and is spreading more rapidly into the southern United States. But the impact it will have there is likely to be minimal compared with that in less developed regions of the world because of lifestyle differences, says Reiter. Americans spend more time indoors, he says, and are more likely to have window screens to keep mosquitoes out. ADVERTISEMENT Laura Harrington, who studies mosquito-borne diseases at Cornell University in Ithaca, New York, agrees. "In the context of vector-borne diseases, climate change is probably going to have a minimal role in comparison to other factors," she says. Even so, Gething's results are likely to be controversial, cautions Richard Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies in Millbrook, New York. Although global analyses such as Gething's are useful, he says, they may miss important regional trends — such as the spread of mosquitoes from the lowlands to the highlands of eastern Africa, which some argue is the result of rising temperatures. "There's a pretty strong spatial disconnect between areas where there is strong economic development and increasing control of mosquitoes, versus those areas where the risk of climate-induced disease is highest," he says. Others worry that the results of the study will be misinterpreted. "On smaller scales, climate change certainly has big effects on disease," says Harrington. "This does not diminish the importance of climate change at all." 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.
• Pacific tuna population may crash at any time
  - Nature (London) 465(7296):280 (2010)
  Researchers warn that confidence in stock's health could be misplaced. Numbers of Pacific bluefin tuna may be about to go the same way as those of their Atlantic cousins. The Pacific population was thought to be the endangered fish's only remaining stronghold. But official reports on stock sizes have overlooked changes to fishing practices that could mean they are heading for a crash, according to recent assessments. Pacific bluefin tuna are in high demand.R. HERRMANN/PHOTOLIBRARY.COM In the Atlantic Ocean and the Mediterranean Sea, fishing has caused tuna populations to fall below 15% of their historical levels. Even so, an attempt this year to ban trade in the fish failed to gain international approval at a meeting in March of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (see Nature doi:10.1038/news.2010.139; 2010). By contrast, Pacific bluefin (Thunnus orientalis) populations had been thought to be stable, with enough young fish maturing each year to replace those caught. In July 2009, a working group of the International Scientific Committee for Tuna and Tuna-like Species in the North Pacific Ocean (ISC) concluded that recruitment of juveniles to the population "does not appear to have been adversely affected by the relatively high rate of exploitation". But the working group admitted that a lack of data meant recruitment since 2005 is highly uncertain. And the belief that the stock is stable is based on a false assumption that fishing practices have not changed, says Toshio Katsukawa, a fisheries expert at Mie University in Tsu City, Japan. From speaking to fishermen, Katsukawa is most concerned that, in the past few years, boats have begun targeting the tuna's spawning grounds. This tactic increases catches, simultaneously making the stock seem bigger but damaging the fish's breeding capacity. "If things go on like this, the Pacific [bluefin] populations will be the first to collapse [before the Atlantic stock]," says Katsukawa. The change in fishing practice has gone hand in hand with a growth in the market for juvenile tuna, says Chien-Chung Hsu, a fisheries biologist at the National Taiwan University in Taipei. Juveniles 10–15 centimetres long fetch US$100 each in Japanese markets, he says. By contrast, adult Pacific bluefins can sell for $100,000 or more, and Katsukawa points out that fishermen could make more profit by waiting for the fish to mature. Overall, more than 70% of the Pacific bluefin catch is taken by fishermen from Japan, where the fish is prized for its use in sushi. Data from the ISC show that more than 70% of Pacific bluefin tuna caught today are less than one year old, compared with around 60% in the 1960s, although Katsukawa believes that even this increase is an underestimate. More than 90% of the catch is less than two years old. "The increasing juvenile catch is increasing the risk of population collapse," says Hsu. "The population is dropping for all age classes and we see signs of serious problems if no management measures are set immediately." ADVERTISEMENT Responding to concerns about the health of the stock, Japan's Fisheries Agency last week outlined new measures to monitor and manage the tuna populations. These specify limits on the weight of fish that each boat can catch, restrictions for the large boats using encircling nets that account for most tuna fishing, along with new requirements for other boats to report their catches. And fish farmers, who collect an increasing but unknown number of juveniles and raise them in pens, will be required to register and report their activities. The agency plans to implement the restrictions by April 2011. The measures also call for better information on juvenile stocks and spawning areas, and for the establishment of an international network of researchers to study and manage Pacific bluefin tuna fisheries. "To protect these spawning regions, we have to find out where they are and when the peak seasons are. Then we can start to make restrictions on which ones can be fished and when they can be fished," says Yukio Takeuchi, a researcher at the National Research Institute of Far Seas Fisheries, an arm of the Fisheries Agency based in Shizuoka, Japan, who chaired the ISC working-group report. Katsukawa says that the new measures, "if done effectively", could have a major impact. But he fears they will be implemented too slowly to head off an irrecoverable drop. "It could happen suddenly, but we won't see it until it happens." There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Correction
  - Nature (London) 465(7296):281 (2010)
  The News story 'China and Taiwan strengthen academic ties' (Nature 465, 148–149; 2010) incorrectly stated that Xiao-fan Wang is the first mainland-China-born president of the Society of Chinese Bioscientists in America. In fact, he is the first president to be born, raised and educated under the communist government of the People's Republic of China. The News Feature 'Life after death' (Nature 465, 150–155; 2010) misspelt the name of Debra Moriarity throughout. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Neuroscience: The rat pack
  - Nature (London) 465(7296):282 (2010)
  Studying primates is the only way to understand human cognition — or so neuroscientists thought. But there may be much to learn from rats and mice, finds Alison Abbott. Download a PDF of this story. Anne Churchland had little time for rats. In the course of 13 years' work on decision-making in monkeys, she had never questioned that primate studies were the only way to understand the neurobiology of human cognition. Her work in the lab of Michael Shadlen at the University of Washington, Seattle, had monkeys watch moving dots flitting about on a screen until the animals indicated, with a flick of their eyes, the direction in which most of the dots were going. She recorded from single brain neurons as the monkeys slowly made sense of this 'fuzzy' information — the sort of sophisticated experiment that she did not think was possible in rodents. "I didn't think rats would have the right sorts of brains to contemplate accumulating evidence," says Churchland. And with poor eyesight, and heads that bob around, "I didn't imagine they would be able to convey to us any decision they might be silently making". All that changed a year ago, when Churchland visited Cold Spring Harbor Laboratory in New York. Working with scientists there, she saw that rats could also learn to gather 'fuzzy' sensory information — in this case to decide whether the frequency of a rapid sequence of tones was mostly high or low. And they could convey their decision with a poke of the nose. Churchland was not alone in her earlier scepticism. Neurophysiological research into higher cognitive functions such as decision-making, attention, working memory — even risk-taking — have traditionally been carried out on non-human primates. That seemed an obvious choice, given the closeness of their brain anatomy to that of humans, the sophistication and breadth of their behaviour and their ability to reliably report to experimenters much of what is going on in their minds through eye, hand or other movements. But primate work comes with major downsides: the animals are so expensive, and their use so highly regulated, that a research paper typically relies on data from just a couple of precious animals, which have been used for multiple experiments over their lifetime. This raises concerns that observations could be unique to those animals, rather than a general property of the primate brain. Mice and rats, by contrast, can be studied in the tens or hundreds. But with brains a fraction of the size of those of humans or non-human primates — and no prefrontal cortex, the highly-evolved brain area where 'higher' cognition is thought to take place — neuroscientists assumed that rodents were simply incapable of learning complex behavioural paradigms. That scepticism is dissolving, thanks in large part to a 'rodent cognition movement' started by a small group of researchers at Cold Spring Harbor almost a decade ago and now spreading far beyond its grounds. Using carefully designed tasks, these researchers have shown that rodents can undertake some types of complex cognitive behaviour just like experimental primates, and just like humans. "Primate used to be the only game in town," says Zachary Mainen, now at the Champalimaud Neuroscience Programme in Lisbon, Portugal, but one of the founders of the rodent movement when he was at Cold Spring Harbor. "Now we are starting to appear as a small force in cognition meetings." Evolutionary similarities Mainen joined Cold Spring Harbor Laboratory in 1999, the same year as his colleague Tony Zador. Both wanted to move beyond their backgrounds in computational neuroscience and cellular neurophysiology, and find out how electrical activity in neurons — such as that stimulated by sensory input — related to behaviours such as decision-making. They thought that these components of behaviour "would likely be evolutionarily similar across mammals", says Mainen. And rats, they thought, would move the field forwards faster than primates, particularly given the greater availability of tools for manipulating rodent genes. Researchers including Zachary Mainen (left) and Tony Zador founded a 'rodent cognition movement'.R. OCHÔA/FUNDAÇÃO CHAMPALIMAUD Zador sees the choice of primates for cognition experiments as a "historical accident", naturally evolving from research begun in the 1960s to understand how vision was processed in the brain. "Using primates made complete sense, because vision is so highly specialized in primates for functions such as face recognition," he says. Then, in the 1980s, some primate-research groups went on to ask how visual information couples to motor output; having seen an object, what happens in an animal's brain as it decides whether to reach for it? The interesting questions were now about cognition. "At this point primates offered no unique advantage, because the tasks that the researchers were asking monkeys to do were so simple," says Zador. To study these tasks in rats, Zador and Mainen had to decide what sensory system to use, and establish a behavioural read-out. Rodents primarily rely on senses other than vision, such as hearing and smell, to guide their behaviour. So Zador began to look at how rats processed auditory information; Mainen focused on odours. It took a few years, and a lot of trial and error. But by 2003 Mainen had published his first paper1 showing that rats could be trained to reliably repeat behaviour, discriminating between similar smells after a single whiff. More to the point, he showed that they could indicate their detection of an odour by poking their noses through a 'port' in the cage wall. A rat indicates a decision by poking its nose through a 'port' when it has discriminated between two odours.A. MENDONÇA That paper was an eye-opener for Carlos Brody, a computational neuroscientist at Cold Spring Harbor. "I had theories that I would have liked to test in a primate lab, but this paper showed that you could do equally rigorous work with rats," he says. Brody joined forces with Mainen and Zador and the three of them persuaded the laboratory to set up the Center for Neural Mechanisms of Cognition in 2006, devoted to rodent work. In 2008, Mainen published a second watershed paper, using electrophysiology to show how rats make everyday decisions on the basis of fuzzy evidence2. This time he trained rats to distinguish between two odours delivered through the central port of a row of three. If a mixture had more of odour one, the rat had to poke its nose through the left-hand port; if it had more of odour two, it had to select the right-hand one. The decision became very difficult when the mixtures contained nearly equal parts of the two odours, but if the rats decided correctly, and waited long enough at the correct port, they received a drink reward there. The more confident rats were about their decision, Mainen found, the longer they were prepared to wait. And when he took recordings from single neurons in the orbital frontal cortex, a brain area involved in decision-making, he found patterns of electrical activity that correlated with the rats' conviction. "It hadn't been clear whether the rat bra! in was going to be up to the task of estimating confidence in decisions," says Mainen. "But we showed it was, and at least in this sort of task, rats are as good as monkeys as subjects." In certain ways, rodents are better. In the past few years the development of 'optogenetic' tools has allowed rodent researchers to engineer particular neurons so that their activity can be switched on or off with flashes of laser light3, allowing the role of neurons in a behaviour circuit to be dissected. Right now these systems work best in mice. But because most behavioural studies have been carried out using rats, cognitive scientists have mostly chosen to start on rats in the hope that the techniques will be quickly transferred. Zador says it's still not clear whether the smaller-brained mouse is capable of the behaviours in which the field is interested. Rodent logic Churchland is so taken with the experimental possibilities afforded by rodents that she is staking her career on them. This summer she is moving to Cold Spring Harbor, where she will establish her own lab to study rat decision-making. Looking back, she wonders why she doubted rats' cognitive abilities so much. "They also have to make decisions in the wild in order to survive, and would obviously have to accumulate and sift evidence to do so." She wants to explore why some rats choose a strategy of decision-making that sacrifices accuracy for speed. "With higher numbers, we can start to look at individual differences," she says. "The rat brain shares some of the most fundamental design principles with those of humans." Other committed primate researchers, such as Daeyeol Lee, a neuroeconomist at Yale University School of Medicine in Connecticut, are also exploring the use of rodents. Lee has been working on primate decision-making for 15 years. "The rat brain shares some of the most fundamental design principles with those of humans and other primates, such as connectivity between the cortex and some sub-cortical areas," he says. "Rats may be able to teach us a lot." And behavioural researchers are working to see how far they can go with rodents, developing new paradigms in rats that might even mimic some classic human psychology tests, including a version of the Iowa gambling task, which probes the ability to make appropriate decisions in the face of stacked odds4. Researchers have also claimed that a paradigm based on the prisoner's dilemma, which explores why people might not cooperate even when it is in their best interests, shows that rats can understand the complex pay-offs that coop! eration entails5. Some primate researchers, though, remain unconvinced. "It is good to develop rodent models and see what they are capable of," says Shadlen. "But it still isn't clear to me that rodents do any serious deliberating in decision-making." And Daniel Salzman at Columbia University in New York says that the differences, rather than the similarities, in brain anatomy and circuitry are going to be decisive, such as the smaller rodent frontal cortex. Rodent researchers "are quickly going to run up against a wall," he predicts. ADVERTISEMENT Still, few on either side of the species divide care to be too categorical. Rodent-cognition researchers have presented enough new data at meetings to discourage dogmatism from primate loyalists. And rodent proponents emphasize that primates will always be required to reality-check the theories about cognition spawned by rodent research. "Primates are going to be capable of some cognitive processes that rats are simply not capable of," says Brody, who thinks both types of research should run in parallel. "But the jury is still very much out in terms of where the capability border lies, and we think it is worth finding out." * References * Uchida, N. & Mainen, Z. F.Nature Neurosci.6, 1224-1229 (2003). * Kepecs, A. , Uchida, N. , Zariwala, H. A. & Mainen, Z. F.Nature455, 227-231 (2008). * Buchan, L.Nature465, 26-28 (2010). * Zeeb, F. D. , Robbins, T. W. & Winstanley, C. A.Neuropsychopharmacol.34, 2329-2343 (2009). * Viana, D. S. , Gordo, I. , Sucena, E. & Moita, M. A.PLoS ONE5, e8483 (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.
• Oceanography: Death and rebirth in the deep
  - Nature (London) 465(7296):284 (2010)
  When a submarine volcano erupts, the results can be devastating — and fascinating. Jane Qiu finds new drama in underwater biogeography. Download a PDF of this story. Richard Lutz, a marine biologist at Rutgers University in New Brunswick, New Jersey, and his colleagues were 2,500 metres beneath the ocean's surface when they encountered the 'blizzard'. It was April 1991, and an underwater ridge, 900 kilometres off the coast of Acapulco, Mexico, was splitting open, introducing 1,200 °C molten rock to 2 °C water. The results were apocalyptic. While the researchers kept a safe distance from the action in their submersible, the 'snow' of microbial debris blowing around them signalled devastation at the site of the eruption. The bacteria had been thriving at the mouths of hydrothermal vents in the area, extracting energy from the hydrogen sulphide and other chemicals pouring out of the sea bed. In turn, the bacteria nourished a diverse ecosystem of organisms: clams, crabs, mussels and armies of tubeworms. The eruption had laid waste to nearly all of this. But nature wasn't permanently obliterating life at this site at latitude 9° 50′ N on the East Pacific Rise — rather, it was hitting the reset button. Lutz and his colleagues now had an opportunity to see how life returns to the vents. Putting monitoring equipment in place and returning regularly, they documented the drama of life-after-death as it unfolded. And after 15 years of research, nature repeated the experiment: Nine North, as the researchers call the site, erupted again in 2006. "It is the only deep-sea location where a full eruptive cycle has been observed," says Lauren Mullineaux, an ecologist at Woods Hole Oceanographic Institution (WHOI) in Massachusetts who has been working at the site. Nine North has allowed marine biologists to identify the first species to return to a vent and the parade of life that follows. And now, four years on from the latest eruption, researchers have begun to answer tougher questions: where do these species come from, how do they travel and how do their populations shift over time? "Habitat turnover is a window into evolutionary pressures that contribute to speciation." But more than that, says Robert Vrijenhoek, a molecular ecologist at the Monterey Bay Aquarium Research Institute in Moss Landing, California, "habitat turnover is a window into evolutionary pressures that contribute to speciation and genetic diversity". By identifying more vent sites around the world, researchers are starting to untangle the intricate interconnectedness between these tiny islands of life scattered through the abyss and separated by vast distances and rugged topography. These sites share similar geological features, with mineral-spewing vents and daunting ridges and valleys. But they don't always share the same species. Researchers are now starting to understand why. Rapid succession The first glimpses through the window provided by Nine North revealed a picture of a community rebuilding quickly, says Timothy Shank, a marine biologist at WHOI who collaborates with Lutz (see 'The cycle of life'). The microbial snowfall that piled around the volcano after the 1991 eruption first attracted grazers — shrimps, crabs and fish — both vent and non-vent in origin. Within a year of the eruption, the tubeworms returned. First came Tevnia jerichonana, which thrives at high sulphide concentrations; then, as sulphide levels dwindled in the subsequent year, dense bushes of Riftia pachyptila, the giant tubeworm, took over. Click for a larger version.N. SPENCER Thousands of these creatures, with sturdy tubes up to two-metres long, created a rich environment for other organisms to inhabit. Snails, and more crabs and swarming shrimps arrived1. It was a never-before-told story of biological succession. But it was unclear whether the organisms taking over the vents were from local sources or came from far away. Nor was it clear whether species composition in the region had changed as a result of the eruption, says Shank, because the area had not been studied in great detail previously. This is where Mullineaux, a specialist in marine larvae, comes