Hot off the presses! Jun 04 Nature

The Jun 04 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:

• Microscopic marvels
  - Nature 459(7247):615 (2009)
  Microscopes are changing the face of biology. Researchers should innovate and collaborate if they want to be part of the new vision.
• Stem-cell clarity
  - Nature 459(7247):615-616 (2009)
  The draft NIH guidelines on stem-cell research are a good first step, but some revision is needed.
• Power vacuum
  - Nature 459(7247):616 (2009)
  The US president's delay in naming an NIH director is symptomatic of a widespread problem.
• Animal behaviour: Pretty please
  - Nature 459(7247):618 (2009)
  
• Evolution: Carnivore claim quashed
  - Nature 459(7247):618 (2009)
  
• Astronomy: A big head start
  - Nature 459(7247):618 (2009)
  
• Palaeontology: Bone study bugbear
  - Nature 459(7247):618 (2009)
  
• Genetics: Setting the biological clock
  - Nature 459(7247):618 (2009)
  
• Neurobiology: Squeaking in tongues
  - Nature 459(7247):619 (2009)
  
• Chemistry: Toxic toadstools
  - Nature 459(7247):619 (2009)
  
• Genetics: Filling mouse holes
  - Nature 459(7247):619 (2009)
  
• Quantum physics: Attack of the giant neutrinos
  - Nature 459(7247):619 (2009)
  
• Journal club
  - Nature 459(7247):619 (2009)
  