in. Although many vent inhabitants are fused to the sea floor or to other organisms as adults, most spend their early lives as free-swimming larvae that can ride the currents to new homes. She and her team have been studying larvae at Nine North ever since the 1991 eruption. They've collected them at different depths and at the sea floor to get a sense of abundance and species make-up. As Mullineaux and her colleagues describe in a paper published this year2, the species composition of the larvae at the hydrothermal vents changed markedly after the 2006 eruption. Larvae from species common at the site before the eruption were nowhere to be seen afterwards — even though there were potential sources of recolonization within a few kilometres. By contrast, other species that had been rare became abundant after the catastrophe. The Woods Hole team also discovered larvae of a species never seen before at Nine North, a rock-clinging snail called Ctenopelta porifera. The nearest hydrothermal system known to host the species is more than 300 kilometres to the north. "This has greatly exceeded our expectation of how far vent larvae could travel in the ocean," says Mullineaux. Mullineaux's group had in 2001 calculated that a larva with a lifespan of about a month could travel at most up to 100 kilometres from Nine North and that the majority stayed within 60 kilometres3. Even if larvae lived longer, they wouldn't be able to travel farther; the flow of the current reverses every few weeks along the ridge axis and so limits how far larvae could go. How C. porifera had made a 300-kilometre journey was a mystery. Complex flow The researchers had based their calculation of flow on measurements of the current at a single location at the crest of the ridge, and assumed that the direction and speed of the currents were the same over the whole area. "This is a reasonable assumption in many parts of the ocean," says Andreas Thurnherr, a physical oceanographer at Columbia University's Lamont-Doherty Earth Observatory in Palisades, New York. But the topography of Nine North disrupts current flow significantly, he says. To better estimate currents, Thurnherr, Mullineaux and their colleagues placed 15 current-measuring devices along the crest and both flanks of the ridge; they also deployed two mobile current meters that travelled between the sea floor and the top of the ridge, sampling as they went. The team found that currents near the crest of the ridge were faster than those farther away, and that currents on the eastern flank of the ridge flowed southwards, whereas those on the west side went northwards. Surprisingly, the study shows that currents closer to the sea floor are among the strongest, at about 10 centimetres per second4. This caught the researchers by surprise. "Our observations are markedly different from the much weaker and wider currents we see in many areas of the deep ocean," says Thurnherr. It may also explain how C. porifera larvae could travel so far. Diane Adams, a former graduate student of Mullineaux's, uncovered another surprise. She had noted a drop in larval abundance at Nine North whenever surface eddies — loops of rotating currents resulting from differences in water density interacting with Earth's rotation — were passing by above. The researchers hadn't thought that surface eddies could reach down to the ocean floor, but they were able to pick up signals of rotating current loops a short time after surface eddies passed by. "The surface eddies could, in effect, blast larvae off the ridge and have an important role in their dispersal," says Mullineaux. Such interplay between geology and ocean currents has fascinated researchers of chemosynthetic life for decades. "It's important not only for recolonization after natural disasters but for the evolutionary connectivity of marine life," says Robert Cowen, a marine biologist at the University of Miami in Florida. Researchers want to know why pockets of life-enabling chemicals in different parts of the ocean host distinct yet overlapping assemblages of species. And where did these species originate? Did they arise first at the vents or perhaps in shallow-water cold seeps — areas where hydrogen sulphide and hydrocarbon sources such as methane leak out from Earth's interior? And how do organisms such as those living off the sulphide-laden oozes of dead whales contribute to the connectivity between chemosynthetic communities? The key to the divergence and convergence of these marine species during evolution lies in the ability of larvae to negotiate ocean currents, geological barriers and changes in sea-floor topology over millions of years. In this amount of time, the movement of only a small number of larvae is sufficient to allow genetic exchange between geographically separated populations. The scale of such connectivity "can be astonishing", says Charles Fisher, a marine biologist at Pennsylvania State University in University Park. Long-distance taxi Fisher's team has found, for example, that some species of tubeworm and mussel living on cold seeps in the Gulf of Mexico are genetically related to their counterparts off the west coast of Nigeria, an indication of genetic exchange between two regions that are more than 10,000 kilometres apart5. This connectivity occurs over numerous generations through steps that are not yet clear. But researchers suspect it may be aided by the equatorial deep jets in the Atlantic, which alternate between easterly and westerly flow depending on depth and so could transport larvae both ways. In other instances, larval dispersal is blocked over quite short distances, leading to speciation. In the northeastern Pacific Ocean, the 450-kilometre-long Blanco transform fault has separated the Juan de Fuca and Gorda ridge systems, off the coast of Washington State and Oregon (see 'Curiosities of the deep'). Vrijenhoek's team has found that similar-looking snails at Juan de Fuca and Gorda are related, but quite different, species that diverged roughly 11 million years ago, consistent with the time of the fault's formation6. Click for a larger version. But, says Vrijenhoek, "the barrier doesn't affect all animals in the same way". The tubeworms at the two ends of the fault, for example, are the same species, even though there are some slight genetic differences7. Gene flow has taken place from populations in the north to their southern counterparts, the same direction as the ocean currents in the region. "Tubeworm larvae probably have a sufficiently long lifespan or stay at the right parts of the water column to allow them to make that jump," he says. Geological changes may have separated species in other locations as well. For example, the Logatchev hydrothermal vent, located just east of the Caribbean, is the only place in the Mid-Atlantic Ridge known to host vesicomyid clams, which are more typical of the Pacific. Some researchers suspect that the animals might have originated from the Pacific — arriving through an ancient seaway between North and South America before the rise of the isthmus of Panama 5 million years ago. Other marine biologists, including Cindy Van Dover, a deep-sea biologist at Duke University Marine Laboratory in Beaufort, North Carolina, say that the clam species are probably more common on the Mid-Atlantic Ridge than it looks at present and didn't necessarily originate in the Pacific. "We simply don't have enough samples to know for sure." This highlights a limitation for this relatively young research field: scientists have only a rudimentary knowledge of the distribution of chemosynthetic life, let alone the underlying mechanisms of connectivity and speciation8. So far, only 200 or so hydrothermal vents and a few dozen cold seeps have been discovered around the world. "Most parts of the ocean are unexplored," says Paul Tyler, a marine biologist at the National Oceanography Centre in Southampton, UK, and chair of the Biogeography of Deep-Water Chemosynthetic Ecosystems (ChEss) programme of the Census of Marine Life, a global initiative to document the biodiversity of the ocean. "Some strategic locations are missing pieces of the puzzle of how things have evolved." These include the Arctic and the Antarctic, where thick ice and turbulent seas make exploration immensely challenging. Others include the Chile triple junction, where three tectonic plates meet, resulting in the subduction of the Chile rise, a mid-ocean ridge, under the South American plate. "There you have the potential for vents and seeps in close proximity," says Tyler. "This allows you to address the evolutionary relationship between vent and seep animals without the variable of geography." ADVERTISEMENT The great unknown To many, the Caribbean, especially the little-explored Mid-Cayman rise near the island of Grand Cayman, might hold the key to some of the most perplexing questions in deep-sea biology. At almost 5,000 metres deep, hydrothermal vents in the region should exist at unrecorded environmental extremes and may reveal new species. The location is also ideal for studying the role of the isthmus of Panama in the divergence and connectivity of vent species. Researchers wonder whether the fauna on the Mid-Cayman rise will be more closely related to that on the East Pacific Rise, on the other side of the Panama land bridge, or to the organisms on the Mid-Atlantic Ridge. Chris German, a marine geochemist at WHOI and co-chair of the ChEss programme, led an expedition in October 2009 that detected signals of hydrothermal plumes near the Mid-Cayman rise. A follow-up expedition by the UK National Oceanography Centre managed to find the vents at a depth of 5,000 metres, the deepest ever recorded. As to what they found there, the team would say little. Nevertheless, German warns to keep expecting surprises. "A few years ago, we thought we knew everything about geological barriers and ocean currents to predict what we are going to find, but we have been wrong every time since." Jane Qiu writes for Nature from Beijing, China. * References * Shank, T. M.et al. Deep Sea Res. II45, 465-515 (1998). * Mullineaux, L. S. , Adams, D. K. , Mills, S. W. & Beaulieu, S. E.Proc. Natl Acad. Sci. USA107, 7829-7834 (2010). * Marsh, A. G. , Mullineaux, L. S. , Young, C. M. & Manahan, D. T.Nature411, 77-80 (2001). * McGillicuddy, D. J. , Lavelle, J. W. , Thurnherr, A. M. , Kosnyrev, V. K. & Mullineaux, L. S.Deep-Sea Res. I (in the press). * Cordes, E. E.et al. Deep Sea Res. I54, 637-653 (2007). * Johnson, S. B. , Young, C. R. , Jones, W. J. , Waren, A. & Vrijenhoek, R. C.Biol. Bull.210, 140-157 (2006). * Young, C. R. , Fujio, S. & Vrijenhoek, R. C.Mol. Ecol.17, 1718-1731 (2008). * Van Dover, C. , German, C. R. , Speer, K. G. , Parson, L. P. & Vrijenhoek, R. C.Science295, 1253-1257 (2002). There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• World view: Disaster, unmitigated
  - Nature (London) 465(7296):287 (2010)
  An oil slick will not re-engage the public with environmental issues, warns Colin Macilwain, but it might lead to a saner US energy policy. The economist Paul Krugman suggested in his New York Times column earlier this month that the BP oil leak in the Gulf of Mexico could provide the flagging environmental movement with the renewed impetus it so badly needs. The modern movement, he pointed out, gained a great deal of momentum from a fire on the Cuyahoga River in Cleveland, Ohio, on 22 June 1969. Legend holds that the sight of the blazing river fuelled public support for measures including the creation of the powerful Environmental Protection Agency by Richard Nixon in 1970, and the passage of the Clean Water Act two years later. Environmentalists have long since lost the power, in the United States and elsewhere, to achieve legislative success on anything like that scale. And it will take more than an environmental disaster on the shores of the southern states to restore that kind of influence. The river fire reflected the chronic urban pollution being experienced by a great many people at that time — at home, at work and on holiday. The conundrum for environmental activists and scientists today is that the issues that matter most no longer affect voters in developed countries so immediately. Having dealt successfully with the flagrant issues of filthy water and urban smog, environmentalists have turned to global trends that pose existential threats to our world. But the two leading problems — climate change and biodiversity conservation — come across to many people as mere abstractions. Remote control Environmental activism in the United States has changed in other ways. By moving on from neighbourhood-based, grass-roots campaigning to a reliance on expensive court actions — an approach that has, admittedly, yielded successes — environmental groups have distanced themselves from the ordinary people whose interests they seek to serve. This sense of remoteness pervades not just the leadership of the main environmental activist groups, it also clings to the scientific and semi-scientific bodies, such as the Intergovernmental Panel on Climate Change and the Convention on Biological Diversity (CBD), set up to confront environmental challenges. The result is that environmental issues consistently rank close to bottom on the list of voters' priorities. In an Opinion Research Corporation poll for CNN in March, for example, "energy and environmental policies" were identified as "the most important issue" in congressional elections by just 2% of voters. In retrospect, 1992's Earth Summit in Rio de Janeiro was something of a high-water mark for the political salience of green issues. There, world leaders sought to catalyse international action to meet grave environmental threats by agreeing to the Framework Convention on Climate Change and the CBD. "The global approach to environmental issues has violated the axiom that all politics is local." Instead of galvanizing public concern, this global approach has diluted it by violating the axiom that all politics is local. Take the CBD. On 10 May, it released its third Global Biodiversity Outlook report, summarizing the progress made by the parties to the convention. It makes grim reading: despite some local successes, none of 21 subsidiary targets to the CBD's 2002 goal of achieving a "significant reduction" in the rate of biodiversity loss by 2010 has been met. Ten of 15 indicators tracking biodiversity show negative trends. Ahmed Djoghlaf, who runs the CBD's secretariat in Nairobi, Kenya, hopes the findings will get world leaders to acknowledge the importance of biodiversity. "This report makes it clear why their response to the economic crisis must take on board the biodiversity agenda," he says. A day of biodiversity talks is planned for heads of state at the United Nations in September, followed by the expected endorsement of a new strategic plan at the next conference of the 193 parties to the CBD in Nagoya, Japan, in October. But asked what the CBD is doing to build public support for faster action to conserve biodiversity, Djoghlaf points to the designation of 2010 as the International Year of Biodiversity (it's also the International Day for Biodiversity this Saturday, 22 May). It is very hard to see such sterile designations registering with the wider public, however. In the United States, the Senate has failed even to ratify the CBD, signed by President Bill Clinton in 1993, because public pressure on senators to vote for it is too weak to overcome the mild objections of the drug industry to its call for bioprospectors to share patent rights with local people. Troubled waters The oil leak in the Gulf has certainly elicited a sharper short-term political response than the slow-burn issue of biodiversity conservation has ever managed. Arnold Schwarzenegger, the governor of California, was soon in full Terminator mode. "All of you have seen, when you turn on the television, the devastation in the Gulf. That will not happen here in California," he said, reversing his previous support for fresh oil drilling off Santa Barbara. The weather, together with the success or otherwise of BP's well-capping efforts, will determine the extent to which the Gulf spill will ingrain itself on the public consciousness. If it makes its mark, the spill could shift US energy policy, forcing the administration to push both renewable sources and nuclear power even harder than it has already. So far, President Barack Obama's policy response has been measured: he remains committed to offshore drilling, but is tightening its regulation. However, the spill is unlikely to reinvigorate an environmental movement whose interests and mode of operation remain too far removed from mainstream politics to match the influence that was fleetingly enjoyed four decades ago. Public indifference to environmental issues, if left unchecked, could eventually undermine support for scientists in the plethora of subdisciplines, from ecology to atmospheric physics, that are now strongly oriented towards meeting global environmental threats. There has always been a lively debate (originally in ecology, and now more widely) about whether a scientist can mix objectivity with advocacy. It's not an argument that needs to be resolved: it depends on the outlook and temperament of the scientist. However, those researchers who do feel comfortable with advocacy need to spend more time on the ground, talking to real people about why their work matters. Colin Macilwain is based in the United Kingdom. e-mail: cfmworldview@gmail.com There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• How government spending cuts put lives at risk
  - Nature (London) 465(7296):289 (2010)
  World leaders currently making tough economic decisions should be guided by the physicians' mantra: "First, do no harm". Austerity programmes, even if justifiable in terms of promoting growth (itself highly questionable), may exacerbate the health risks posed by financial crises.
• Biodiversity: linking Singapore's fragmented habitats
  - Nature (London) 465(7296):289 (2010)
  As we celebrate the International Day for Biological Diversity on 22 May, Singapore — a participant in the preparatory committee of the 1992 United Nations Earth Summit and a signatory to the Convention on Biological Diversity — is making another contribution.In addition to its proposed index on cities' biodiversity, to measure urban efforts towards conservation and sustainable development (Nature 460, 33; doi:10.1038/460033a2009
• Biodiversity: need for balanced reports of solutions and failures
  - Nature (London) 465(7296):289 (2010)
  Some leading conservation biologists deliver unnecessarily gloomy addresses, closing with no solutions or a few anecdotal success stories. Non-governmental organizations (NGOs), by contrast, can be too optimistic in their fund-raising lectures and magazines: false starts and dead ends don't figure, because donors prefer winners.
• Controls needed to reduce problem of plastic contamination
  - Nature (London) 465(7296):289 (2010)
  Your online News report about assay contamination by chemicals leaching from plastic containers (http://go.nature.com/R7eAFN
• Scientific steps to nuclear disarmament
  - Nature (London) 465(7296):290 (2010)
  An advisory group and a network of international labs is needed to lay the groundwork for multilateral disarmament and forge links between nations, say Martin Rees, Ben Koppelman and Neil Davison.
• Decentralize, adapt and cooperate
  - Nature (London) 465(7296):292 (2010)
  Two years ago Raphael D. Sagarin and colleagues proposed that security systems should learn from nature. Now they've worked with defence professionals on putting that call into practice.
• Science, freedom and trade
  - Nature (London) 465(7296):294 (2010)
  Michael Shermer enjoys two books that examine economics and politics from a scientific perspective — one explaining the experimental basis for democracy, another placing trade in an evolutionary context.
• A flowering of pleasure and pain
  - Nature (London) 465(7296):295 (2010)
  The latest collaborative artwork from neuroscientist Morten Kringelbach and artist Annie Cattrell reveals — and revels in — sensory dialogues in the brain, explains Martin Kemp.
• Drug discovery: Priming the antimalarial pipeline
  - Nature (London) 465(7296):297 (2010)
  Emerging resistance to existing antimalarial drugs could nullify efforts to eliminate this deadly disease. The discovery of thousands of agents active against malaria parasites offers hope for developing new drugs.
• Biomaterials: Intelligent glue
  - Nature (London) 465(7296):298 (2010)
  Spiders' webs are coated with microscopic droplets of glue, but the properties of this adhesive were unclear. It has now been found that the glue's stretchiness underpins its role in catching flies.
• Developmental biology: Roots respond to an inner calling
  - Nature (London) 465(7296):299 (2010)
  In plant roots, patterning of two types of water-conducting xylem tissue is determined by a signalling system that involves the reciprocal dance of a mobile transcription factor and mobile microRNAs.
• Extrasolar planets: Larger than they ought to be
  - Nature (London) 465(7296):300 (2010)
  The finding that some gas-giant exoplanets are much larger than theory predicts has been boggling astronomers' minds. Planetary heating caused by gravitational tidal interactions might be a piece of the puzzle.
• DNA repair: Decision at the break point
  - Nature (London) 465(7296):301 (2010)
  Many decisions affect the fate of damaged DNA — for example, how to repair the damage, or whether to repair it at all and instead let the damaged cell die. An intricate web of molecular interactions affects such decisions.
• Supernovae: New explosions of old stars?
  - Nature (London) 465(7296):303 (2010)
  Examples of stellar explosions have emerged that fall outside the traditional types of supernova. The nature of the stars that produce them and the mechanism by which they explode is far from clear.
• Global change: The ocean is warming, isn't it?
  - Nature (London) 465(7296):304 (2010)
  A reappraisal of the messy data on upper-ocean heat content for 1993–2008 provides clear evidence for warming. But differences among various analyses and inconsistencies with other indicators merit attention.
• Thousands of chemical starting points for antimalarial lead identification
  - Nature (London) 465(7296):305 (2010)
  Nature | Article Thousands of chemical starting points for antimalarial lead identification * Francisco-Javier Gamo1 Search for this author in: * NPG journals * PubMed * Google Scholar * Laura M. Sanz1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jaume Vidal1 Search for this author in: * NPG journals * PubMed * Google Scholar * Cristina de Cozar1 Search for this author in: * NPG journals * PubMed * Google Scholar * Emilio Alvarez1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jose-Luis Lavandera1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dana E. Vanderwall2 Search for this author in: * NPG journals * PubMed * Google Scholar * Darren V. S. Green3 Search for this author in: * NPG journals * PubMed * Google Scholar * Vinod Kumar4 Search for this author in: * NPG journals * PubMed * Google Scholar * Samiul Hasan4 Search for this author in: * NPG journals * PubMed * Google Scholar * James R. Brown4 Search for this author in: * NPG journals * PubMed * Google Scholar * Catherine E. Peishoff5 Search for this author in: * NPG journals * PubMed * Google Scholar * Lon R. Cardon6 Search for this author in: * NPG journals * PubMed * Google Scholar * Jose F. Garcia-Bustos1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:305–310Date published:(20 May 2010)DOI:doi:10.1038/nature09107Received08 February 2010Accepted22 April 2010 Abstract * Abstract * Author information * Supplementary information * Comments Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P. falciparum, of which 13,533 were confirmed to inhibit parasite growth by at least 80% at 2 µM concentration. More than 8,000 also showed potent activity against the multidrug resistant strain Dd2. Most (82%) compounds originate from internal company projects and are new to the malaria community. Analyses using historic assay data suggest several novel mechanisms of antimalarial action, such as inhibition of protein kinases and host–pathogen interaction related targets. Chemical structures and associated data are hereby made public to encourage additional drug lead identification ! efforts and further research into this disease. View full text Subject terms: * Parasitology * Drug discovery Figures at a glance * Figure 1: Three-dimensional plot of some of the novel chemical diversity present in TCAMS. Compounds are represented by coloured spheres plotted against their assigned molecular framework number, chemical fingerprint cluster number and estimated antiplasmodial potency (pXC50 = -logXC50, where XC50 is in molar units and pXC50 is dimensionless; XC50 = 1 μM corresponds to pXC50 = 6). Inserted structures are examples of drug-like molecules not previously described to possess antiplasmodial activity. * Figure 2: Description of TCAMS and its target space. , Relative molecular mass distributions of the TCAMS molecules and the general GSK screening collection. , Relative clogP distributions of the TCAMS molecules and the general GSK screening collection. , Distribution of target classes affected by the compounds in the set with potency and selectivity criteria described in the text. The number of targets in each class is indicated. , Target classes remaining after applying the criterion that human targets be enriched at least twofold among the hits relative to the screening compound library, plus antimicrobial targets known to be relevant for Plasmodium. Number of targets in each class is indicated, with the number of identified malarial orthologues (BLASTP E-value ≤ 1.0-20) in parentheses. * Figure 3: Phylogenetic tree of combined human and P. falciparum kinomes. P. falciparum and human lineages are coloured red and black, respectively. Major human kinase subfamilies are labelled. TK: tyrosine kinases; TKL: tyrosine-like kinases; STE: homologues of yeast sterile 7, 11 and 20 kinases; CK1: casein kinase 1; AGC: PKA, PKG and PKC kinases; CAMK: calcium/calmodulin kinases; CMGC: CDK, MAPK, GSK3 and CLK kinases. Malarial kinases that are hypothesized targets in Table 1 are labelled. This neighbour-joining tree is based on pairwise amino acid sequence similarity for all known human22 and P. falciparum24, 27 kinase domains. Nodes supported by ≥ 60% of 1,000 bootstrap replicates are indicated by '*' (see Methods for tree reconstruction and Supplementary Fig. 1). Author information * Abstract * Author information * Supplementary information * Comments Affiliations * Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain * Francisco-Javier Gamo, * Laura M. Sanz, * Jaume Vidal, * Cristina de Cozar, * Emilio Alvarez, * Jose-Luis Lavandera & * Jose F. Garcia-Bustos * Computational and Structural Chemistry, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709-3398, USA * Dana E. Vanderwall * Computational and Structural Chemistry, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Hertfordshire, Stevenage SG1 2NY, UK * Darren V. S. Green * Computational Biology, Quantitative Sciences, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA * Vinod Kumar, * Samiul Hasan & * James R. Brown * Computational and Structural Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA * Catherine E. Peishoff * Quantitative Sciences, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA * Lon R. Cardon Contributions F.-J.G. and J.F.G.-B. planned and designed the work. F.-J.G. supervised all experimental work and analysed the screening data, L.M.S., J.V., C.d.C. and E.A. performed the screening assays and contributed to data analysis. J.-L.L., D.E.V., D.V.S.G. and C.E.P. performed the cheminformatic analyses and wrote sections of the manuscript. V.K., S.H. and J.R.B. performed the bioinformatic analyses and J.R.B. contributed the relevant sections to the manuscript. L.R.C and J.F.G.-B integrated individual contributions and wrote the final manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Jose F. Garcia-Bustos (jose.f.garcia-bustos@gsk.com) Chemical structures and data described have been deposited at EBI (http://www.ebi.ac.uk/chemblntd). Supplementary information * Abstract * Author information * Supplementary information * Comments Excel files * Supplementary Table 1 (3.3M) This table contains an annotated list of all positives from the P. falciparum screen. Structures are shown as "SMILES" codes. * Supplementary Table 2 (437K) This table shows compounds in TCAMS with literature references on their mode of action. PDF files * Supplementary Information (675K) This file contains Supplementary Figures 1-3 with legends and Supplementary Tables 3-5. Additional data
• Chemical genetics of Plasmodium falciparum
  - Nature (London) 465(7296):311 (2010)
  Nature | Article Chemical genetics of Plasmodium falciparum * W. Armand Guiguemde1 Search for this author in: * NPG journals * PubMed * Google Scholar * Anang A. Shelat1 Search for this author in: * NPG journals * PubMed * Google Scholar * David Bouck1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sandra Duffy2 Search for this author in: * NPG journals * PubMed * Google Scholar * Gregory J. Crowther3 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul H. Davis4 Search for this author in: * NPG journals * PubMed * Google Scholar * David C. Smithson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michele Connelly1 Search for this author in: * NPG journals * PubMed * Google Scholar * Julie Clark1 Search for this author in: * NPG journals * PubMed * Google Scholar * Fangyi Zhu1 Search for this author in: * NPG journals * PubMed * Google Scholar * María B. Jiménez-Díaz5 Search for this author in: * NPG journals * PubMed * Google Scholar * María S. Martinez5 Search for this author in: * NPG journals * PubMed * Google Scholar * Emily B. Wilson6 Search for this author in: * NPG journals * PubMed * Google Scholar * Abhai K. Tripathi7 Search for this author in: * NPG journals * PubMed * Google Scholar * Jiri Gut8 Search for this author in: * NPG journals * PubMed * Google Scholar * Elizabeth R. Sharlow9 Search for this author in: * NPG journals * PubMed * Google Scholar * Ian Bathurst10 Search for this author in: * NPG journals * PubMed * Google Scholar * Farah El Mazouni11 Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph W. Fowble12 Search for this author in: * NPG journals * PubMed * Google Scholar * Isaac Forquer13 Search for this author in: * NPG journals * PubMed * Google Scholar * Paula L. McGinley14 Search for this author in: * NPG journals * PubMed * Google Scholar * Steve Castro14 Search for this author in: * NPG journals * PubMed * Google Scholar * Iñigo Angulo-Barturen5 Search for this author in: * NPG journals * PubMed * Google Scholar * Santiago Ferrer5 Search for this author in: * NPG journals * PubMed * Google Scholar * Philip J. Rosenthal8 Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph L. DeRisi6 Search for this author in: * NPG journals * PubMed * Google Scholar * David J. Sullivan7 Search for this author in: * NPG journals * PubMed * Google Scholar * John S. Lazo9 Search for this author in: * NPG journals * PubMed * Google Scholar * David S. Roos4 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael K. Riscoe13 Search for this author in: * NPG journals * PubMed * Google Scholar * Margaret A. Phillips11 Search for this author in: * NPG journals * PubMed * Google Scholar * Pradipsinh K. Rathod12 Search for this author in: * NPG journals * PubMed * Google Scholar * Wesley C. Van Voorhis3 Search for this author in: * NPG journals * PubMed * Google Scholar * Vicky M. Avery2 Search for this author in: * NPG journals * PubMed * Google Scholar * R. Kiplin Guy1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:311–315Date published:(20 May 2010)DOI:doi:10.1038/nature09099Received20 January 2010Accepted21 April 2010 Abstract * Abstract * Author information * Supplementary information * Comments Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library—many of which showed potent in vitro activity against drug-resistant P. falciparum strains—and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific co! mmunity with new starting points for malaria drug discovery. View full text Subject terms: * Parasitology * Chemical biology * Therapeutics * Drug discovery Figures at a glance * Figure 1: Chemical structure network graph and antimalarial potencies of the 1,300 primary screen hits. Topologically similar molecules cluster together in the branches of the network. To construct the graph, molecules were first abstracted to scaffolds and then further to cores using the Murcko algorithm10. Each of these structural entities is represented as a node, and nodes are connected via edges according to topological relationships with closeness being defined using the Tanimoto coefficient. Molecular nodes are coded to reflect potency against P. falciparum strains K1 (low, white; high, blue) and 3D7 (low, small; high, large). The highly branched structure of the full network graph (bottom half of the figure) indicates that the 1,300 compounds are organized into clusters of clusters: cores are well sampled by multiple scaffolds, and the cores themselves are grouped into families of related chemotypes. Previously reported antimalarial compounds are highlighted in the lower centre. The top half of the figure provides greater detail on three potent chemotypes with well-dev! eloped structure activity relationships: , tetrahydroisoquinoline; , diaminonaphthoquinone; , dihydropyridine. Data are in Supplementary Information. * Figure 2: Reduced representation of the network map showing synergistic activities with clinically relevant antimalarials. The size of the nodes reflects the magnitude of the logarithmic difference between EC50 in the presence and absence of EC10 of exemplar antimalarial drugs. Absolute differences less than one log unit were not considered significant. Synergistic and antagonistic compounds are uniformly colour-coded blue and red, respectively. Highly synergistic compounds can be seen with artemisinin and mefloquine. Data are in Supplementary Information. * Figure 3: Reduced representation of the network map showing the interaction of the cross-validated hits with potential biological targets. The network map on the left displays compounds targeting well-validated protein targets as measured in inhibition assays (EC50 ≤ 15 μM). The map on the right shows compounds that bind to purified malarial proteins according to thermal melt shift experiments. The size of nodes representing active or binding compounds is increased for clarity. Data are in Supplementary Information. * Figure 4: Phylochemogenetic profiling. Phylochemogenetic analysis of the cross-validated compounds using a two-way hierarchical clustering of growth inhibition against P. falciparum strains (3D7, K1, V1/S), other eukaryotic parasites (Toxoplasma gondii (Tg), Trypanosoma brucei (Tb), Leishmania major (Lm)) and human cell lines (HEK293, BJ, Raji and HepG2). Columns represent single compounds and are clustered according to potency against the cell lines and organisms. Neighbouring compounds share a similar potency spectrum. Rows represent a single cell line or organism and are clustered according to their chemosensitivity to the compounds in the study. A phylogenetic tree of the organisms in this study is provided for reference. Note that despite the many known examples of taxonomically conserved pathways, on a global level, phylogeny is a poor predictor of chemical sensitivity profiles: Toxoplasma responses more closely parallel human than their evolutionary siblings, Plasmodium. Data are in Supplementary Informati! on. Author information * Abstract * Author information * Supplementary information * Comments Affiliations * Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA * W. Armand Guiguemde, * Anang A. Shelat, * David Bouck, * David C. Smithson, * Michele Connelly, * Julie Clark, * Fangyi Zhu & * R. Kiplin Guy * Discovery Biology, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane 4111, Australia * Sandra Duffy & * Vicky M. Avery * Department of Medicine, University of Washington, Seattle, Washington 98195-7185, USA * Gregory J. Crowther & * Wesley C. Van Voorhis * Department of Biology and the Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA * Paul H. Davis & * David S. Roos * GlaxoSmithKline, Tres Cantos Medicines Development Campus, Diseases of Developing World, Tres Cantos 28760, Spain * María B. Jiménez-Díaz, * María S. Martinez, * Iñigo Angulo-Barturen & * Santiago Ferrer * Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2542, USA * Emily B. Wilson & * Joseph L. DeRisi * W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA * Abhai K. Tripathi & * David J. Sullivan * Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, USA * Jiri Gut & * Philip J. Rosenthal * Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA * Elizabeth R. Sharlow & * John S. Lazo * Medicines for Malaria Venture, Geneva 1215, Switzerland * Ian Bathurst * Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041, USA * Farah El Mazouni & * Margaret A. Phillips * Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA * Joseph W. Fowble & * Pradipsinh K. Rathod * Experimental Chemotherapy Lab, Portland VA Medical Center, Portland, Oregon 97239, USA * Isaac Forquer & * Michael K. Riscoe * Department of Chemistry and Chemical Biology Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA * Paula L. McGinley & * Steve Castro Contributions W.A.G. and R.K.G. designed and coordinated the project. A.A.S. wrote the algorithms for the data analysis and generated the figures. Assays were conceived, performed and analysed by W.A.G. and D.B. (P. falciparum phenotypic screen), M.C. (human cell lines), D.C.S. (T. brucei), P.H.D. and D.S.R. (T. gondii), J.S.L. and E.R.S. (L. major), A.K.T. and D.J.S. (haemozoin inhibition), G.J.C. and W.C.V.V. (thermal melt experiments), M.A.P., P.K.R., F.E.M. and I.B. (PfDHOD), J.W.F. and P.K.R. (P. falciparum dihydrofolate reductase), J.G. and P.J.R. (PfFP-2), I.F. and M.K.R. (cytochrome bc1), J.C. (P. falciparum mutant drug sensitivity). E.B.W., S.D., J.L.D. and V.M.A. (independent antimalarial in vitro experiments), F.Z. (in vitro pharmacokinetics), M.B.J.D., M.S.M., I.A.-B. and S.F. (in vivo pharmacokinetics and efficacy), I.B. (coordination of technology development and network development), S.C. and P.L.M. (re-synthesis). W.A.G., A.A.S. and R.K.G. wrote the manuscript. All authors! contributed to the design of the experiments and the preparation of the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * R. Kiplin Guy (kip.guy@stjude.org) Supplementary information * Abstract * Author information * Supplementary information * Comments Excel files * Supplementary Data (4.9M) This file contains Structural information and Primary screening for 1536 compounds, Screening data from 228 compounds for the Bland-Altman analysis, Calculated medicinal chemistry properties, Cytotoxic activity, Screen sensitivity and Differential activity for 172 compounds, Raw data from the Hemozoin polymerization inhibition assay, summary of activity of 172 compounds in the thermal melt assays and Raw data and calculated Kd for thermal melt assay hits. PDF files * Supplementary Information (932K) This file contains Supplementary Information comprising: Compound Library Screened; Parasite and cell-based assay methods; Enzymatic and protein assays; Data processing and screening results; Multiple-lab cross-validation study; Chemical structure network graph; Additional mechanistic studies; Detailed analysis of three early lead compounds; Other high-value compounds; Data availability; Supplementary Tables S1-S8, Supplementary Figures S1-S5 with legends and References. Additional data
• Cell signalling by microRNA165/6 directs gene dose-dependent root cell fate
  Carlsbecker A Lee JY Roberts CJ Dettmer J Lehesranta S Zhou J Lindgren O Moreno-Risueno MA Vatén A Thitamadee S Campilho A Sebastian J Bowman JL Helariutta Y Benfey PN - Nature (London) 465(7296):316 (2010)
  Nature | Article Cell signalling by microRNA165/6 directs gene dose-dependent root cell fate * Annelie Carlsbecker1, 2, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Ji-Young Lee3, 4, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Christina J. Roberts2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jan Dettmer1 Search for this author in: * NPG journals * PubMed * Google Scholar * Satu Lehesranta1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jing Zhou3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Ove Lindgren1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Miguel A. Moreno-Risueno6 Search for this author in: * NPG journals * PubMed * Google Scholar * Anne Vatén1 Search for this author in: * NPG journals * PubMed * Google Scholar * Siripong Thitamadee1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ana Campilho1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jose Sebastian3 Search for this author in: * NPG journals * PubMed * Google Scholar * John L. Bowman7 Search for this author in: * NPG journals * PubMed * Google Scholar * Ykä Helariutta1, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Philip N. Benfey6, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:316–321Date published:(20 May 2010)DOI:doi:10.1038/nature08977Received29 May 2009Accepted01 March 2010Published online21 April 2010 Abstract * Abstract * Author information * Supplementary information * Comments Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg A key question in developmental biology is how cells exchange positional information for proper patterning during organ development. In plant roots the radial tissue organization is highly conserved with a central vascular cylinder in which two water conducting cell types, protoxylem and metaxylem, are patterned centripetally. We show that this patterning occurs through crosstalk between the vascular cylinder and the surrounding endodermis mediated by cell-to-cell movement of a transcription factor in one direction and microRNAs in the other. SHORT ROOT, produced in the vascular cylinder, moves into the endodermis to activate SCARECROW. Together these transcription factors activate MIR165a and MIR166b. Endodermally produced microRNA165/6 then acts to degrade its target mRNAs encoding class III homeodomain-leucine zipper transcription factors in the endodermis and stele periphery. The resulting differential distribution of target mRNA in the vascular cylinder determines xylem! cell types in a dosage-dependent manner. View full text Subject terms: * Developmental biology * Plant sciences * Molecular biology * Genetics * Genomics Figures at a glance * Figure 1: Endodermal SHR and SCR control xylem patterning via PHB. , Schematic representation of the Arabidopsis root meristem and stele. Cells in the ground tissue layer adjacent to the stele are marked with asterisks. , CRE1::SHRΔNLELDV:nlsGFP in shr-2. , UAS::SHR:YFP in shr-2 harbouring J0571. , UAS::SCR:YFP in shr-2, J0571.–, Toluidine blue-stained cross-sections and confocal laser scanning micrographs of basic fuchsin-stained xylem of wild type (WT) (), shr-2 (), scr-4 (), phb-7d (), and phb-6 shr-2 (). Filled arrowhead indicates metaxylem, and unfilled indicates protoxylem. Scale bars, 10 µm. * Figure 2: SHR post-transcriptionally represses PHB. , , In situ hybridization with a PHB mRNA specific probe on cross- and longitudinal sections of WT () and phb-7d () roots. –, In situ hybridization with CNA (), ATHB8 () and REV () specific probes on cross-sections of WT roots. , Confocal laser scanning micrographs of transcriptional fusion of PHB to GFP in WT and shr-2. , PHB mRNA in situ hybridization to cross-section of shr-2. Inset is a section of shr-2 hybridized with a PHB sense probe. , Expression of translational fusion of PHB to GFP in WT and shr-2. , Expression of translational fusion of PHB with the phb-7d mutation to GFP. Asterisks, endodermis position; arrowheads, protoxylem position; scale bars, 10 µm. * Figure 3: miR165/6 activated by SHR in the endodermis is active in the stele. , Expression of pMIR165a::GFP in WT and scr-1 meristems and in maturation zone. , Expression of pMIR166b::GFP in WT, scr-1 and shr-2 meristems. , Real-time PCR of ChIP on the upstream regulatory regions of MIR165a and MIR166b using anti-GFP antibodies and a transgenic plant expressing pSHR::SHR:GFP. The binding to the MAGPIE (MGP) promoter confirmed previously21 was used as positive control. Asterisks, endodermis position. * Figure 4: Non-cell-autonomous action of MIR165a. , miR165/6 GFP sensor under the U2 promoter in WT and shr-2., miR166-specific LNA probe hybridization to sections proximal to the quiescent centre of WT, athb8-11cna-2 phb-13 phv-11 rev-6 and shr-2. , Protoxylem forms in shr and scr backgrounds when UAS::MIR165a is introduced into shr-2 and scr-4 harbouring J0571. , Real-time RT–PCR of pri-MIR165/6 and HD-ZIP III in WT and a line with UAS::MIR165a in shr-2, J0571.n = 4. Error bars indicate ±s.d. Asterisks, endodermis/ground tissue position; arrowheads, protoxylem position; scale bars, 10 µm. * Figure 5: HD-ZIP III levels determine xylem type. , Basic fuchsin-stained xylem and cross-section of cna-2 phb-13 phv-11 rev-6. , Cleared root and cross-section of athb8-11 cna-2 phb-13 phv-11 rev-6., , Stained xylem of roots in which MIR165a is expressed from the CRE1 promoter in WT and shr-2. Asterisks, endodermis position; arrowheads, protoxylem position; scale bars, 10 µm. Author information * Abstract * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Annelie Carlsbecker, * Ji-Young Lee, * Ykä Helariutta & * Philip N. Benfey Affiliations * Institute of Biotechnology/Department of Biosciences, University of Helsinki, FIN-00014, Finland * Annelie Carlsbecker, * Jan Dettmer, * Satu Lehesranta, * Ove Lindgren, * Anne Vatén, * Siripong Thitamadee, * Ana Campilho & * Ykä Helariutta * Department of Physiological Botany, Evolutionary Biology Center, Uppsala University, Norbyvägen 18D, SE-752 36 Uppsala, Sweden * Annelie Carlsbecker & * Christina J. Roberts * Boyce Thompson Institute for Plant Research, Tower Road, Ithaca, New York 14853, USA * Ji-Young Lee, * Jing Zhou & * Jose Sebastian * Graduate Field of Plant Biology, Cornell University, Ithaca, New York 14853, USA * Ji-Young Lee & * Jing Zhou * Institute of Technology, University of Tartu, Tartu 50411, Estonia * Ove Lindgren * Biology Department and IGSP Center for Systems Biology, Duke University, Durham, North Carolina 27708, USA * Miguel A. Moreno-Risueno & * Philip N. Benfey * School of Biological Sciences, Monash University, Melbourne, Victoria 3800, Australia * John L. Bowman Contributions A.C. and J.-Y.L. contributed equally to this work, C.J.R., J.D., S.L. and J.Z. contributed equally to this work, O.L., M.A.M.-R. and A.V. contributed equally to this work, Y.H. and P.N.B. contributed equally to this work, and the name order was determined by raffle. A.C. designed and performed experiments to characterize HD-ZIP III transcription factors and miR165/6 in vascular patterning, J.-Y.L. identified and characterized the regulatory network of SHR, SCR and miR165/6 in the xylem patterning, C.J.R. analysed the miRNA expression by in situ hybridization and participated in HD-ZIP III mutant characterization. J.D. participated in the analysis of expression of PHB (including mutant forms) and other HD-ZIP III and generated pCRE1::MIR165a as well as participated in the generation of J0571 lines to rescue scr and shr. S.L. participated in the PHB and HD-ZIP III expression analysis, phb-7d mutant characterization and generated the pSCR::MIR165a to rescue scr. J.Z. developed ! and characterized the xylem patterning led by non-mobile SHR and PHB-m. O.L. participated in the characterization of various HD-ZIP III mutant lines. M.A.M.-R. showed the non-cell autonomous action of non-mobile SHR. A.V. participated in positional cloning of phb-7d and establishment of the J0571 lines to rescue shr. S.T. identified the phb-7d mutant. A.C. identified the scr-6 allele. J.S. characterized shr/scr and HD-ZIP III double mutants and embryo expression patterns in GFP lines. J.L.B. shared informative non-published materials. Y.H. and P.N.B. participated in experimental design. A.C., J.-Y.L., Y.H. and P.N.B. wrote the manuscript. A.C. and J.-Y.L. are co-corresponding authors. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Ykä Helariutta (yrjo.helariutta@helsinki.fi) or * Philip N. Benfey (philip.benfey@duke.edu) Supplementary information * Abstract * Author information * Supplementary information * Comments PDF files * Supplementary Information (31.4M) This file contains Supplementary Figures 1-20 with legends, Supplementary Tables 1-2, Supplementary Methods and References. Additional data