• Mouse patent sparks 'uncivil' spat
  - Nature 459(7247):620-621 (2009)
  The Jackson Laboratory, a non-profit genetics research centre in Bar Harbor, Maine, is embroiled in its first ever patent dispute — with another non-profit research institute. "It is almost unheard of for one academic institute to sue another over patent infringement," says the Jackson Lab's corporate lawyer, David Einhorn, who described the dispute on 21 May at a meeting in Rome on sharing data and resources for functional genomics.
• Funding struggle for mercury monitoring
  - Nature 459(7247):620-621 (2009)
  Researchers look to quantify pollution levels. Nicola Pirrone may need all the help he can get next week. In the hallways of a conference in Guiyang, China, Pirrone — the director of Italy's CNR-Institute for Atmospheric Pollution Research — will be trying to rustle up support for a global network to monitor mercury pollution. Such a network would underlie a United Nations Environment Programme (UNEP) treaty to control mercury emissions, which negotiators plan to forge by 2013. So far, countries from Mexico to South Africa to Japan have expressed interest in setting up a monitoring system. But to turn interest into reality, researchers are facing a complex task on what may be shoestring budgets. Anthropogenic sources emit about 2,500 tonnes of mercury every year, more than half of which comes from fossil-fuel power plants (see chart). But so far, global monitoring endeavours have been relatively uncoordinated; hundreds of sporadic efforts can include one-time samplings from a ship cruise or aeroplane flight. Click to enlarge.Click to enlarge.SOURCE: MERCURY FATE AND TRANSPORT IN THE GLOBAL ATMOSPHERE (SPRINGER, 2009). The United States and Canada do have networked and standardized stations that can monitor mercury deposition at a high enough precision over the long term to be useful in a treaty. These include sophisticated monitors made by Tekran Instruments Corporation in Knoxville, Tennessee, which can collect mercury from both rainfall and dry air and determine its chemical form. US researchers have been working to combine data from about a dozen Tekran-equipped sites, along with other longer-term studies, into a national monitoring effort called MercNet that could serve as a starting point for a global network. Some initial high-quality worldwide data are starting to become available, for instance from Taiwan's Changbai Mountain (Q. Wan et al. Environ. Res. 109, 201–206; 2009). But expanding the number of sites globally will be expensive. A top-of-the-line Tekran monitor costs about US$100,000, not including operational costs. On top of that, mercury researchers would like to see a host of other measurements, including regularly scheduled aeroplane monitoring high in the troposphere to see how chemical reactions change airborne mercury; research cruises to measure what is happening in the ocean–air boundary layer; and more data on mercury levels in the oceans themselves. One money-saving option might be to piggyback mercury measurements on other sites that already collect atmospheric data, says Robert Mason, an environmental chemist at the University of Connecticut in Groton. Mason is advising researchers who are working to set up a network in China, Japan and Korea, including expanding existing stations. But some researchers worry that the focus on air monitoring may mean that other parts of the environment get overlooked. "There has to be a biological component to this," says David Evers of the BioDiversity Research Institute in Gorham, Maine. That could mean, for instance, identifying 'hot spots' that receive airborne mercury and turn it into a form that could be taken up by fish and then humans. Pierrette Blanchard, an atmospheric chemist at Environment Canada, notes that even fish in seemingly pristine lakes in national forests in the United States and Canada can contain high levels of mercury. In particular, Evers wants to see estuarine and marine sampling in the Amazon basin, where small-scale gold mining releases mercury into environments where fish are caught for food. He and his colleagues have also proposed a marine and estuaries network for monitoring the US Atlantic coast. And Evers and others have been advising Senator Susan Collins (Republican, Maine) on a bill that would provide funding from the US Environmental Protection Agency for a national mercury network to include air, water, soils and animals. Collins has tried several times before; in 2007, for instance, she requested that $18 million be designated, but the effort died at the committee stage. Collins hopes to reintroduce the bill this summer. ADVERTISEMENT Advertisement The costs of an international monitoring system are unknown, and will depend on how much various countries are willing to put up for equipment and staffing. That may be a point for discussion when negotiations for the UNEP treaty begin in earnest early next year. The talks have been boosted by the United States, which had long called for voluntary-only mercury monitoring but in February indicated it would support an international regulatory structure. "What we need to do is to inform the negotiations," says a US state department official who requested anonymity because of the talks. Bettina Hitzfeld, a UNEP negotiator for the Swiss Federal Office for the Environment, says that treaty discussions need to start moving ahead even in the absence of a complete monitoring system. "We cannot afford to wait," she says, "for a mercury network to be up and running." Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Europe's parliamentary priorities