• A faint type of supernova from a white dwarf with a helium-rich companion
  - Nature (London) 465(7296):322 (2010)
  Nature | Letter A faint type of supernova from a white dwarf with a helium-rich companion * H. B. Perets1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * A. Gal-Yam3 Search for this author in: * NPG journals * PubMed * Google Scholar * P. A. Mazzali4, 5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * D. Arnett7 Search for this author in: * NPG journals * PubMed * Google Scholar * D. Kagan8 Search for this author in: * NPG journals * PubMed * Google Scholar * A. V. Filippenko9 Search for this author in: * NPG journals * PubMed * Google Scholar * W. Li9 Search for this author in: * NPG journals * PubMed * Google Scholar * I. Arcavi3 Search for this author in: * NPG journals * PubMed * Google Scholar * S. B. Cenko9 Search for this author in: * NPG journals * PubMed * Google Scholar * D. B. Fox10 Search for this author in: * NPG journals * PubMed * Google Scholar * D. C. Leonard11 Search for this author in: * NPG journals * PubMed * Google Scholar * D.-S. Moon12 Search for this author in: * NPG journals * PubMed * Google Scholar * D. J. Sand2, 13 Search for this author in: * NPG journals * PubMed * Google Scholar * A. M. Soderberg2 Search for this author in: * NPG journals * PubMed * Google Scholar * J. P. Anderson14, 15 Search for this author in: * NPG journals * PubMed * Google Scholar * P. A. James15 Search for this author in: * NPG journals * PubMed * Google Scholar * R. J. Foley2 Search for this author in: * NPG journals * PubMed * Google Scholar * M. Ganeshalingam9 Search for this author in: * NPG journals * PubMed * Google Scholar * E. O. Ofek16 Search for this author in: * NPG journals * PubMed * Google Scholar * L. Bildsten17, 18 Search for this author in: * NPG journals * PubMed * Google Scholar * G. Nelemans19 Search for this author in: * NPG journals * PubMed * Google Scholar * K. J. Shen17 Search for this author in: * NPG journals * PubMed * Google Scholar * N. N. Weinberg9 Search for this author in: * NPG journals * PubMed * Google Scholar * B. D. Metzger9 Search for this author in: * NPG journals * PubMed * Google Scholar * A. L. Piro9 Search for this author in: * NPG journals * PubMed * Google Scholar * E. Quataert9 Search for this author in: * NPG journals * PubMed * Google Scholar * M. Kiewe1 Search for this author in: * NPG journals * PubMed * Google Scholar * D. Poznanski9, 20 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:322–325Date published:(20 May 2010)DOI:doi:10.1038/nature09056Received17 May 2009Accepted23 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 Supernovae are thought to arise from two different physical processes. The cores of massive, short-lived stars undergo gravitational core collapse and typically eject a few solar masses during their explosion. These are thought to appear as type Ib/c and type II supernovae, and are associated with young stellar populations. In contrast, the thermonuclear detonation of a carbon-oxygen white dwarf, whose mass approaches the Chandrasekhar limit, is thought to produce type Ia supernovae1, 2. Such supernovae are observed in both young and old stellar environments. Here we report a faint type Ib supernova, SN 2005E, in the halo of the nearby isolated galaxy, NGC 1032. The 'old' environment near the supernova location, and the very low derived ejected mass (~0.3 solar masses), argue strongly against a core-collapse origin. Spectroscopic observations and analysis reveal high ejecta velocities, dominated by helium-burning products, probably excluding this as a subluminous3, 4 or ! a regular1 type Ia supernova. We conclude that it arises from a low-mass, old progenitor, likely to have been a helium-accreting white dwarf in a binary. The ejecta contain more calcium than observed in other types of supernovae and probably large amounts of radioactive 44Ti. View full text Subject terms: * Astronomy * Astrophysics Figures at a glance * Figure 1: The environment of SN 2005E. , NGC 1032, the host galaxy of SN 2005E, as observed by the Sloan Digital Sky Survey (SDSS), before the supernova explosion. The galaxy is an isolated, edge-on, early-type spiral galaxy, showing no signs of star-formation activity, warping or interaction. Its luminosity is dominated by the cumulative contribution of a multitude of low-mass old stars (yellow light in this image). , The LOSS29 discovery of SN 2005E on 2005 January 13 (shown in negative). Note the remote location of the supernova (marked with a red arrow) with respect to its host, 22.9 kpc (projected) from the galaxy nucleus and 11.3 kpc above the disk, whose edge-on orientation is well determined (). , An image of NGC 1032 in the light of the Hα emission line, emitted by interstellar gas ionized by ultraviolet radiation, and a good tracer of recent star formation. There are no traces of recent star-formation activity (usually appearing as irregular, compact emission sources) near the supernova location or! anywhere else in the host. Panels – are 275″ × 175″; north is up, and east is to the left; scale bar in applies to and also. , Zoom-in on the location of SN 2005E in pre-explosion SDSS r-band images. No source is detected near the supernova location, marked with a yellow circle (radius 3″; the astrometric uncertainty in the supernova location is <0.5″). The SDSS catalogue does not list any objects near that position (for example, putative faint dwarf satellites of NGC 1032), down to a typical limit of r = 22.5 mag. , , Deeper photometry of the supernova location. A red image is shown in , while an ultraviolet (u-band) image is shown in . At the distance of NGC 1032, the point-source upper limits we find, Mr < -7.5(-6.9) and  mag at 3(2)σ, respectively, indicate that we would have detected faint star-forming galaxies or star-forming regions at the supernova location, or indeed even individual massive red supergiant or luminous blue supergiant stars. ! , Zoom-in on the location of SN 2005E in Hα light (see for de! tails). No trace of star-formation activity is seen near the supernova location. Panels – are 64″ × 36″; scale bar in applies also to –. Technical details about the observations can be found in Supplementary Information section 1. * Figure 2: The mass and composition of the ejecta of SN 2005E. , Photospheric spectra of SN 2005E. The top spectrum is obviously photospheric and shows absorption lines of the He i series (marked with black ticks after application of an 11,000 km s-1 blueshift, at the top). Nebular lines of intermediate-mass elements, most notably calcium, begin to emerge in the middle spectrum. Calcium dominates the latest nebular spectrum at the bottom, and nebular oxygen is visible as well. We note that the typical Si lines of type Ia supernovae are absent in all spectra, while the nebular spectrum of SN 2005E clearly rules out a type Ia identification (comparison with the underluminous SN 1991bg is shown; note the lack of the typical iron-group line blends in the blue side). The derived line velocities are consistent with SN 2005E exploding within its putative host galaxy, NGC 1032. , The nebular spectrum of SN 2005E compared with a model fit. From the fit we can derive elemental abundances and masses in the ejecta of SN 2005E. We find masses ! of 0.1, 0.037, 0.135 and 0.003M⊙ for carbon, oxygen, calcium and radioactive nickel, respectively. Both the low total ejected mass of ~0.275M⊙ and the relative abundances are unique among previously studied events. The lack of prominent C/O-burning products such as S and Fe (typically seen in type Ia supernovae; Supplementary Information section 4) argues against a C/O white dwarf origin. Technical details of observations and additional references can be found in Supplementary Information section 1. * Figure 3: The cumulative distribution of host galaxies of supernovae from the KAIT (Katzman Automatic Imaging Telescope) supernova survey. We corrected the classification of a few hosts of type Ib/c supernovae using higher-quality observations from the Palomar 60-inch telescope (SN 2005ar, SN 2006ab and SN 2006lc were found to be hosted by spiral galaxies rather than elliptical galaxies). After correcting the classification, we find that all type Ib/c supernovae found in early-type galaxies are faint Ca-rich supernovae similar to SN 2005E. Note that the SN 2005E-like supernova host distribution is very different from that of other type Ib/c supernovae, as well as that of type II (known to have young massive progenitors) and that of SN 2002cx-like type Ia, with half of the SN 2005E-like group (four out of eight) observed in early-type (elliptical or S0) galaxies. The progenitors of SN 2005E and the other members of its group are therefore likely to belong to an old, low-mass stellar population. The total numbers of host galaxies included in this figure are 244, 25, 8, 257, 30, 63, 14, and 8 for supernovae of typ! es Ia, SN 1991bg (91bg), SN 1991T (91T), II, Ib, Ic, SN 2002cx (02cx) and SN 2005E (05E), respectively. Author information * Author information * Supplementary information * Comments Affiliations * Department of Particle Physics and Astrophysics, Faculty of Physics, The Weizmann Institute of Science, Rehovot 76100, Israel * H. B. Perets & * M. Kiewe * Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, Massachusetts 02138, USA * H. B. Perets, * D. J. Sand, * A. M. Soderberg & * R. J. Foley * Department of Particle Physics and Astrophysics, Faculty of Physics, The Weizmann Institute of Science, Rehovot 76100, Israel * A. Gal-Yam & * I. Arcavi * Max-Planck-Institut für Astrophysik, Karl-Schwarzschild-Str. 1, 85748 Garching, Germany * P. A. Mazzali * Scuola Normale Superiore, Piazza Cavalieri 7, 56127 Pisa, Italy * P. A. Mazzali * INAF – Oss. Astron. Padova, vicolo dell'Osservatorio, 5, 35122 Padova, Italy * P. A. Mazzali * Steward Observatory, University of Arizona, 933 North Cherry Avenue, Tucson, Arizona 85721, USA * D. Arnett * Department of Astronomy, University of Texas at Austin, Austin, Texas 78712, USA * D. Kagan * Department of Astronomy, University of California, Berkeley, California 94720-3411, USA * A. V. Filippenko, * W. Li, * S. B. Cenko, * M. Ganeshalingam, * N. N. Weinberg, * B. D. Metzger, * A. L. Piro, * E. Quataert & * D. Poznanski * Department of Astronomy and Astrophysics, Pennsylvania State University, University Park, Pennsylvania 16802, USA * D. B. Fox * Department of Astronomy, San Diego State University, San Diego, California 92182, USA * D. C. Leonard * Department of Astronomy and Astrophysics, University of Toronto, 50 St George Street, Toronto, ON M5S 3H4, Canada * D.-S. Moon * Las Cumbres Observatory Global Telescope Network, 6740 Cortona Dr., Suite 102, Goleta, California 93117, USA * D. J. Sand * Departamento de Astronomia, Universidad de Chile, Camino El Observatorio 1515, Las Condes, Santiago, Casilla 36-D, Chile * J. P. Anderson * Astrophysics Research Institute, Liverpool John Moores University, Twelve Quays House, Birkenhead CH41 1LD, UK * J. P. Anderson & * P. A. James * Department of Astronomy, 105-24, California Institute of Technology, Pasadena, California 91125, USA * E. O. Ofek * Kavli Institute for Theoretical Physics, Kohn Hall, University of California, Santa Barbara, California 93106, USA * L. Bildsten & * K. J. Shen * Department of Physics, University of California, Santa Barbara, California 93106, USA * L. Bildsten * Department of Astrophysics, Radboud University Nijmegen, PO Box 9010, NL-6500 GL, The Netherlands * G. Nelemans * Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA * D. Poznanski Contributions H.B.P. led the project, performed the calculations related to hyper-velocity stars, examined other putative SN 2005E-like events, collected and analysed archival data concerning supernova properties and their hosts, and wrote the manuscript. A.G.-Y. is the Principal Investigator of the CCCP programme and initiated the project, collected and analysed photometric and spectroscopic data, coordinated further observational and theoretical work, and managed the project. P.A.M. conducted the nebular spectral analysis and its interpretation, and determined the elemental abundances in the ejecta. D.A. determined that the measured composition requires He burning and performed nucleosynthesis calculations to confirm this. D.K. investigated local star-formation tracers at the location of SN 2005E. A.V.F. and W.L. contributed spectroscopic and photometric observations and reductions of SN 2005E and of similar Ca-rich objects, a class they originally identified, and provided most of the d! ata on supernova host galaxies. A.V.F. also edited the paper. I.A. analysed the CCCP photometry of SN 2005E and cross-calibrated it with other data. S.B.C., D.B.F., D.C.L., D.-S.M., D.J.S. and A.M.S. are members of the CCCP and contributed to initial observations of SN 2005E. J.P.A. and P.A.J. obtained and analysed narrow-band images of NGC 1032 and the location of SN 2005E. R.J.F. and M.G. contributed to spectroscopic observations and reductions. E.O.O. obtained deep photometric observations of the location of SN 2005E. L.B., G.N., K.J.S. and N.N.W. investigated the relation of SN 2005E to .Ia models and contributed to the text. B.D.M., A.L.P. and E.Q. investigated the relation of SN 2005E to accretion-induced collapse models and contributed to the text. M.K. performed custom reductions of CCCP spectra. D.P. carried out synthetic photometry analysis. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * A. Gal-Yam (avishay.gal-yam@weizmann.ac.il) or * H. B. Perets (hperets@cfa.harvard.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (1.4M) This file contains Supplementary Information and Data, Supplementary Figures S1- S5 with legends, Supplementary Tables 1-4 and References. Additional data
• A massive star origin for an unusual helium-rich supernova in an elliptical galaxy
  - Nature (London) 465(7296):326 (2010)
  Nature | Letter A massive star origin for an unusual helium-rich supernova in an elliptical galaxy * K. S. Kawabata1 Search for this author in: * NPG journals * PubMed * Google Scholar * K. Maeda2 Search for this author in: * NPG journals * PubMed * Google Scholar * K. Nomoto2 Search for this author in: * NPG journals * PubMed * Google Scholar * S. Taubenberger3 Search for this author in: * NPG journals * PubMed * Google Scholar * M. Tanaka2, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * J. Deng5 Search for this author in: * NPG journals * PubMed * Google Scholar * E. Pian6 Search for this author in: * NPG journals * PubMed * Google Scholar * T. Hattori7 Search for this author in: * NPG journals * PubMed * Google Scholar * K. Itagaki8 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:326–328Date published:(20 May 2010)DOI:doi:10.1038/nature09055Received02 June 2009Accepted24 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 unusual helium-rich (type Ib) supernova SN 2005E is distinguished from all supernovae hitherto observed by its faint and rapidly fading light curve, prominent calcium lines in late-phase spectra and lack of any mark of recent star formation near the supernova location. These properties are claimed1 to be explained by a helium detonation in a thin surface layer of an accreting white dwarf. Here we report that the observed properties of SN 2005cz, which appeared in an elliptical galaxy, resemble those of SN 2005E. We argue that these properties are best explained by a core-collapse supernova at the low-mass end (8–12 solar masses) of the range of massive stars that explode2. Such a low-mass progenitor lost its hydrogen-rich envelope through binary interaction, had very thin oxygen-rich and silicon-rich layers above the collapsing core, and accordingly ejected a very small amount of radioactive 56Ni and oxygen. Although the host galaxy NGC 4589 is an elliptical, some stud! ies have revealed evidence of recent star-formation activity3, consistent with the core-collapse model. View full text Subject terms: * Astronomy * Astrophysics Figures at a glance * Figure 1: Early-time spectra of stripped-envelope core-collapse supernovae. Red, spectrum of type Ib SN 2005cz taken on 2005 July 28 with the Keck Telescope. Also shown are the spectra of type Ib SN 2000H at t = +8 days (black) and t = +29 days (grey)18, type IIb SN 1993J at t = +8 days (blue) and t = +24 days (cyan)19, and type Ic SN 1994I at t = +7 days (magenta) and t = +26 days (green)20, 21. The type Ib is characterized by strong helium lines and weak silicon lines, while in the type Ic both helium and silicon lines are weak. The type IIb shows a type II-like spectrum characterized by the strong hydrogen features at early times, and becomes type Ib/c-like at late times. All these supernovae are thought to have partly or fully stripped off their outer layers of hydrogen and helium before the explosions. The epochs are also shown in the figure. The overall appearance of spectral features in SN 2005cz is quite similar to those of the type Ib SN 2000H at t = +29 days, the type IIb SN 1993J at t = +24 days (despite its stronger H lines! ), and also the typical type Ic SN 1994I at t = +26 days (despite its lack of the strong He lines). The spectra are corrected for the host redshift and the reddening. We adopted a total (Milky Way + host) reddening of E(B - V) = 0.13 (0.03 + 0.1) mag in SN 2005cz, 0.23 (0.23 + 0.0) mag in SN 2000H, 0.45 mag in SN 1994I, and 0.3 mag in SN 1993J. The flux is on an absolute scale for SN 2005cz, calibrated with the Calar Alto photometry obtained four nights later. For the comparison supernovae, the fluxes are on an arbitrary scale and constants are added for presentation. The positions of the prominent He i lines are shown by the dashed lines. The spectrum of SN 2005cz is consistent with the post-maximum spectra of type Ib supernovae. * Figure 2: Late-time spectra of stripped-envelope core-collapse supernovae and faint supernovae. Red, calcium-rich late-time spectrum of type Ib SN 2005cz taken on 2006 December 27 (t = +179 days). Also shown are type Ib SN 2004dk at t ≈ 392 days (black)22, type IIb SN 1993J at t = +203 days (blue)19, type Ic SN 1994I at t = +147 days (magenta)21, peculiar (pec.) type Ia SN 2005hk at t = +232 days (green)23, and peculiar (possibly type I) SN 2008ha at t = +65 days (yellow)24. As time goes by, the ejecta become transparent to optical light, following the expansion and density decrease. Late-time spectra of type Ib/c supernovae are thus characterized by various emission lines, mostly of forbidden transitions. The spectrum of SN 2004dk is typical for type Ib/c supernovae at late times (for example, see figure 2 of ref. 22). The spectra are corrected for the host redshift, but not for reddening. The flux is on an approximate absolute scale for SN 2005cz, calibrated with the spectroscopic standard star (but not with photometry), whereas it is on an arbitrary scale ! for the comparison supernovae. The asterisk on SN 2004dk indicates days since its discovery (not maximum light). It is unique that SN 2005cz shows only weak [O i] lines at 6,300 Å and 6,364 Å, and much stronger [Ca ii] lines at 7,291 Å and 7,323 Å than [O i]. The relatively weak Ca ii infrared triplet compared with other supernovae might suggest lower density ejecta for SN 2005cz. It is interesting that the [Ca ii] line is considerably narrow (half-width at half-maximum, 0.005c, which is probably the typical expansion velocity of the inner core emitting the [Ca ii] line) compared with the blueshift of the absorption in the Ca ii infrared triplet in the early-time spectrum (~0.04c), which is attributed to the expansion velocity of the outer layer. * Figure 3: Absolute R-band light curves of relevant supernovae. Red circles, light curve of the rapidly fading type Ib SN 2005cz. It is compared with those of type IIb SN 1993J (cyan triangles), type Ic SN 1994I (blue stars), type Ib SN 2007Y (green squares), type IIn SN 2008S (black open circles), and the possibly type I SN 2008ha (orange open squares). Also shown is the light curve of SN 1994I, but dimmed by 1.5 mag (magenta open stars), which is magnified in the inset for convenience of comparison with that of SN 2005cz. For SN 2005cz, the first three points denote unfiltered magnitudes, which are approximately R-band magnitudes. The two points with downward arrows are 3σ upper limits. The distance moduli, μ, and total reddening values, E(B - V), both in units of magnitude, are taken as follows: [µ, E(B - V)] = (32.23, 0.13) for SN 2005cz (Supplementary Information section 1), (27.8, 0.3) for SN 1993J, (29.6, 0.45) for SN 1994I, (31.43, 0.112) for SN 2007Y, (31.55, 0.076) for SN 2008ha, and (28.78, 0.687) for SN 2008S. We! assume RV = 3.1 to convert the colour excess to the R-band extinction. The data points, as well as the distance and the reddening, are from the literature19, 24, 25, 26, 27. The putative explosion date for SN 2005cz is assumed to be 2005 June 17, 30 days before the discovery and 15 days before maximum brightness (Supplementary Information section 1). The tail of the light curve of SN 2005cz is similar to those of type IIn SN 2008S and type Ic SN 1994I (dimmed by 1.5 mag). From this, we estimate the mass of 56Ni as , assuming a nickel mass of M(56Ni) = 0.07M⊙ produced in the typical type Ic SN 1994I28. * Figure 4: Bolometric light curve. Filled red circles, pseudobolometric light curve of type Ib SN 2005cz. It is compared with a simple γ-ray and positron deposition model with M(56Ni) = 0.02M⊙ and (red line), where E51 is the kinetic energy EK expressed in units of 1051 erg. We also plot the bolometric light curve of type Ic SN 1994I (open black squares)25 and a simple deposition model with M(56Ni) = 0.07M⊙ (black line) for comparison. Except for the last point (upper limit), we simply assume the bolometric correction BC ≡ Mbol – MR = 0.5, derived from SN 1998bw, SN 2002ap and SN 2008D at similar epochs14, 29, 30. As this is a very crude estimate, we adopt an error bar of ±0.5 mag for the bolometric luminosity. The deposition models adopt the γ-ray opacity for the Compton scattering ( ) and assume the full deposition of positrons. The decline rate from the intermediate to the late phase is consistent with . Combining this expression with (Mej,⊙/E51) ≈ 1 as indicated by the simil! arity in the absorption velocity seen in SN 2005cz and those in SN 1993J and SN 1994I (Fig. 1, Supplementary Fig. 1), we estimate Mej,⊙ ≤ 1 and E51 ≤ 1. The luminosity requires that M(56Ni) ≤ 0.02M⊙. Note that the estimate for M(56Ni) is sensitively affected by the explosion date. The upper limit to M(56Ni) is only M(56Ni) ≤ 0.005M⊙, if the explosion date is as late as 2005 July 15 (just a few days before the discovery). Author information * Author information * Supplementary information * Comments Affiliations * Hiroshima Astrophysical Science Center, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan * K. S. Kawabata * Institute for the Physics and Mathematics of the Universe (IPMU), University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8583, Japan * K. Maeda, * K. Nomoto & * M. Tanaka * Max-Planck-Institut für Astrophysik, Karl-Schwarzschild-Straße 1, 85741 Garching, Germany * S. Taubenberger * Department of Astronomy, School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan * M. Tanaka * National Astronomical Observatories, CAS, 20A Datun Road, Chaoyang District, Beijing 100012, China * J. Deng * INAF Osservatorio Astronomico di Trieste, Via Tiepolo 11, I-3413 Trieste, Italy * E. Pian * Subaru Telescope, National Astronomical Observatory of Japan, Hilo, Hawaii 96720, USA * T. Hattori * Itagaki Astronomical Observatory, Teppo-cho, Yamagata 990-2492, Japan * K. Itagaki Contributions K.S.K., K.M., K.N., J.D. and E.P. organized the observations and discussions; K.M., K.N and K.S.K. wrote the manuscript; K.S.K., S.T. and K.I. were responsible for data acquisition and reduction; J.D. and E.P. were the Principal Investigators of the relevant Subaru programmes, S05B-132 and S05B-054, respectively; M.T. and S.T. contributed to discussions; and T.H. provided expertise on data acquisition at the Subaru Telescope. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * K. S. Kawabata (kawabtkj@hiroshima-u.ac.jp) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (579K) This file contains Supplementary Information 1-3, Supplementary Figures 1- 3 with legends and References. Additional data
• GaAs photovoltaics and optoelectronics using releasable multilayer epitaxial assemblies
  - Nature (London) 465(7296):329 (2010)
  Nature | Letter GaAs photovoltaics and optoelectronics using releasable multilayer epitaxial assemblies * Jongseung Yoon1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Sungjin Jo1, 4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Ik Su Chun2 Search for this author in: * NPG journals * PubMed * Google Scholar * Inhwa Jung1 Search for this author in: * NPG journals * PubMed * Google Scholar * Hoon-Sik Kim1 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew Meitl3 Search for this author in: * NPG journals * PubMed * Google Scholar * Etienne Menard3 Search for this author in: * NPG journals * PubMed * Google Scholar * Xiuling Li2 Search for this author in: * NPG journals * PubMed * Google Scholar * James J. Coleman2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ungyu Paik4 Search for this author in: * NPG journals * PubMed * Google Scholar * John A. Rogers1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:329–333Date published:(20 May 2010)DOI:doi:10.1038/nature09054Received09 December 2009Accepted25 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 Compound semiconductors like gallium arsenide (GaAs) provide advantages over silicon for many applications, owing to their direct bandgaps and high electron mobilities. Examples range from efficient photovoltaic devices1, 2 to radio-frequency electronics3, 4 and most forms of optoelectronics5, 6. However, growing large, high quality wafers of these materials, and intimately integrating them on silicon or amorphous substrates (such as glass or plastic) is expensive, which restricts their use. Here we describe materials and fabrication concepts that address many of these challenges, through the use of films of GaAs or AlGaAs grown in thick, multilayer epitaxial assemblies, then separated from each other and distributed on foreign substrates by printing. This method yields large quantities of high quality semiconductor material capable of device integration in large area formats, in a manner that also allows the wafer to be reused for additional growths. We demonstrate some cap! abilities of this approach with three different applications: GaAs-based metal semiconductor field effect transistors and logic gates on plates of glass, near-infrared imaging devices on wafers of silicon, and photovoltaic modules on sheets of plastic. These results illustrate the implementation of compound semiconductors such as GaAs in applications whose cost structures, formats, area coverages or modes of use are incompatible with conventional growth or integration strategies. View full text Subject terms: * Materials science * Engineering * Applied physics * Methods * Materials Figures at a glance * Figure 1: Schematic illustration, optical and SEM images, and SIMS profile of GaAs/AlAs multilayers. , Schematic illustration of a multilayer stack of GaAs/AlAs and schemes for release through selective etching of the layers of AlAs. , Corresponding SIMS profile of this stack. , Cross-sectional SEM image after partial etching of the AlAs layers. , Optical image of a large collection of GaAs solar cells formed by release from a three-layer stack, and then solution casting onto another substrate. Inset, high magnification view. , Cross-sectional SEM image of a 40 repeat multilayer stack of GaAs (200 nm)/AlAs with ultrathin (20 nm) AlAs sacrificial layers. Inset, high-magnification view. , Cross-sectional SEM image (coloured) of a heterogeneous multilayer stack composed of three layers for MESFETs (green), one layer for an NIR detector (yellow) and one layer for a single junction solar cell (blue). The substrate is purple. Each of the device layers is separated by 20 nm AlAs (red). Details of stack design and corresponding SIMS profile are in Supplementary Information. * Figure 2: Multilayer GaAs MESFETs and logic circuits. , Schematic illustration of a GaAs MESFET on a polyimide (PI) coated glass substrate. , Optical image of arrays of MESFETs on glass substrate. Inset, a single MESFET with source (S), drain (D) and gate (G) metal layers. , VDS (drain–source voltage) versus IDS (drain–source current) curves of MESFETs fabricated from first, second, third, fourth and fifth layers at gate–source voltages (VGS) of 0.4, 0.2, 0, -0.2, -0.4 and -0.6 V, from top to bottom. , IDS versus VGS transfer curves of MESFETs fabricated from first, second, third, fourth and fifth layers, at VDS = 1.5 V. , Amplitude plots for current gain (H21) and MAG measured from the fourth layer device. The unity current gain frequency (fT) and unity power gain frequency (fmax) are ~2 and ~6 GHz, respectively. , Optical image of NAND and NOR gates on polyimide (VA, VB, input voltages for switching transistors; Vdd, drain voltage for load transistor; VO, output voltage). , Output–input characteristics of NAND g! ates using devices from the first, second and third layers. , As but for NOR gates. * Figure 3: Multilayer GaAs NIR imagers. , Schematic illustration of a GaAs metal–semiconductor–metal (MSM) NIR detector on a Si wafer coated with a photocurable polyurethane (PU). Inset, Schottky blocking diode (SD). , Optical image of a NIR imager consisting of a 16 × 16 array of detectors (12 pixels are shown). Inset, a unit cell before interconnect metallization. , I/V characteristics of a cell formed with material from the first, second, third and fourth layers. Open circles and lines correspond to responses in the dark and under NIR illumination (wavelength 830 nm), respectively. , Photograph of an NIR imager mounted on a printed circuit board. , Image acquired with an NIR imager formed with material from the second layer. , As but using material from the fourth layer. Insets in and correspond to objects that were imaged. * Figure 4: Multilayer GaAs single-junction solar cells. , Schematic illustration of GaAs single-junction solar cell on a PET substrate coated with a photodefinable epoxy. , Optical image of arrays of such devices formed on the source wafer. Inset, magnified view of top (n-type) and bottom (p-type) contacts. , Representative light current density (J)-voltage (V) curves for Zn-doped solar cells formed from the first (top), second (middle) and third (bottom) layers, under AM1.5D illumination measured on the source wafer with a single-layer ARC of Si3N4. , Short-circuit current density (Jsc), fill factor (FF) and open circuit voltage (Voc) of first, second and third layer devices. Error bars, s.d. , IQE and EQE of first and second layer devices. , Projected efficiencies (η) and Jsc values without ARC and with double-layer ARCs (DLARC; MgF2/ZnS) for devices formed using material from the first and second layers. , Photograph of a solar module consisting of a 10 × 10 array of GaAs solar cells (each ~500 μm × 500 μm) on! a PET substrate. , Light current–voltage (I/V) and power–voltage (P/V) curves for such a module with parallel interconnection of 10 cells. , As but with series interconnection. Both measurements were made in a flat configuration. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Jongseung Yoon & * Sungjin Jo Affiliations * Department of Materials Science and Engineering, Beckman Institute for Advanced Science and Technology, and Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA * Jongseung Yoon, * Sungjin Jo, * Inhwa Jung, * Hoon-Sik Kim & * John A. Rogers * Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA * Ik Su Chun, * Xiuling Li, * James J. Coleman & * John A. Rogers * Semprius, Inc., Durham, North Carolina 27713, USA * Matthew Meitl & * Etienne Menard * Division of Materials Science Engineering, WCU Department of Energy Engineering, Hanyang University, Seoul 133-791, South Korea * Sungjin Jo & * Ungyu Paik Contributions J.Y., S.J., I.S.C., I.J., H.-S.K., M.M., E.M., X.L., J.J.C., U.P. and J.A.R. designed the experiments; J.Y., S.J., I.S.C., I.J., H.-S.K., M.M., E.M., X.L., J.J.C., U.P. and J.A.R. performed experiments and analyses; and J.Y., S.J., I.J. and J.A.R. wrote the paper. Competing financial interests E.M. and M.M. are co-founding and staff scientists, respectively, with a company (Semprius, Inc) that is pursuing single-layer lift-off and printing methods for utility scale concentrator photovoltaics. J.A.R. is a founder of this company, and sits on its Board of Directors Corresponding authors Correspondence to: * John A. Rogers (jrogers@uiuc.edu, for any aspect of this work) or * Ungyu Paik (upaik@hanyang.ac.kr, for MESFET processing) or * Matthew Meitl (matt.meitl@semprius.com, for design and characterization of solar cells) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (3M) This file contains Supplementary Methods, Supplementary Notes and Discussion, Supplementary References, Supplementary Figures S1-S21 with legends and Supplementary Tables S1-S2. Additional data
• Robust warming of the global upper ocean
  - Nature (London) 465(7296):334 (2010)
  Nature | Letter Robust warming of the global upper ocean * John M. Lyman1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Simon A. Good3 Search for this author in: * NPG journals * PubMed * Google Scholar * Viktor V. Gouretski4 Search for this author in: * NPG journals * PubMed * Google Scholar * Masayoshi Ishii5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Gregory C. Johnson2 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew D. Palmer3 Search for this author in: * NPG journals * PubMed * Google Scholar * Doug M. Smith3 Search for this author in: * NPG journals * PubMed * Google Scholar * Josh K. Willis7 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:334–337Date published:(20 May 2010)DOI:doi:10.1038/nature09043Received08 December 2009Accepted22 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 A large (~1023 J) multi-decadal globally averaged warming signal in the upper 300 m of the world's oceans was reported roughly a decade ago1 and is attributed to warming associated with anthropogenic greenhouse gases2, 3. The majority of the Earth's total energy uptake during recent decades has occurred in the upper ocean3, but the underlying uncertainties in ocean warming are unclear, limiting our ability to assess closure of sea-level budgets4, 5, 6, 7, the global radiation imbalance8 and climate models5. For example, several teams have recently produced different multi-year estimates of the annually averaged global integral of upper-ocean heat content anomalies (hereafter OHCA curves) or, equivalently, the thermosteric sea-level rise5, 9, 10, 11, 12, 13, 14, 15, 16. Patterns of interannual variability, in particular, differ among methods. Here we examine several sources of uncertainty that contribute to differences among OHCA curves from 1993 to 2008, focusing on ! the difficulties of correcting biases in expendable bathythermograph (XBT) data. XBT data constitute the majority of the in situ measurements of upper-ocean heat content from 1967 to 2002, and we find that the uncertainty due to choice of XBT bias correction dominates among-method variability in OHCA curves during our 1993–2008 study period. Accounting for multiple sources of uncertainty, a composite of several OHCA curves using different XBT bias corrections still yields a statistically significant linear warming trend for 1993–2008 of 0.64 W m-2 (calculated for the Earth's entire surface area), with a 90-per-cent confidence interval of 0.53–0.75 W m-2. View full text Subject terms: * Climate science * Earth sciences Figures at a glance * Figure 1: OHCA curves using published methods. Globally integrated annual average OHCA curves from 0 to 700 m, estimated using methods published in papers cited in the key. All OHCA curves are estimated using different baseline climatologies, mapping methods and XBT corrections (first reference). Types of XBT bias corrections used include depth, depth-dependent temperature and depth with sea surface height (SSH; second reference, if different from first). Each curve has had its 1993–2006 mean removed to aid comparison, except for the depth5, 22 curve, which has been aligned with the 1993–2002 mean of the other curves. Error bars, 1 s.e.m. (Supplementary Information). * Figure 2: OHCA curves produced using the same mapping technique. Solid lines are OHCA curves with a single 1993–2002 climatology and variously corrected XBT data provided by individual research teams. Dashed and dotted lines show the same thing as the solid lines, but using a single 2005–2008 climatology (dashed) or applying different published XBT corrections to the identical EN3 (version 2a) XBT data set (dotted). The key describes the type of XBT bias correction, with references. The trend estimate of the mean curve (black line; red error bars, 90% confidence intervals) is 0.64 ± 0.11 W m-2 and has 5.7 effective degrees of freedom (Supplementary Information); red error bars show the overall uncertainty, determined from combining all of the individual uncertainties in Fig. 3 assuming they are uncorrelated. Black error bars show XBT correction and XBT quality-control uncertainty from Fig. 3. The difference between the global means of the two climatologies has been added to the dashed lines. * Figure 3: Uncertainties in OHCA. Estimates of uncertainties (described in Supplementary Information) arising from the choice of climatology (magenta line), the method of XBT correction and XBT quality control (black line), the choice of mapping methodology (blue line) and the effects of irregular and sparse sampling (green line). All uncertainties are displayed as 1 s.e.m. The overall uncertainty, calculated by combining the individual uncertainties assuming they are uncorrelated, is also shown (red line). Author information * Author information * Supplementary information * Comments Affiliations * Joint Institute for Marine and Atmospheric Research, University of Hawaii at Manoa, Honolulu, Hawaii 96822, USA * John M. Lyman * NOAA/Pacific Marine Environmental Laboratory, Seattle, Washington 98115-6349, USA * John M. Lyman & * Gregory C. Johnson * Met Office Hadley Centre, Exeter EX1 3PB, UK * Simon A. Good, * Matthew D. Palmer & * Doug M. Smith * KlimaCampus, University of Hamburg, Grindelberg 5, 20144 Hamburg, Germany * Viktor V. Gouretski * Climate Research Department, Meteorological Research Institute, 1-1 Nagamine, Tsukuba, Ibaraki 305-0052, Japan * Masayoshi Ishii * Japan Agency for Marine-Earth Science and Technology, 3173-25 Showa-machi, Kanazawa-ku, Yokohama 236-0001, Japan * Masayoshi Ishii * Jet Propulsion Laboratory, California Institute of Technology, Pasadena, California 91109, USA * Josh K. Willis Contributions J.M.L. led the writing and analysis, with writing contributions from G.C.J., J.K.W., M.D.P. and S.A.G., and analysis contributions from S.A.G., V.V.G., M.I., M.D.P., D.M.S. and J.K.W. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * John M. Lyman (john.lyman@noaa.gov) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (215K) This file contains Supplementary Methods, References, Supplementary Table S1 and Supplementary Figure S1 with legend. Additional data
• Reconciling surface plate motions with rapid three-dimensional mantle flow around a slab edge
  - Nature (London) 465(7296):338 (2010)
  Nature | Letter Reconciling surface plate motions with rapid three-dimensional mantle flow around a slab edge * Margarete A. Jadamec1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Magali I. Billen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:338–341Date published:(20 May 2010)DOI:doi:10.1038/nature09053Received20 October 2009Accepted26 March 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The direction of tectonic plate motion at the Earth's surface and the flow field of the mantle inferred from seismic anisotropy are well correlated globally, suggesting large-scale coupling between the mantle and the surface plates1, 2. The fit is typically poor at subduction zones, however, where regional observations of seismic anisotropy suggest that the direction of mantle flow is not parallel to3, 4, 5, 6, 7 and may be several times faster than6 plate motions. Here we present three-dimensional numerical models of buoyancy-driven deformation with realistic slab geometry for the Alaska subduction–transform system and use them to determine the origin of this regional decoupling of flow. We find that near a subduction zone edge, mantle flow velocities can have magnitudes of more than ten times the surface plate motions, whereas surface plate velocities are consistent with plate motions8 and the complex mantle flow field is consistent with observations from seismic aniso! tropy5. The seismic anisotropy observations constrain the shape of the eastern slab edge and require non-Newtonian mantle rheology. The incorporation of the non-Newtonian viscosity9, 10 results in mantle viscosities of 1017 to 1018 Pa s in regions of high strain rate (10-12 s-1), and this low viscosity enables the mantle flow field to decouple partially from the motion of the surface plates. These results imply local rapid transport of geochemical signatures through subduction zones and that the internal deformation of slabs decreases the slab-pull force available to drive subducting plates. View full text Subject terms: * Geophysics * Geology * Earth sciences Figures at a glance * Figure 1: Schematic of full model domain and slab geometry. Outline of the high-resolution mesh region (dashed grey line); the portion of the slab geometry that is varied (short-dashed black line); the PBSZ and southern mesh boundary shear zone (SMSZ) (thick dark-grey lines); Juan de Fuca Ridge (JdFR, double black line); and the locations of the cross-sections shown in Fig. 3 (AA′ and BB′, black). NAM, North American plate; PAC, Pacific plate; T, temperature. See Methods and Supplementary Information. * Figure 2: Maps of flow field. –, Surface velocity field and viscosity (colour scale) for three models (σy = 500 MPa; PBSZ viscosity, 1020 Pa s). The observed NUVEL-1A Pacific motion vector, assuming North America to be fixed8, is indicated using a white arrow. AVO, Alaska Volcano Observatory (Supplementary Information). –, Mantle velocity field at 100-km depth and vertical velocity magnitude (colour scale). The implied strong vertical gradient in velocity illustrates the significant decoupling of the overriding plate from the mantle flow. * Figure 3: 3D mantle flow field and viscosity structure. Calculated using the model with slabE115 and composite rheology (σy = 500 MPa; PBSZ viscosity, 1020 Pa s). Figures show subset of modelled domain. , Isosurface and cross-sections (AA′ and BB′) through composite viscosity show the strong slab and the low-viscosity regions in the mantle wedge and beneath the slab. Low-viscosity regions correlate with regions of high strain rate. , Isosurface of viscosity showing an oblique, cross-sectional, radial slice through the velocity field. The cross-section BB′ shows poloidal flow and along-strike flow. The plan view shows anticlockwise toroidal flow and an upward component of flow east of the slab edge. * Figure 4: Velocity and ISA orientations at 100-km depth. , Velocity field shows a trench-parallel component of flow near the slab nose for slabE115 with composite viscosity (σy = 500 MPa; PBSZ viscosity, 1020 Pa s). , The Newtonian viscosity has a damping effect on the toroidal component of flow. , There is no toroidal flow above the slab nose for slabE325. –, ISA orientations coloured by the lag parameter (Π, colour scale). Superimposed are SKS fast-axis directions (blue) back-projected along the ray path to 100-km depth5. ISA orientation provides a good estimate of LPO for Π < 1.0. Author information * Author information * Supplementary information * Comments Affiliations * Department of Geology, University of California, Davis, California 95616, USA * Margarete A. Jadamec & * Magali I. Billen * Present address: School of Mathematical Sciences & School of Geosciences, Monash University, Clayton, Victoria 3800, Australia. * Margarete A. Jadamec Contributions Both authors contributed equally to the overall development of the project, model design considerations, analysis and interpretations. M.A.J. performed all of the numerical modelling, except for the ISA calculations, which were done by M.I.B. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Margarete A. Jadamec (majadamec@ucdavis.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (2.7M) This files contains Supplementary Notes comprising Model design; Slab structure; Thermal structure; Rheology; Model results; Pacific plate motion and Comparisons of ISA and SKS; Supplementary Figures 1-8 with legends; Supplementary Tables 1-4 and References. Additional data
• Climate change and the global malaria recession
  - Nature (London) 465(7296):342 (2010)