  - Nature 459(7247):622-623 (2009)
  Chris Davies, a former British Member of Parliament who has been a Member of the European Parliament (MEP) for the last ten years, is convinced that "you can do more for environment legislation in Brussels through parliamentary committee work than you can in any national parliament". His view is shared by many MEPs across parties, political groups, nations and political themes.
• Quaternary geologists win timescale vote
  - Nature 459(7247):624 (2009)
  Redefinition rescues once-threatened terminology from extinction. J. BLAIR/CORBIS In 2006, astronomers reached a decision on the planetary status of Pluto; now, geologists may have done the same for the status of the Quaternary, the time period in which humans evolved and live today. But, as was the case with Pluto, resolving this long-standing controversy has left some researchers feeling alienated. The International Commission on Stratigraphy (ICS) has elected to formally define the base of the Quaternary at 2.6 million years before present, and also to lower the base of the Pleistocene — an epoch that encompasses the most recent glaciations — from its historical position at 1.8 million years to 2.6 million years ago. The decision, finalized on 21 May, will now be passed to the executive committee of the International Union of Geological Sciences (IUGS) for ratification, which is expected in the next month or two. The vote shifts an 800,000-year slice, formerly part of the Pliocene epoch, into the Pleistocene. "It's kind of a land grab," says Philip Gibbard, a geologist at the University of Cambridge, UK, who has fought for the redefinition since 2001. "But we see it as just putting straight a mistake that was made 25–30 years ago." In 1985, the beginning of the Pleistocene was defined at 1.8 million years ago, calibrated to an outcropping of marine strata in southern Italy. But some geologists have long felt that was a localized, arbitrary boundary that did not reflect worldwide changes — and argued instead for the 2.6-million-year mark, when the entire planet cooled. The term Quaternary was adopted in the early 1800s, when geologists divvied up fossil records of Earth's history into four periods: the Primary, Secondary, Tertiary and Quaternary. The first two terms were discarded long ago, and although Tertiary is still sometimes used, in recent decades some geologists came to consider the Quaternary an outmoded relic. In 2004, a major publication left the Quaternary out of the ICS timescale altogether, making it vulnerable to extinction from scientific nomenclature. In place of the Quaternary, it extended the prior 'Neogene', which began 23 million years ago, up to the present. The Quaternary community went into open revolt. "The geologic timescale is fundamental for expressing the history of the Earth," says Stan Finney, a geologist at California State University in Long Beach and chair of the ICS. "This is our clock — we need the units of our timescale and their boundaries to be precisely defined." ICS Finney inherited the debate when he took his post at the ICS in 2008, and he vowed to come up with a democratic process to resolve it. After several months of open discussions and formal proposals from the Quaternary and Neogene communities, two rounds of voting took place, in April and May. The redefinition proposal passed with approval from 16 of the 18 voting members. Although for some the debate is settled, others are not pleased. "We don't take a metre stick in Paris and add a foot-and-a-half to it," says Lucy Edwards, a marine geologist with the US Geological Survey in Reston, Virginia. "You can redefine it by being more precise, but you don't increase its size by 40%." Edwards has practical concerns as well: in the 1980s, the USGS reworked all of its maps and terminology to reflect the decision to place the Pleistocene at 1.8 million years ago. Now that the international standards have changed, it will have to do so again. ADVERTISEMENT Advertisement Marie-Pierre Aubry of Rutgers University in Piscataway, New Jersey, who lobbied against the change, says that the rules of science are being violated. Whereas other major boundaries in Earth's history are associated with faunal extinctions and turnover, she says, "you come to the Neogene–Quaternary boundary, and there is nothing there". She notes that the term Neogene, not Quaternary, is used widely in textbooks to describe the current period. The Neogene community has already responded by petitioning the IUGS to suspend the vote. Others are moving on. "In the end, it is only a shift in nomenclature," says Martin Van Kranendonk, a geologist at the Geological Survey of Western Australia in East Perth, and one of the two voting members who voted against the Quaternary proposal. "The rocks and time itself haven't changed," he says. "It's just what we have chosen to call them." Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Spooky research cuts
  - Nature 459(7247):625 (2009)
  Two leading researchers in quantum computing have had their funds cut off by a US intelligence-research agency in what seems to be an administrative technicality. The controversy has underscored some scientists' fears that the field in the United States is too dependent on the spy world for funding.
• Sweden likely winner for neutron source
  - Nature 459(7247):626 (2009)
  Sweden is claiming victory in a long-running battle to host Europe's next-generation neutron-science facility. The European Spallation Source (ESS), a €1.
• University wins injunction against animal activists
  - Nature 459(7247):627 (2009)
  