  Nature | Letter Climate change and the global malaria recession * Peter W. Gething1 Search for this author in: * NPG journals * PubMed * Google Scholar * David L. Smith2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Anand P. Patil1 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew J. Tatem2, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert W. Snow5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Simon I. Hay1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:342–345Date published:(20 May 2010)DOI:doi:10.1038/nature09098Received03 February 2010Accepted16 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The current and potential future impact of climate change on malaria is of major public health interest1, 2. The proposed effects of rising global temperatures on the future spread and intensification of the disease3, 4, 5, and on existing malaria morbidity and mortality rates3, substantively influence global health policy6, 7. The contemporary spatial limits of Plasmodium falciparum malaria and its endemicity within this range8, when compared with comparable historical maps, offer unique insights into the changing global epidemiology of malaria over the last century. It has long been known that the range of malaria has contracted through a century of economic development and disease control9. Here, for the first time, we quantify this contraction and the global decreases in malaria endemicity since approximately 1900. We compare the magnitude of these changes to the size of effects on malaria endemicity proposed under future climate scenarios and associated with widely used! public health interventions. Our findings have two key and often ignored implications with respect to climate change and malaria. First, widespread claims that rising mean temperatures have already led to increases in worldwide malaria morbidity and mortality are largely at odds with observed decreasing global trends in both its endemicity and geographic extent. Second, the proposed future effects of rising temperatures on endemicity are at least one order of magnitude smaller than changes observed since about 1900 and up to two orders of magnitude smaller than those that can be achieved by the effective scale-up of key control measures. Predictions of an intensification of malaria in a warmer world, based on extrapolated empirical relationships or biological mechanisms, must be set against a context of a century of warming that has seen marked global declines in the disease and a substantial weakening of the global correlation between malaria endemicity and climate. View full text Subject terms: * Parasitology * Epidemiology Author information * Author information * Supplementary information * Comments Affiliations * Spatial Ecology and Epidemiology Group, Tinbergen Building, Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK * Peter W. Gething, * Anand P. Patil & * Simon I. Hay * Emerging Pathogens Institute, University of Florida, Gainesville, Florida 32610, USA * David L. Smith & * Andrew J. Tatem * Department of Biology, University of Florida, Gainesville, Florida 32610, USA * David L. Smith * Department of Geography, University of Florida, Gainesville, Florida 32611, USA * Andrew J. Tatem * Malaria Public Health and Epidemiology Group, Centre for Geographic Medicine, KEMRI – University of Oxford – Wellcome Trust Collaborative Programme, Kenyatta National Hospital Grounds (behind NASCOP), P.O. Box 43640-00100, Nairobi, Kenya * Robert W. Snow * Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, CCVTM, Oxford OX3 7LJ, UK * Robert W. Snow Contributions S.I.H. conceived the research. P.W.G. and S.I.H. drafted the manuscript. P.W.G. led, and A.P.P., D.L.S., A.J.T. and R.W.S. contributed to, the analyses. All authors discussed the results and contributed to the revision of the final manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Simon I. Hay (simon.hay@zoo.ox.ac.uk) or * Peter W. Gething (peter.gething@zoo.ox.ac.uk) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (644K) This file contains Supplementary Information on (A) the weakening geographical relationship between climate and malaria endemicity 1900-2007 and (B) estimating changing endemicity in terns of PfR0 effect size, Supplementary References, Supplementary Figures S1-S2 with legends and Supplementary Tables S1-S3. Additional data
• Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization
  - Nature (London) 465(7296):346 (2010)
  Nature | Letter Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization * Tadayuki Iwase1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yoshio Uehara2 Search for this author in: * NPG journals * PubMed * Google Scholar * Hitomi Shinji1 Search for this author in: * NPG journals * PubMed * Google Scholar * Akiko Tajima1 Search for this author in: * NPG journals * PubMed * Google Scholar * Hiromi Seo2 Search for this author in: * NPG journals * PubMed * Google Scholar * Koji Takada3 Search for this author in: * NPG journals * PubMed * Google Scholar * Toshihiko Agata4 Search for this author in: * NPG journals * PubMed * Google Scholar * Yoshimitsu Mizunoe1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:346–349Date published:(20 May 2010)DOI:doi:10.1038/nature09074Received28 December 2009Accepted08 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 Commensal bacteria are known to inhibit pathogen colonization; however, complex host–microbe and microbe–microbe interactions have made it difficult to gain a detailed understanding of the mechanisms involved in the inhibition of colonization1. Here we show that the serine protease Esp2, 3 secreted by a subset of Staphylococcus epidermidis, a commensal bacterium, inhibits biofilm formation and nasal colonization by Staphylococcus aureus, a human pathogen4. Epidemiological studies have demonstrated that the presence of Esp-secreting S. epidermidis in the nasal cavities of human volunteers correlates with the absence of S. aureus. Purified Esp inhibits biofilm formation and destroys pre-existing S. aureus biofilms. Furthermore, Esp enhances the susceptibility of S. aureus in biofilms to immune system components. In vivo studies have shown that Esp-secreting S. epidermidis eliminates S. aureus nasal colonization. These findings indicate that Esp hinders S. aureus colonizati! on in vivo through a novel mechanism of bacterial interference, which could lead to the development of novel therapeutics to prevent S. aureus colonization and infection. View full text Subject terms: * Epidemiology * Medical research * Environmental science * Drug discovery Figures at a glance * Figure 1: Inhibition of S. aureus biofilm formation and destruction of S. aureus biofilms by S. epidermidis. , , The inhibitory effect of S. epidermidis culture supernatants () or cells () on S. aureus biofilm formation. , The destructive effect of S. epidermidis culture supernatants on S. aureus biofilms. After these treatments by S. epidermidis culture supernatants or cells on S. aureus, the amount of S. aureus biofilms was measured. Filled bars, effect of inhibitory S. epidermidis (JK16 strain); open bars, effect of non-inhibitory S. epidermidis (JK11 strain). Bars show the mean value of the experiments (n = 3). Error bars show standard deviation (s.d.). * Figure 2: Isolation and characterization of the serine protease Esp, the factor responsible for the biofilm-destruction activity, secreted by inhibitory S. epidermidis. , Growth curve (open circles) of inhibitory S. epidermidis (JK16 strain) and the biofilm-destruction activity (closed circles) of the culture supernatants of the same strain. The activity of the supernatants at 8 h is shown as 100%. , A protein having the biofilm-destruction activity was purified from the culture media of inhibitory S. epidermidis (arrow). M, molecular mass markers. , Effects of the culture supernatants of inhibitory S. epidermidis (JK16, wild-type strain), an isogenic esp-deficient strain and a complemented strain on S. aureus biofilms. , The biofilm-destruction activity of purified Esp was blocked by APMSF. (+) or (-) indicate the presence or absence of Esp and APMSF. , Esp inhibited S. aureus biofilm formation in a dose-dependent manner. , Esp destroyed S. aureus biofilms in a time-dependent manner. The biofilms were incubated in the presence (closed circles) or absence (open circles) of Esp for the indicated times. , Microscopic observation of S. aureu! s biofilms incubated for 6 h in the presence () or absence (–) of Esp. Gram staining ( and ) and scanning electron micrographs (, , , and ) of the biofilms with scale bars (10 μm in , , , and , and 1 μm in and ). The arrows in indicate the intercellular matrix. , Esp enhanced the susceptibility of S. aureus in biofilms to hBD2. Viability of S. aureus cells in biofilms, which was incubated in the presence (+ or triangles) or absence (-) of Esp (1 μM) and hBD2 (1, 5 and 10 μM, from left to right in each triangle) for 6 h. The cell viability without Esp and hBD2 was set as 100%. Plots and columns show mean and s.d. (n = 3). Statistical significance is indicated as *P < 0.05 and **P < 0.01. * Figure 3: Elimination effect of inhibitory S. epidermidis cells on S. aureus nasal colonization. , Representative culture images of samples from test persons after administration of inhibitory S. epidermidis (JK16, wild-type strain). The nasal swabs from the volunteers were cultured on mannitol salt agar with egg yolk. , The bacterial counts of S. aureus from the nasal swabs after the administration of S. epidermidis cells. JK16 strain (closed circles; n = 7) or an isogenic esp-deficient strain (open circles; n = 6) were placed into the nasal cavities of the volunteers. Plots show mean and s.d. Statistical significance is indicated at *P < 0.05. NS, not significant; DL, detection limit. , Carrier rate of S. aureus after the administration of S. epidermidis wild type cells (closed circles; n = 7) and esp-deficient cells (open circles; n = 6). Statistical significance according to Kaplan–Meier method and log-rank test is at *P < 0.05. Author information * Author information * Supplementary information * Comments Affiliations * Department of Bacteriology, The Jikei University School of Medicine, Tokyo, 105-8461 Japan * Tadayuki Iwase, * Hitomi Shinji, * Akiko Tajima & * Yoshimitsu Mizunoe * Department of General Medicine, Kochi Medical School, Nankoku, 783-8505 Japan * Yoshio Uehara & * Hiromi Seo * Department of Biochemistry, The Jikei University School of Medicine, Tokyo, 105-8461 Japan * Koji Takada * Department of Environmental Health, The Jikei University School of Medicine, Tokyo, 105-8461 Japan * Toshihiko Agata Contributions T.I. and Y.M. designed the research and wrote the manuscript. All authors contributed the experiments; T.I., H.S., A.T., K.T. and Y.M. for in vitro study and epidemiological study, Y.U. and H.S. for in vivo study, T.A. for statistics. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Tadayuki Iwase (iwase.tadayuki@jikei.ac.jp) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (976K) This file contains Supplementary Table 1 and Supplementary Figures 1- 6 with legends. Additional data
• Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection
  Košmrlj A Read EL Qi Y Allen TM Altfeld M Deeks SG Pereyra F Carrington M Walker BD Chakraborty AK - Nature (London) 465(7296):350 (2010)
  Nature | Letter Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection * Andrej Košmrlj1, 2, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Elizabeth L. Read1, 3, 4, 9 Search for this author in: * NPG journals * PubMed * Google Scholar * Ying Qi5 Search for this author in: * NPG journals * PubMed * Google Scholar * Todd M. Allen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Marcus Altfeld1 Search for this author in: * NPG journals * PubMed * Google Scholar * Steven G. Deeks6 Search for this author in: * NPG journals * PubMed * Google Scholar * Florencia Pereyra1 Search for this author in: * NPG journals * PubMed * Google Scholar * Mary Carrington1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Bruce D. Walker1, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Arup K. Chakraborty1, 3, 4, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:350–354Date published:(20 May 2010)DOI:doi:10.1038/nature08997Received13 October 2009Accepted11 March 2010Published online05 May 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals ('elite controllers') maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8+ T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV ep! itopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies. View full text Subject terms: * Immunology * Medical research * Virology Figures at a glance * Figure 1: Thymic selection against fewer self peptides leads to a more cross-reactive T-cell repertoire. , Histogram of the frequency with which T cells recognize viral peptides (that is, not seen in the thymus) through only a small number (0, 1, 2, 3) of important contacts is shown for three T-cell repertoires that developed with different numbers of self-peptide–HLA complexes in the thymus. Important contacts were determined by making single point mutations. If the TCR–peptide–HLA interaction is sufficiently strong, no single point mutation can abrogate recognition, resulting in zero important contacts. A higher frequency of occurrence of a small number of important contacts indicates a more cross-reactive T-cell repertoire because only mutations at these contacts are likely to abrogate recognition. The frequency with which T cells recognize viral peptides through many significant contacts (greater than four) is larger for T-cell repertoires restricted by HLA alleles that present more self peptides in the thymus (not shown). , The probability that a TCR binds to viral p! eptides with a certain interaction strength is shown for three T-cell repertoires (as in ). A particular TCR recognizes a viral peptide when the binding strength exceeds the recognition threshold (dotted black line). Members of a T-cell repertoire selected against fewer self peptides are more likely to recognize a viral peptide. The model we used describes qualitative trends robustly9, 10 (Methods), but is not meant to be quantitatively accurate. * Figure 2: Model of host–pathogen interactions shows superior viral control by cross-reactive CD8+ T-cell repertoires. , Dynamic model: the virus mutates, infects limited-target CD4+ T cells, and is cleared. Infected CD4+ T cells produce more free virus and die. Infected cells present viral peptides in complex with HLA molecules (until peptides unbind from HLA). Activated CD8+ T cells produced by recognition of viral epitopes on antigen-presenting cells (APCs) proliferate and differentiate into effector CTLs. CTLs kill infected cells bearing cognate peptide–HLA complexes, and turn into memory cells that are activated after re-exposure to antigen. , Simulated HIV viral loads versus time for different cross-reactivities (CR) of the CD8+ T-cell repertoire. Black curve, high cross-reactivity; red curve, low cross-reactivity. Each curve is averaged over 500 simulations (each simulation represents a person). The model shows a reduced set-point viral load for people with a more cross-reactive T-cell repertoire. Other models of host–pathogen dynamics show similar effects of T-cell cross-reactivi! ty (Supplementary Figs 7 and 8). , Virus diversity and immune pressure for representative people (that is, representative simulations) with high cross-reactivity (left) and low cross-reactivity (right) of CD8+ T-cell repertoires. Top panels show the relative population sizes of two dominant viral strains: the infecting strain (black), and an emerging, less fit strain (green) (other less populous viral strains are not shown). For people with a more cross-reactive T-cell repertoire, the emergent mutant strain only begins to dominate the infecting strain after 175 days, whereas for low cross-reactivity the mutant increases to nearly 100% of the viral population within 100 days after infection. Bottom panels show the relative immune pressure, defined as the rate of killing of an infected cell (see equation (4), Methods), imposed on each viral strain by different CD8+ T-cell clones. Each curve represents the relative immune pressure exerted on that viral strain by a particular T! -cell clone. For people with a more cross reactive T-cell repe! rtoire, several T-cell clones exert immune pressure on both the infecting and emergent strains. For people with a low-cross-reactivity T-cell repertoire, the emergent strain is not recognized, and thus escapes. * Figure 3: HLA-B alleles associated with greater ability to control HIV correlate with smaller self-peptide binding propensities. The odds ratio (OR) for an allele is defined as: , where pw and pwo are the numbers of individuals in the progressor cohort with and without this HLA, respectively; and cw and cwo are the numbers of individuals in the controller cohort with and without this HLA, respectively. This definition suggests that the OR measures the likelihood of an allele being correlated with progressors versus controllers, with an OR greater than one indicating association with the progressor cohort. The fraction of peptides derived from the human proteome that bind to a given HLA allele was determined using the most accurate predictive algorithms (Methods and Supplementary Table 1). Compared to experimental data, the predictive algorithms for peptide binding by HLA-B*3501 are less accurate than algorithms for the other three alleles (Supplementary Fig. 17 and Supplementary Table 1); the number reported here for HLA-B*3501 using the most accurate algorithm underestimates the binding fraction. The! error bars represent the 95% confidence intervals for OR. The dotted line corresponds to equal odds for an allele being associated with progressors and controllers. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Andrej Košmrlj & * Elizabeth L. Read Affiliations * Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts 02114, USA * Andrej Košmrlj, * Elizabeth L. Read, * Todd M. Allen, * Marcus Altfeld, * Florencia Pereyra, * Mary Carrington, * Bruce D. Walker & * Arup K. Chakraborty * Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA * Andrej Košmrlj * Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA * Elizabeth L. Read & * Arup K. Chakraborty * Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA * Elizabeth L. Read & * Arup K. Chakraborty * Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA * Ying Qi & * Mary Carrington * University of California, San Francisco, California 94110, USA * Steven G. Deeks * Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA * Bruce D. Walker * Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA * Arup K. Chakraborty Contributions A.K. and E.L.R. contributed equally to this work. A.K.C. and B.D.W. initiated the project. A.K., E.L.R. and A.K.C. developed the computational models. A.K., E.L.R., A.K.C. and B.D.W. analysed computational results. Y.Q., F.P., M.C., S.G.D. and B.D.W. collected and analysed the data from cohorts of HIV-infected people. A.K., E.L.R., T.M.A., M.A., M.C., B.D.W. and A.K.C. contributed to the writing of the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Arup K. Chakraborty (arupc@mit.edu) or * Bruce D. Walker (bwalker@partners.org) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (2.7M) This file contains Supplementary Note 1, Supplementary Tables S1-S4, Supplementary Figures S1-S17 with legends, Supplementary Methods, Supplementary Discussions 1-2 and References. Additional data
• Modulation of Shigella virulence in response to available oxygen in vivo
  Marteyn B West NP Browning DF Cole JA Shaw JG Palm F Mounier J Prévost MC Sansonetti P Tang CM - Nature (London) 465(7296):355 (2010)
  Nature | Letter Modulation of Shigella virulence in response to available oxygen in vivo * Benoit Marteyn1 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicholas P. West1, 8 Search for this author in: * NPG journals * PubMed * Google Scholar * Douglas F. Browning2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffery A. Cole2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jonathan G. Shaw3 Search for this author in: * NPG journals * PubMed * Google Scholar * Fredrik Palm4 Search for this author in: * NPG journals * PubMed * Google Scholar * Joelle Mounier5 Search for this author in: * NPG journals * PubMed * Google Scholar * Marie-Christine Prévost6 Search for this author in: * NPG journals * PubMed * Google Scholar * Philippe Sansonetti5, 7 Search for this author in: * NPG journals * PubMed * Google Scholar * Christoph M. Tang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:355–358Date published:(20 May 2010)DOI:doi:10.1038/nature08970Received16 September 2009Accepted02 March 2010Published online02 May 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Bacteria coordinate expression of virulence determinants in response to localized microenvironments in their hosts. Here we show that Shigella flexneri, which causes dysentery, encounters varying oxygen concentrations in the gastrointestinal tract, which govern activity of its type three secretion system (T3SS). The T3SS is essential for cell invasion and virulence1. In anaerobic environments (for example, the gastrointestinal tract lumen), Shigella is primed for invasion and expresses extended T3SS needles while reducing Ipa (invasion plasmid antigen) effector secretion. This is mediated by FNR (fumarate and nitrate reduction), a regulator of anaerobic metabolism that represses transcription of spa32 and spa33, virulence genes that regulate secretion through the T3SS. We demonstrate there is a zone of relative oxygenation adjacent to the gastrointestinal tract mucosa, caused by diffusion from the capillary network at the tips of villi. This would reverse the anaerobic block! of Ipa secretion, allowing T3SS activation at its precise site of action, enhancing invasion and virulence. View full text Figures at a glance * Figure 1: Influence of anaerobiosis and FNR on Shigella invasion. Histological analysis of the gastrointestinal tract infected with S. flexneri strains as indicated. , There was marked destruction of the mucosal surface with loss of villi and infiltration of the submucosa with inflammatory cells following challenge with the wild-type strain, M90T. , , These changes are less pronounced after challenge with M90TΔfnr () or a strain lacking the T3SS (M90TΔmxiD, ). , Complementation of fnr (M90TΔfnr pBM2) restores the pathological changes. Sections were stained with Evans blue; bars, 50 µm. , Epithelial cell invasion by M90T, M90TΔfnr and M90TΔfnr pBM2 in an aerobic or anaerobic cabinet (n = 5 independent experiments). c.f.u., colony-forming units. Error bars show the s.d. and asterisks indicate P < 0.05 (Student's t-test). * Figure 2: T3SS structure and function are modified by ambient O2. , Secreted (Sec.) and cytoplasmic (Cell) Ipas detected by western analysis. Secretion induced by Congo red (CR) was diminished in anaerobic conditions, with effectors retained in the bacteria; this is FNR-dependent. Strains and growth conditions are indicated. , , Detection of T3SS needles (white triangles) on M90T () and M90TΔfnr () by transmission electron microscopy. The average needle length (>200 needles counted in n = 3 experiments, ± s.d.) on strains is shown and results displayed applying a Loess model. Needles on M90T were significantly longer following growth in anaerobic than aerobic conditions (P < 0.001, Student's t-test), and the needle length was more varied (s.d. ± 28 versus 11 nm). * Figure 3: Regulation of Shigella virulence genes by O2 and FNR. , qRT–PCR analysis of relative mRNA levels in wild-type M90T in the presence (dashed line) and absence (black boxes) of O2; the reduction of spa32 and spa33 mRNA levels under anaerobic conditions are FNR dependent (n = 3 independent experiments). Grey boxes, mRNA levels in M90TΔfnr. , Binding of FNR to regions upstream of spa32 and spa33 by electrophoretic mobility shift assay. , IpaB secretion detected by western blot analysis 30 min after transferring anaerobically grown bacteria to different O2 concentrations (indicated). Strains including M90T and M90T containing spa32 and spa33 under the control of their native promoters (M90Tp32/33) or promoters with disrupted FNR boxes (M90Tp#32/#33). , Epithelial cells entry of bacteria in cabinets with (white bars) or without (black bars) O2. Error bars, s.d.; ** indicates P < 0.01; n = 3 independent experiments. * Figure 4: The presence of O2 encountered by Shigella in vitro and in vivo , HeLa cells were transferred to an anaerobic cabinet with or without deoxy-haemoglobin or cytochrome c (6 μM) in the medium, and oxygen tensions measured 10 μm above cells at times afterwards (n = 3 independent experiments, error bars, s.d.). , M90T grown anaerobically or aerobically was transferred to different O2 concentrations with Congo red. Secreted (Sec.) and bacterial (Cell) IpaB was detected 30 min later. , Luminescence of E. coli pXen5 after introduction into loops (arrowed) with unclamped or clamped vascular supply. , Loops were challenged with M90TΔmxiD pFPV25.1, and tissue obtained 18 h later; host cell nuclei stained blue, and bacteria and actin stained red. GFP-positive bacteria were detected in a zone within 70 μm of villi (arrowed). , Shigella is 'primed' within the anaerobic lumen of the gastrointestinal tract; O2 from capillaries creates a permissive environment for T3SS activation. Author information * Author information * Supplementary information * Comments Affiliations * Centre for Molecular Microbiology and Infection, Department of Microbiology, Flowers Building, Imperial College London, London SW7 2AZ, UK * Benoit Marteyn, * Nicholas P. West & * Christoph M. Tang * School of Biosciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK * Douglas F. Browning & * Jeffery A. Cole * Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK * Jonathan G. Shaw * Department of Medical Cell Biology, Biomedical Center, Uppsala University, 751 23 Uppsala, Sweden * Fredrik Palm * Unité de Pathogénie Microbienne Moléculaire, and Unité INSERM786, Institut Pasteur, 28 rue du Dr Roux, F-75724 Paris Cédex 15, France * Joelle Mounier & * Philippe Sansonetti * Plateforme de Microscopie électronique, Institut Pasteur, 25 Rue du Docteur Roux, F-75724 Paris cedex 15, France * Marie-Christine Prévost * Collège de France, 11 Place Marcelin Berthelot, F-75231, Paris Cédex 05, France * Philippe Sansonetti * Present address: Centenary Institute, Newtown, New South Wales 2042, Australia. * Nicholas P. West Contributions B.M., N.P.W. and J.M. performed experiments with Shigella. D.F.B. and J.A.C. provided technical support and advice for electrophoretic mobility shift assays and analysis of the fusions. J.G.S. analysed the lipopolysaccharide, M.-C.P. carried out EM, and F.P. performed the oxygen measurements. C.M.T. and P.S. provided advice and overall direction, and wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Christoph M. Tang (c.tang@imperial.ac.uk) or * Philippe Sansonetti (psanson@pasteur.fr) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (163K) This file contains Supplementary Figures 1-11 with legends, Supplementary Tables S1-S4 and References. Additional data
• Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma
  - Nature (London) 465(7296):359 (2010)
  Nature | Letter Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma * Sebastian Lourido1 Search for this author in: * NPG journals * PubMed * Google Scholar * Joel Shuman1 Search for this author in: * NPG journals * PubMed * Google Scholar * Chao Zhang2 Search for this author in: * NPG journals * PubMed * Google Scholar * Kevan M. Shokat2 Search for this author in: * NPG journals * PubMed * Google Scholar * Raymond Hui3 Search for this author in: * NPG journals * PubMed * Google Scholar * L. David Sibley1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:359–362Date published:(20 May 2010)DOI:doi:10.1038/nature09022Received18 December 2009Accepted17 March 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Calcium-regulated exocytosis is a ubiquitous process in eukaryotes, whereby secretory vesicles fuse with the plasma membrane and release their contents in response to an intracellular calcium surge1. This process regulates various cellular functions such as plasma membrane repair in plants and animals2, 3, the discharge of defensive spikes in Paramecium4, and the secretion of insulin from pancreatic cells, immune modulators from lymphocytes, and chemical transmitters from neurons5. In animal cells, serine/threonine kinases including cAMP-dependent protein kinase, protein kinase C and calmodulin kinases have been implicated in calcium-signal transduction leading to regulated secretion1, 6, 7. Although plants and protozoa also regulate secretion by means of intracellular calcium, the method by which these signals are relayed has not been explained. Here we show that the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is an essential regulator of calcium-dependen! t exocytosis in this opportunistic human pathogen. Conditional suppression of TgCDPK1 revealed that it controls calcium-dependent secretion of specialized organelles called micronemes, resulting in a block of essential phenotypes including parasite motility, host-cell invasion, and egress. These phenotypes were recapitulated by using a chemical biology approach in which pyrazolopyrimidine-derived compounds specifically inhibited TgCDPK1 and disrupted the parasite's life cycle at stages dependent on microneme secretion. Inhibition was specific to TgCDPK1, because expression of a resistant mutant kinase reversed sensitivity to the inhibitor. TgCDPK1 is conserved among apicomplexans and belongs to a family of kinases shared with plants and ciliates8, suggesting that related CDPKs may have a function in calcium-regulated secretion in other organisms. Because this kinase family is absent from mammalian hosts, it represents a validated target that may be exploitable for chemoth! erapy against T. gondii and related apicomplexans. View full text Subject terms: * Parasitology * Chemical biology * Cell biology Figures at a glance * Figure 1: TgCDPK1 is essential for the lytic cycle. , Regulatable, HA9-tagged TgCDPK1 was added to the wild type (WT) to create a merodiploid (mDip). Endogenous TgCDPK1 was replaced with phleomycin resistance (bleR) to generate the cKO. Complementation with c-Myc-tagged mutant alleles (denoted by cKO/'allele'). UTR, untranslated region; YFP, yellow fluorescent protein. , Multiplexed PCR analysis of TgCDPK1. bp, base pairs. , Immunofluorescence analysis of the cKO in the presence or absence of ATc; green, endogenous MIC2; red, HA9 tag; blue, DNA. Scale bar, 5 μm. , Immunoblot of HA9-tagged regulatable and c-Myc-tagged constitutive TgCDPK1 in cKO and complemented strains in the presence or absence of ATc. Aldolase, loading control. , Plaque formation on fibroblast monolayers, in the presence or absence of ATc for 7 days. * Figure 2: TgCDPK1 is required for phenotypes associated with microneme secretion. , Types of gliding motility as quantified by videomicroscopy. Student's t-test; asterisk, P < 0.05; means ± s.e.m. for n = 4 experiments. , Invasion of fibroblasts by wild-type, cKO and complemented strains. Extracellular and intracellular parasites were stained differentially and enumerated as described in Supplementary Information. Student's t-test; three asterisks, P < 0.0005; two asterisks, P < 0.005; means ± s.e.m. for n = 3 experiments. , Ionophore-induced egress of the cKO in the presence or absence of ATc. The time stamps are coded as minutes:seconds after the addition of calcium ionophore. See Supplementary Movies 1 and 2. * Figure 3: Calcium-dependent microneme secretion requires TgCDPK1. , Western blot analysis of microneme protein MIC2 secretion after induction with ethanol for 15 min. Dense granule protein-1 (GRA1) shows constitutive secretion of dense granules. Student's t-test; two asterisks, P < 0.005; means ± s.e.m. for n = 3 experiments. , Ionophore-induced permeabilization detected by vacuolar DsRed leakage monitored by fluorescence videomicroscopy of strains after treatment with ATc for 90 h. The time stamps are coded as minutes:seconds after the addition of calcium ionophore. Cytochalasin D was added to prevent egress. , , Quantification of maximal rate () and timing () of fluorescence loss from rupturing vacuoles. Mann–Whitney test; three asterisks, P < 0.0005; two asterisks, P < 0.005; n = 3 experiments. * Figure 4: PP1 derivatives specifically inhibit TgCDPK1 and block microneme-mediated functions. , Alignment of the kinase subdomain V, highlighting the gatekeeper residue. , Structures of 3-MB-PP1 and 3-BrB-PP1. , Effect of 5 μM 3-MB-PP1 on host cell invasion. Student's t-test; asterisk, P < 0.05; means ± s.e.m. for n = 3 experiments. , Effect of 5 μM 3-MB-PP1 on MIC2 secretion. Student's t-test; asterisk, P < 0.05; means ± s.e.m. for n = 3 experiments. , , Effect of PP1 derivatives on host lysis by T. gondii in the presence or absence of 3-MB-PP1 () and 3-Br-PP1 (). Means ± s.e.m. for n = 3 experiments. Author information * Author information * Supplementary information * Comments Affiliations * Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, Missouri 63110, USA * Sebastian Lourido, * Joel Shuman & * L. David Sibley * Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California 94158, USA * Chao Zhang & * Kevan M. Shokat * Structural Genomics Consortium, University Toronto, MaRS South Tower, Suite 732, 101 College Street, Toronto, Canada M5G 1L7 * Raymond Hui Contributions S.L. designed and performed the majority of experiments, analysed the data, generated the figures and wrote the manuscript. J.S. performed the video miscopy measurements of motility and analysed the data. R.H. provided key insight into the regulation of CDPKs by calcium. C.Z. and K.M.S. provided inhibitors and insight into the strategy for chemical biology experiments. L.D.S. supervised the project, assisted with experimental design and analyses, and contributed to writing the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * L. David Sibley (sibley@borcim.wustl.edu) Supplementary information * Author information * Supplementary information * Comments Movies * Supplementary Movie 1 (3.7M) This movie shows ionophore-tiggered egress of cKO parasites grown in the absence of ATc. Groups of intracellular parasites are observed in round vacuoles. The time lapse covers a period of about 5 min during which time parasites start moving and egress normally from the host cells. Time stamp is given as h:min:sec. * Supplementary Movie 2 (2.7M) This movie shows cKO vacuoles grown in the presence of ATc fail to egress upon ionophore treatment. Independent parasite vacuoles in five host cells can be observed. The time lapse covers a period of about 5 min, during which time wild type parasites would have normally egressed from the host cells, but the TgCDPK1 depleted parasites remain intracellular. Time stamp is given as h:min:sec. * Supplementary Movie 3 (561K) This movie shows PVM permeabilization by DsRed-expressing WT parasites grown in the presence of ATc. Six round parasite vacuoles are shown in three independent host cells. Parasites were treated with ionophore immediately prior to recording, and immobilization with cytochalasin D prevented mechanical rupture by the PVM. The time lapse covers a period of about 9 min during which time DsRed is released from all vacuoles into their respective host cells. Time stamp is given as h:min:sec. * Supplementary Movie 4 (524K) This movie shows PVM permeabilization by DsRed-expressing cKO parasites grown in the presence of ATc. The time lapse covers a period of about 9 min during which time only one of the two of vacuoles releases DsRed at a much slower rate than WT. Time stamp is given as h:min:sec. PDF files * Supplementary Information (3.7M) This file contains Supplementary Figures 1-4 with legends and Supplementary Tables 1-2. Additional data
• A three-dimensional model of the yeast genome
  Duan Z Andronescu M Schutz K McIlwain S Kim YJ Lee C Shendure J Fields S Blau CA Noble WS - Nature (London) 465(7296):363 (2010)
  Nature | Letter A three-dimensional model of the yeast genome * Zhijun Duan1, 2, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Mirela Andronescu3, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Kevin Schutz4 Search for this author in: * NPG journals * PubMed * Google Scholar * Sean McIlwain3 Search for this author in: * NPG journals * PubMed * Google Scholar * Yoo Jung Kim1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Choli Lee3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jay Shendure3 Search for this author in: * NPG journals * PubMed * Google Scholar * Stanley Fields2, 3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * C. Anthony Blau1, 2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * William S. Noble3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:363–367Date published:(20 May 2010)DOI:doi:10.1038/nature08973Received17 November 2009Accepted01 March 2010Published online02 May 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Layered on top of information conveyed by DNA sequence and chromatin are higher order structures that encompass portions of chromosomes, entire chromosomes, and even whole genomes1, 2, 3. Interphase chromosomes are not positioned randomly within the nucleus, but instead adopt preferred conformations4, 5, 6, 7. Disparate DNA elements co-localize into functionally defined aggregates or 'factories' for transcription8 and DNA replication9. In budding yeast, Drosophila and many other eukaryotes, chromosomes adopt a Rabl configuration, with arms extending from centromeres adjacent to the spindle pole body to telomeres that abut the nuclear envelope10, 11, 12. Nonetheless, the topologies and spatial relationships of chromosomes remain poorly understood. Here we developed a method to globally capture intra- and inter-chromosomal interactions, and applied it to generate a map at kilobase resolution of the haploid genome of Saccharomyces cerevisiae. The map recapitulates known fea! tures of genome organization, thereby validating the method, and identifies new features. Extensive regional and higher order folding of individual chromosomes is observed. Chromosome XII exhibits a striking conformation that implicates the nucleolus as a formidable barrier to interaction between DNA sequences at either end. Inter-chromosomal contacts are anchored by centromeres and include interactions among transfer RNA genes, among origins of early DNA replication and among sites where chromosomal breakpoints occur. Finally, we constructed a three-dimensional model of the yeast genome. Our findings provide a glimpse of the interface between the form and function of a eukaryotic genome. View full text Subject terms: * Genomics * Cell biology * Genetics * Molecular biology Figures at a glance * Figure 1: Schematic depiction of the method. Our method relies on the 4C procedure by using cross-linking, two rounds of alternating restriction enzyme (RE) digestion (6-bp-cutter RE1 for the 3C-step digestion and 4-bp-cutter RE2 for the 4C-step digestion) and intra-molecular ligation. At step 7, each circle contains the 6-bp restriction enzyme recognition site originally used to link the two interacting partner sequences (RE1). Diverging from 4C, we relinearize the circles using RE1, then sequentially insert two sets of adaptors, one of which permits digestion with a type IIS or type III restriction enzyme (such as EcoP15I). Following EcoP15I digestion, fragments are produced that incorporate interacting partner sequence at either end, which can be rendered suitable for deep sequencing (see Supplementary Methods). * Figure 2: Validation of the assay. , Graph showing an inverse relationship between interaction frequency and genomic distance (20 kb or larger, excluding self-ligations and adjacent ligations) separating interacting restriction fragments (either HindIII or EcoRI) in each of four experimental but none of five control libraries. Note, the five lines representing the five control libraries are very close to each other. H-Mp, HindIII-MspI; H-Me, HindIII-MseI; E-Mp, EcoRI-MspI and E-Me, EcoRI-MseI library. , The fraction of instances that each HindIII site along chromosome I (chr I) was engaged in an intra-chromosomal interaction was highly correlated between two independently derived experimental H-Mp (HindIII-MspI) libraries (designated A and B, left panel) but was not correlated between experimental and non-cross linked control H-Mp libraries (right panel). , Two-dimensional heat maps demonstrating broad reproducibility of interaction patterns within chromosome I for two independently derived H-Mp libraries (! H-Mp-A and the equivalent sequence depth of H-Mp-B, H-Mp-B1). The chromosomal positions of mappable (green hatches) and un-mappable (black hatches) HindIII fragments are indicated. The binary interaction matrix of all interactions with an FDR threshold of 1% has been smoothed with a Gaussian of width 3 kb. , High degree of correlation between absolute interaction frequencies as determined by our method (symbols) versus relative interaction frequencies as determined by conventional 3C using cross-linked (dark grey bars) and uncross-linked (light grey bars) libraries. Results for 10 potential long-range intra-chromosomal interactions are depicted, of which 6 passed (circles) and 4 did not pass (triangles) an FDR threshold of 1%. Error bars denote standard deviations over three experiments. Interaction sites are as follows. A, Chr III position 11811; B, chr III position 290056; C, chr III position 15939; D, chr III position 314440; E, chr I position 26147; F, chr I position ! 191604; G, chr I position 204567; H, chr VI position 12007; I,! chr VI position 243206; J, chr VI position 249743; K, chr II position 238203; L, chr II position 502988; M, chr II position 512024; N, chr IV position 236977; O, chr IV position 447899; P, chr IV position 239805; Q, chr IV position 461284. * Figure 3: Folding patterns of chromosomes. Chromosomes III (, ) and XII (, ) are shown. The heat maps (, ) and Circos diagrams (, ) were generated using the intra-chromosomal interactions identified from the HindIII libraries at an FDR threshold of 1%. In the heat maps (, ), the chromosomal positions of centromeres (dashed pink lines), telomeres (pink hatches), mappable (green hatches) and un-mappable (black hatches) HindIII fragments are indicated. Circos diagrams (, ) depict each chromosome as a circle. Each arc connects two HindIII fragments and represents a distinct interaction. The shade of each arc, from very light grey to black, is proportional to the negative log of the P-value of the interaction. The chromosomal positions of centromeres (red rectangles), telomeres (red coloured areas), tRNA genes (blue outer hatches), mappable (green inner hatches) and un-mappable (black inner hatches) HindIII fragments are indicated. Black outer hatches and numbers mark genomic positions. Note that the two ends of chromosom! e XII (, ) exhibit extensive local interactions, but very little interaction with each other. Separating the ends of chromosome XII are 100–200 rDNA repeats, of which only two copies are depicted here (from coordinates 450 to 470 kb). Additional heat maps and Circos diagrams for all chromosomes are shown in Supplementary Fig. 8. * Figure 4: Inter-chromosomal interactions. , Circos diagram showing interactions between chromosome I and the remaining chromosomes. All 16 yeast chromosomes are aligned circumferentially, and arcs depict distinct inter-chromosomal interactions. Bold red hatch marks correspond to centromeres. To aid visualization of centromere clustering, these representations were created using the overlap set of inter-chromosomal interactions identified from both HindIII and EcoRI libraries at an FDR threshold of 1%. Additional heat maps and Circos diagrams are provided in Supplementary Fig. 9. , Circos diagram, generated using the inter-chromosomal interactions identified from the HindIII libraries at an FDR threshold of 1%, depicting the distinct interactions between a small and a large chromosome (I and XIV, respectively). Most of the interactions between these two chromosomes primarily involve the entirety of chromosome I, and a distinct region of corresponding size on chromosome XIV. , Inter-chromosomal interactions between al! l pairs of the 32 yeast chromosomal arms (the 10 kb region starting from the midpoint of the centromere in each arm is excluded). For each chromosome, the shorter arm is always placed before the longer arm. Note that the arms of small chromosomes tend to interact with one another. The colour scale corresponds to the natural log of the ratio of the observed versus expected number of interactions (see Supplementary Materials). , Enrichment of interactions between centromeres, telomeres, early origins of replication, and chromosomal breakpoints. To measure enrichment of strong interactions with respect to a given class of genomic loci, we use receiver operating curve (ROC) analysis. * Figure 5: Three-dimensional model of the yeast genome. Two views representing two different angles are provided. Chromosomes are coloured as in Fig. 4a (also indicated in the upper right). All chromosomes cluster via centromeres at one pole of the nucleus (the area within the dashed oval), while chromosome XII extends outward towards the nucleolus, which is occupied by rDNA repeats (indicated by the white arrow). After exiting the nucleolus, the remainder of chromosome XII interacts with the long arm of chromosome IV. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Zhijun Duan & * Mirela Andronescu Affiliations * Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98195-8056, USA * Zhijun Duan, * Yoo Jung Kim & * C. Anthony Blau * Department of Medicine, University of Washington Seattle, Washington 98195-8056, USA * Zhijun Duan, * Yoo Jung Kim, * Stanley Fields & * C. Anthony Blau * Department of Genome Sciences, University of Washington, Seattle, Washington 98195-5065, USA * Mirela Andronescu, * Sean McIlwain, * Choli Lee, * Jay Shendure, * Stanley Fields, * C. Anthony Blau & * William S. Noble * Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, Washington 98195-5065, USA * Kevin Schutz * Howard Hughes Medical Institute * Stanley Fields Contributions Z.D. devised the strategy for characterizing genome architecture, Z.D., J.S, S.F, C.A.B. and W.S.N. designed experiments, Z.D., K.S., Y.J.K., and C.L. performed experiments, Z.D., M.A., S.M., J.S., S.F., C.A.B. and W.S.N. analysed experimental data, M.A., K.S., J.S. and W.S.N. commented on the manuscript drafts, Z.D., S.F., and C.A.B. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * C. Anthony Blau (tblau@u.washington.edu) or * William S. Noble (william-noble@u.washington.edu) Sequencing data have been deposited in the Sequence Read Archive under accession number SRP002120. An interactive website for yeast chromosomal interactions can be found at http://noble.gs.washington.edu/proj/yeast-architecture. Supplementary information * Author information * Supplementary information * Comments Protein data bank files * Supplementary Information (1.7M) This file contains a 3d model of the yeast genome. This file can be opened using Rasmol (http://rasmol.org/). Excel files * Supplementary Table 5 (6.6M) This file contains a list of intra-chromosomal interactions identified from HindIII libraries at the threshold of FDR 1%. * Supplementary Table 6 (22.7M) This file contains a list of inter-chromosomal interactions identified from HindIII libraries at the threshold of FDR 1%. * Supplementary Table 7 (3M) This file contains a list of intra-chromosomal interactions identified from EcoRI libraries at the threshold of FDR 1%. * Supplementary Table 8 (6.7M) This file contains a list of inter-chromosomal interactions identified from EcoRI libraries at the threshold of FDR 1%. * Supplementary Table 9 (27K) This file contains the statistical data with respect to intra- and inter-chromosomal interactions-HindIII. * Supplementary Table 10 (54K) This file contains a list of intra-chromosomal interactions between the 20 and 30 kb regions of the ends of the chromosomes. * Supplementary Table 11 (146K) This file contains a list of Inter-chromosomal telomere pairing. * Supplementary Table 12 (27K) This file contains a list of primers used in this project. * Supplementary Table 13 (392K) This file contains a list of mappable HindIII and EcoRI fragments in each chromosome. PDF files * Supplementary Information (11M) This file contains Supplementary Results, Methods, Data Analysis, References and Validation of Methods, Supplementary Tables 1- 4 and 14 -15 (for Supplementary Tables 5-13 see separate excel files) and Supplementary Figures 1-18 with legends. Minor errors in this file were corrected on 19 May 2010. Additional data
• Opposing roles for calcineurin and ATF3 in squamous skin cancer
  - Nature (London) 465(7296):368 (2010)
  Nature | Letter Opposing roles for calcineurin and ATF3 in squamous skin cancer * Xunwei Wu1 Search for this author in: * NPG journals * PubMed * Google Scholar * Bach-Cuc Nguyen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Piotr Dziunycz2 Search for this author in: * NPG journals * PubMed * Google Scholar * Sungeun Chang1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Yang Brooks1 Search for this author in: * NPG journals * PubMed * Google Scholar * Karine Lefort3 Search for this author in: * NPG journals * PubMed * Google Scholar * Günther F. L. Hofbauer2 Search for this author in: * NPG journals * PubMed * Google Scholar * G. Paolo Dotto1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:368–372Date published:(20 May 2010)DOI:doi:10.1038/nature08996Received19 June 2009Accepted08 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 Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population1. By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent1. Here we report that genetic and pharmacological suppression of calcineurin/nuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xenografts, in immune compromised mice, of H-rasV12 (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the 'enla! rged' AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development. View full text Subject terms: * Cancer * Cell biology * Stem cells Figures at a glance * Figure 1: Calcineurin/NFAT inhibition promotes keratinocyte tumour formation. , Multistep skin carcinogenesis of mice with keratinocyte-specific CnB1 deletion (CnB1-/-)3 together with littermate controls (CnB1+/+). Numbers of total and large (>4.5 mm diameter) tumours were determined weekly. For histology see Supplementary Fig. 1. , Grafting of H-rasV12-expressing HKCs onto Scid mice plus/minus subsequent CsA treatment. Epidermal–dermal junction, black arrows. For higher magnification images and experimental conditions see Supplementary Fig. 2a. , H-rasV12-expressing HKCs were injected at dermal–epidermal junction of Scid mice plus/minus subsequent CsA or FK506 treatment. Similar assays were performed with H-rasV12-expressing HKCs with siRNA-mediated CnB1 knockdown (siCnB1) versus control (siCtrl). Histological analysis was 10 days later, summarized on the right. For higher magnification images and experimental conditions, see Supplementary Fig. 2b, c. , , Lesions formed by H-rasV12-expressing HKCs or SCC13 cells in mice plus/minus CsA-treatme! nt () or plus/minus CnB1 and p53 knockdown () were analysed by in situ chromogenic assay for senescence-associated β-galactosidase activity17. For additional images, data quantification and experimental conditions see Supplementary Figs 3–5. * Figure 2: Calcineurin/NFAT signalling negatively controls ATF3 expression. , , HKCs plus/minus CsA or VIVIT treatment () or CnB1 or Nfatc1 knockdown () were analysed in parallel with controls by immunoblotting. Similar results were obtained at mRNA level (Supplementary Fig. 8a–c). , HKCs infected with retroviruses expressing constitutively active NFATC1 (+)19 or GFP control (-) plus/minus subsequent CsA treatment were analysed for ATF3 expression. Similar results were obtained by real time RT–PCR (Supplementary Fig. 8f). , HKCs plus/minus CsA/VIVIT treatment and cycloheximide (CHX) exposure were analysed at various times (hours) for Atf3 expression by real-time RT–PCR. Error bars represent mean ± s.d. (n = 3 replicates). , Extracts of HKCs plus/minus CsA treatment or Nfatc1 knockdown (left panel) or intact human epidermis (right panel) were processed for chromatin immunoprecipitation with anti-NFATC1 antibodies or non-immune IgGs, followed by real-time PCR of Atf3 promoter regions containing and lacking high-affinity NFATC1 binding sites! (black and white boxes in the map above). Chromatin immunoprecipitation assays of the NFAT-binding region of the calcipressin (Rcna1) gene20, and a β-actin genomic region without NFAT binding sites were included. , SCCs from three patients under CsA treatment and from untreated patients (Untr) from the general population were analysed by immunoblotting for ATF3 expression, in parallel with HKCs infected with an ATF3-expressing retrovirus (ATF3) versus empty vector control. Similar differences in Atf3 mRNA expression were observed with an independent set of patients (Supplementary Fig. 9a). , Tissue arrays of cutaneous SCCs from patients under CsA treatment versus general untreated population (Untr) were analysed for ATF3 expression by immunohistochemistry. Representative staining is shown along with quantification of ATF3-positive nuclei in each visual field of tumour tissues. Error bars represent mean ± s.d. (n = 18, 16, 126 and 127 tumours per group, from left to r! ight). * Figure 3: ATF3 upregulation enhances keratinocyte tumour formation and suppresses cancer cell senescence. , HKCs infected with ATF3-expressing (ATF3) and control retroviruses were analysed by real time RT–PCR for indicated genes. Error bars represent mean ± s.d. (n = 3 replicates). , HKCs plus/minus infection with ATF3 and H-rasV12-expressing retroviruses were analysed for p53 expression by immunoblotting. , HKCs plus/minus Atf3 knockdown and CsA/VIVIT treatment were analysed by real time RT–PCR for p53 and DcR2 (also known as Ccr6) expression. Additional results are shown in Supplementary Fig. 10a. , HKCs plus/minus H-rasV12 expression, Atf3 knockdown and CsA treatment as indicated were analysed for ATF3 and p53 expression by immunoblotting. For densitometric quantification and experimental conditions see Supplementary Fig. 10b. , , H-rasV12-expressing HKCs () or SCC13 cells () infected with ATF3-expressing and control retroviruses were injected at the dermal-epidermal junction of Scid mice. Shown are histological images of lesions recovered 6 weeks later. For quanti! fication see Supplementary Fig. 11a, b. , H-rasV12-expressing HKCs plus/minus Atf3 knockdown were injected at the dermal-epidermal junction of Scid mice, followed by CsA treatment. Mice were killed 10 days later. For histological images see Supplementary Fig. 11c. , Lesions from the previous experiment were analysed for SA-β-Gal activity. Low magnification images and quantification are shown in Supplementary Fig. 11d. * Figure 4: Calcineurin inhibition and increased ATF3 enhance cancer initiating cell populations. –, H-rasV12-expressing HKCs sorted for high α6 integrin and low CD71 expression (α6briCD71dim cells) were injected in the indicated numbers into NOD/SCID-Il2rg-/- mice22, plus/minus subsequent CsA treatment for 4 weeks. Similar experiments were also performed with sorted H-rasV12expressing HKCs plus/minus ATF3 overexpression. , Histological images of nodules formed by 2,500 H-rasV12-HKCs in mice plus/minus CsA treatment. , Quantification of proliferative centres and , cysts or solid tumours formed by the indicated cell numbers. Error bars represent mean ± s.d. (n = 4 nodules per condition). For low magnification images, quantification criteria and immunofluorescence analysis see Supplementary Fig. 12a, b. , , Sorted α6briCD71dim populations of SCC13 cells plus/minus ATF3 overexpression were injected in the indicated numbers into Scid mice. Shown are quantification of the results and representative histological images. Experimental conditions were the same as with! CD133 sorted cells (Supplementary Fig. 13). , , Cells dissociated from tumours formed by H-rasV12-HKCs in mice plus/minus CsA treatment, or with ATF3 overexpression () or from tumours formed by SCC13 cells plus/minus ATF3 overexpression () were injected in decreasing numbers into secondary recipient mice (Scid), with tissue retrieval 4 weeks later. For representative images and experimental conditions see Supplementary Fig. 14. Author information * Author information * Supplementary information * Comments Affiliations * Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA * Xunwei Wu, * Bach-Cuc Nguyen, * Sungeun Chang, * Yang Brooks & * G. Paolo Dotto * Department of Dermatology, University Hospital Zurich, Zürich CH-8091 * Piotr Dziunycz & * Günther F. L. Hofbauer * Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland * Karine Lefort & * G. Paolo Dotto * Present address: Department of Dermatology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. * Sungeun Chang Contributions B-C.N., P.D, S.C, Y.B., K.L. and G.F.L.H. performed research and analysed data; X.W. and G.P.D. designed and performed research, analysed data and wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * G. Paolo Dotto (gian-paolo.dotto@unil.ch) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (40.9M) This file contains Supplementary Figures 1-14 with legends, Supplementary Tables I-III and References. Additional data
• Myosin II contributes to cell-scale actin network treadmilling through network disassembly
  - Nature (London) 465(7296):373 (2010)
  Nature | Letter Myosin II contributes to cell-scale actin network treadmilling through network disassembly * Cyrus A. Wilson1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark A. Tsuchida1 Search for this author in: * NPG journals * PubMed * Google Scholar * Greg M. Allen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Erin L. Barnhart1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kathryn T. Applegate2 Search for this author in: * NPG journals * PubMed * Google Scholar * Patricia T. Yam1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Lin Ji2 Search for this author in: * NPG journals * PubMed * Google Scholar * Kinneret Keren1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Gaudenz Danuser2, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Julie A. Theriot1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:373–377Date published:(20 May 2010)DOI:doi:10.1038/nature08994Received22 June 2007Accepted04 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 Crawling locomotion of eukaryotic cells is achieved by a process dependent on the actin cytoskeleton1: protrusion of the leading edge requires assembly of a network of actin filaments2, which must be disassembled at the cell rear for sustained motility. Although ADF/cofilin proteins have been shown to contribute to actin disassembly3, it is not clear how activity of these locally acting proteins could be coordinated over the distance scale of the whole cell. Here we show that non-muscle myosin II has a direct role in actin network disassembly in crawling cells. In fish keratocytes undergoing motility, myosin II is concentrated in regions at the rear with high rates of network disassembly. Activation of myosin II by ATP in detergent-extracted cytoskeletons results in rear-localized disassembly of the actin network. Inhibition of myosin II activity and stabilization of actin filaments synergistically impede cell motility, suggesting the existence of two disassembly pathways, o! ne of which requires myosin II activity. Our results establish the importance of myosin II as an enzyme for actin network disassembly; we propose that gradual formation and reorganization of an actomyosin network provides an intrinsic destruction timer, enabling long-range coordination of actin network treadmilling in motile cells. View full text Subject terms: * Cell biology Figures at a glance * Figure 1: Myosin II in keratocytes co-localizes with the primary sites of actin network disassembly. –, Data and analysis of a single live keratocyte. , Phase-contrast image of the keratocyte moving upwards. , FSM image of the actin network labelled with a low concentration of phalloidin. , F-actin flow field based on speckle tracking, in the laboratory frame of reference. Arrow length and colour both indicate the speed of actin network flow. , F-actin flow field in the cell frame of reference. , Steady-state net F-actin assembly and disassembly. , Fluorescence image of YFP-tagged myosin regulatory light chain in a keratocyte of similar size and shape to that shown in –. Myosin II is found at low levels throughout the lamellipodium and at the highest concentrations in two foci flanking the cell body, which coincide with the primary sites of actin network disassembly as shown in . * Figure 2: Inhibition of myosin II blocks inward flow and alters the pattern of disassembly of the actin network. –, Analysis of actin network flow in a single keratocyte before (left) and approximately 10 min after (right) addition of 50 µM blebbistatin. , Raw F-actin speckle flow measurements (yellow arrows) in the laboratory frame of reference, superimposed on the corresponding FSM frames. , Resampled flow field in the laboratory frame of reference. , Resampled flow field in the cell frame of reference. , Maps showing the component of network flow perpendicular to the direction of cell movement ('perpendicular flow') in the cell frame of reference. Red indicates F-actin flow towards the right; blue, towards the left. Actin network movement in the green regions is parallel to the direction of cell locomotion. Blebbistatin treatment abolishes inward flow. , Steady-state assembly/disassembly maps. Before blebbistatin treatment, the highest rate of disassembly is found in two foci flanking the cell body. After blebbistatin treatment, disassembly is distributed along the rear m! argin. , Inward perpendicular flow of the actin network in untreated (white circles; n = 23) and blebbistatin-treated (black triangles; n = 8) cells. Error bars indicate average ± s.d. over each movie (typically 4 min). Measurements were made before and after treatment for two of the cells; blue and black arrows connect the corresponding data points. The data points connected by the blue arrow correspond to the cell shown in –. Compare with Supplementary Movie 1. * Figure 3: Jasplakinolide specifically halts actin dynamics of cells in which myosin II is inhibited. , Raw F-actin speckle flow measurements in the cell frame of reference (yellow arrows) superimposed on the corresponding FSM frames, for a cell in 50 µM blebbistatin before (top) and approximately 2 min after (middle) addition of 1 µM jasplakinolide. Bottom, a separate cell in jasplakinolide alone. , F-actin flow magnitude maps corresponding to . The combination of blebbistatin and jasplakinolide immobilizes the actin network, an effect that is not achieved by either drug alone. –, Fixed, phalloidin-labelled keratocytes, untreated () or treated with 50 µM blebbistatin () or 1 µM jasplakinolide (). Consistent with impaired actin-network disassembly, blebbistatin-treated cells accumulate F-actin along the rear margin, jasplakinolide-treated cells underneath the cell body. , Treatment with either 5 nM latrunculin A, 50 µM blebbistatin or 1 µM jasplakinolide can slow cells relative to the control population. The combination of blebbistatin and latrunculin! A or jasplakinolide and latrunculin A has no significant further effect on cell speed than either drug alone. The combination of blebbistatin and jasplakinolide significantly (P < 0.05 by Tukey's test) and synergistically slows cell locomotion. , Blebbistatin causes significant (P < 0.05 by Tukey's test) F-actin accumulation in the trailing 'tails' (but not in the cell body), whereas jasplakinolide causes accumulation underneath the cell body (but not in the 'tails'), relative to untreated cells. a.u., Arbitrary units (see Methods). Compare –. Box-and-whisker plots ( and ) indicate the mean, 95% confidence interval (CI), extrema and quartiles for the indicated number of cells (n) in each treatment group. Compare with Supplementary Movie 3. * Figure 4: Actin network disassembly in the rear of detergent-extracted keratocyte cytoskeletons is ATP dependent and blebbistatin sensitive, consistent with a direct role for myosin II in this process. –, ATP triggers an acute loss of actin network in the rear region of the cell, where myosin II is localized (compare with Fig. 1f). , A detergent-extracted and phalloidin-labelled keratocyte cytoskeleton6. , The same cytoskeleton 7 min after addition of 1 mM ATP. , Overlay of initial frame (, cyan) and frame at 7 min (, yellow); regions with increase, decrease or no change in net intensity appear yellow, cyan or white, respectively. , Time evolution of fluorescence intensities (normalized at t = 0) in the indicated regions. Time points for a mock buffer wash (chevron) and ATP addition (black arrowhead) are indicated. –, In a cell treated with 50 µM blebbistatin for 30 min before extraction, addition of ATP does not induce a loss of actin network. There is a slow loss of fluorescence owing to photobleaching or background dissociation. –, The F-actin severing protein villin rapidly disassembles the lamellipodial actin network, demonstrating that this part of t! he cytoskeleton is not protected against a general disassembling activity. GST–villin (0.1 µM) was added instead of ATP (arrow in ). –, Addition of GST–villin (arrows in , ) in addition to ATP (arrowheads in , ), in either order, results in complete, rapid disassembly of the actin network. Compare with Supplementary Movie 4. Author information * Author information * Supplementary information * Comments Affiliations * Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA * Cyrus A. Wilson, * Mark A. Tsuchida, * Greg M. Allen, * Erin L. Barnhart, * Patricia T. Yam, * Kinneret Keren & * Julie A. Theriot * Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA * Kathryn T. Applegate, * Lin Ji & * Gaudenz Danuser * Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA * Julie A. Theriot * Present addresses: Institute for Creative Technologies, University of Southern California, Marina del Rey, California 90292, USA (C.A.W.); Montreal Neurological Institute, Montreal, Quebec, H3A 2B4, Canada (P.T.Y.); Department of Physics and the Russell Berrie Nanotechnology Institute, Technion – Israel Institute of Technology, Haifa 32000, Israel (K.K.); Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA (G.D.). * Cyrus A. Wilson, * Patricia T. Yam, * Kinneret Keren & * Gaudenz Danuser Contributions C.A.W., M.A.T. and J.A.T. conceived and designed the experiments. C.A.W. and P.T.Y. performed FSM on untreated motile keratocytes. C.A.W. performed the pharmacological manipulation experiments, FSM observation and the analysis. L.J. and G.D. developed the flow tracking algorithm specific to the needs of this analysis. C.A.W. and P.T.Y. developed methods and software to integrate the flow tracking algorithm with these experiments and analysis. K.T.A., C.A.W. and G.D. developed algorithms for the F-actin turnover analysis. E.L.B. imaged myosin II localization. G.M.A., K.K. and E.L.B. collected the cell speed data and observed fixed cells under the different treatments; G.M.A. and C.A.W. analysed these data. M.A.T. performed experiments on detergent-extracted cytoskeletons and analysed the results. M.A.T., C.A.W. and J.A.T. wrote the paper. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Julie A. Theriot (theriot@stanford.edu) Supplementary information * Author information * Supplementary information * Comments Movies * Supplementary Movie 1 (20.3M) This movie shows that myosin II inhibition alters actin network Ô¨Çow (see Supplementary Information file for full caption). * Supplementary Movie 2 (8.4M) This movie shows that inward traction force generation requires myosin II activity (see Supplementary Information file for full caption). * Supplementary Movie 3 (15.3M) This movie shows that jasplakinolide halts actin dynamics of cells in which myosin II is inhibited (see Supplementary Information file for full caption). * Supplementary Movie 4 (424K) This movie shows that actin network disassembly in the rear of detergent-extracted keratocyte cytoskeletons is ATP-dependent and blebbistatin-sensitive (see Supplementary Information file for full caption). PDF files * Supplementary Information (5.4M) This file contains Supplementary Notes 1-3, Supplementary Figures 1-6 with legends, captions for Supplementary Movies 1-4 and References. Additional data
• eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation
  - Nature (London) 465(7296):378 (2010)
  Nature | Letter eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation * Martin D. Jennings Search for this author in: * NPG journals * PubMed * Google Scholar * Graham D. Pavitt Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:378–381Date published:(20 May 2010)DOI:doi:10.1038/nature09003Received28 July 2009Accepted10 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 In protein synthesis initiation, the eukaryotic translation initiation factor (eIF) 2 (a G protein) functions in its GTP-bound state to deliver initiator methionyl-tRNA (tRNAiMet) to the small ribosomal subunit and is necessary for protein synthesis in all cells1, 2. Phosphorylation of eIF2 [eIF2(αP)] is critical for translational control in diverse settings including nutrient deprivation, viral infection and memory formation3, 4, 5. eIF5 functions in start site selection as a GTPase accelerating protein (GAP) for the eIF2·GTP·tRNAiMet ternary complex within the ribosome-bound pre-initiation complex6, 7, 8. Here we define new regulatory functions of eIF5 in the recycling of eIF2 from its inactive eIF2·GDP state between successive rounds of translation initiation. First we show that eIF5 stabilizes the binding of GDP to eIF2 and is therefore a bi-functional protein that acts as a GDP dissociation inhibitor (GDI). We find that this activity is independent of the GAP functi! on and identify conserved residues within eIF5 that are necessary for this role. Second we show that eIF5 is a critical component of the eIF2(αP) regulatory complex that inhibits the activity of the guanine-nucleotide exchange factor (GEF) eIF2B. Together our studies define a new step in the translation initiation pathway, one that is critical for normal translational controls. View full text Subject terms: * Biochemistry * Molecular biology Figures at a glance * Figure 1: eIF5 has GDI activity. , Scheme for GDI activity assay. , Increasing eIF5 stabilizes GDP-binding to eIF2. Koff GDP from 60 pmol eIF2 with varying concentrations of GST–eIF5 (0–240 pmol, open circles) or GST alone (filled circle). Molar eIF2:GST–eIF5 protein ratios are indicated. , Defining regions required for GDI activity. Mean Koff GDP (60 pmol eIF2) for indicated constructs derived from reactions with GST– or Flag–eIF5 proteins (120 pmol). Black bars represent a significant reduction in Koff GDP (P < 0.0001, unpaired Student's t-test). Errors show standard deviation (n > 3). Mg2+ (2.9 mM) was used in and . * Figure 2: The CTD of eIF5 is critical for interaction with eIF2. , , Affinity chromatography assay between eIF2 (110 pmol) and the indicated immobilized GST–eIF5 constructs. eIF2 was detected by immunoblotting using antibodies specific for eIF2γ () or eIF2α (). Representative blots are shown. Signal intensity was quantified (Adobe Photoshop) and the mean ± standard deviation (n = 3) are shown below. , Total protein in each sample stained with Ponceau S. Inputs (lanes 1) represent 10% of total. * Figure 3: The linker region of eIF5 interacts with γ subunit of eIF2. Affinity chromatography as in Fig. 2 between indicated immobilized GST–eIF5 constructs and total cell extracts (500 μg) expressing c-Myc–6×His–eIF2γ from either a single copy (sc) or high copy (hc) plasmid. Immunoblots were developed with anti-c-Myc and eIF2α antibodies. Total protein in each sample was stained with SimplyBlue. Inputs (lane 1) represent 5% (blots) or 1% (stain) of total. * Figure 4: GDI activity antagonizes eIF2B and affects GCN4 activation in vivo. –, Strains expressing single (sc) or high copy (hc) eIF5 plasmids as the source of eIF5 and co-transformed with plasmids expressing GCN2, vector alone (gcn2Δ) (, ) or the constitutively active mutant GCN2M788V,E1591K (GCN2c) () were grown as stated. WT, wild type. , Left, immunoblots following Flag–eIF5 immune precipitation of protein complexes from cells grown in nutrient sufficient conditions (SCD) and following starvation (SD+3AT). Right, quantification ± standard deviation (n = 3). ) Model for recycling and regulation of eIF2, incorporating eIF5 GDI activity. Dashed grey arrows indicate steps that limit eIF2 recycling. Author information * Author information * Supplementary information * Comments Affiliations * Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK Contributions G.D.P. conceived the experiments, directed research, interpreted the experiments and wrote the manuscript. M.D.J. performed the experiments, interpreted the experiments and co-wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Graham D. Pavitt (graham.pavitt@manchester.ac.uk) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (3.5M) This file contains Supplementary Tables S1-S3, Supplementary Figures S1-S6 with legends and References. Additional data
• Mind expeditions
  - Nature (London) 465(7296):390 (2010)
  Fighting the good fight.