• Economic gloom threatens renewables investment
  - Nature 459(7247):627 (2009)
  SOURCE: IEA Renewable-energy projects are struggling the most in terms of investment in the energy sector, according to a report published by the International Energy Agency (IEA) on 27 May. The agency predicts that a sharp fall in energy demand could see global electricity consumption drop by up to 3.5% this year — the first contraction since 1945. Combined with tighter access to credit, the weak demand means that many firms in the oil, gas and coal sectors are having to cut back on their spending. The slump is even more pronounced for renewables projects, which are often developed by smaller companies. Government stimulus spending will trigger additional public and private investment in renewable energy (see chart), but the agency thinks that the stimulus funding needs to be increased sixfold if patterns of energy use are to be altered sufficiently to keep the global temperature rise within 2 °C of pre-industrial levels. Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Malaria vaccine enters phase III clinical trials
  - Nature 459(7247):627 (2009)
  
• Africa declares its stance for climate-change talks
  - Nature 459(7247):627 (2009)
  More than 300 African negotiators, ministers, experts and agency representatives converged on Nairobi last week to forge a shared vision on climate change. Their conclusion: to ask for more financial and technical support to help Africa cope, but with few specifics. "It was difficult to agree on how much to ask for," says Sputnik Ratner, a spokesman for Buyelwa Sonjica, South Africa's minister of water and environmental affairs, who chaired the ministerial meetings. "Different countries have different needs." The 'Nairobi declaration' also asks industrialized countries to reduce their greenhouse-gas emissions towards the upper end of the pledged 25–40% cut below 1990 levels by 2020. The declaration is meant to serve as a starting point for Africa's negotiations at climate meetings being held this week in Bonn, Germany, and scheduled for December in Copenhagen, to hammer out a successor to the Kyoto Protocol. Despite the declaration's vagueness, the United Nations Environment Programme hailed it as a "landmark position" and a "major milestone on the road for combating climate change on the continent". Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Changes at the top for Indian science
  - Nature 459(7247):627 (2009)
  Prithviraj Chavan.Prithviraj Chavan.I. MUKHERJEE/AFP PHOTO/GETTY IMAGES India's Prime Minister Manmohan Singh last week named Prithviraj Chavan as his new science minister, after spring elections returned Singh's party to power (see Nature 459, 311; 2009). Chavan, who has a master's degree in engineering from the University of California, Berkeley, takes charge of the ministries of science and technology and of Earth sciences. But he will continue as minister of state in the prime minister's office, a role he has held since 2004, and which involves interactions with the space and atomic-energy agencies. "I am personally happy that we have a science minister who is also ideally positioned in the prime minister's office," says Thirumalachari Ramasami, secretary for the department of science and technology. With former science minister Kapil Sibal placed in charge of the human-resource development (education) ministry, Ramasami says the combination "signifies a very bright future for Indian science as a whole". Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Open-access publishing gains another convert
  - Nature 459(7247):627 (2009)
  
• Correction
  - Nature 459(7247):627 (2009)
  In the News story 'Fusion dreams delayed' (Nature 459, 488–489; 2009), the pie chart of ITER partners inadvertently omitted India. Like all non-European Union partners, India contributes 9% to the overall cost of the project. The html version of the story has been amended to show the correct chart, and a corrected PDF can be downloaded from http://tinyurl.com/nnwt9w. Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Climate future
  - Nature 459(7247):628 (2009)
  Scientists sometimes describe the way human activities are changing the composition of Earth's atmosphere as a giant (and dangerous) experiment: we don't know enough about the complexities of the climate system to fully gauge all of the impacts of the increase in greenhouse-gas levels. Less frequently noted is that the antidote to global climate change is also a giant (although necessary) experiment: we don't know enough about the complexities of the economic system to fully gauge all of the impacts of a cap-and-trade system to limit greenhouse-gas emissions.
• Microscopic marvels: Magnifying power
  - Nature 459(7247):629 (2009)
  Close-ups of cork, lice and fly's eyes do not inspire the rhapsodies that they did more than 300 years ago when Robert Hooke first observed them under a microscope. But other pictures do — the boughs and twigs of a branching neuron in its forest; the scuttle of vesicles delivering molecular loads; the endless thrill of a cell carving itself in two again — and again, and again — as an embryo buds into being.
• Microscopic marvels: Seeing the system
  - Nature 459(7247):630-631 (2009)
  "We don't pretend to have invented new physics," says Ernst Stelzer modestly, standing next to an equally modest layout of lasers, mirrors and lenses. "It has all just been plain common sense.
• Microscopic marvels: Microscope for the masses
  - Nature 459(7247):632-633 (2009)
  Download a PDF of this story Download a PDF of this story Blurry specks in the eye seem an unlikely source of inspiration for a revolutionary microscope. But 'floaters' — tiny debris that floats inside the eyeball — led Changhuei Yang at the California Institute of Technology in Pasadena to devise a microscope so small, cheap and mass-producible that it could, according to its inventor, transform the way that microscopy is done. The human eye registers floaters when bright light casts the shadow of debris directly onto the retina. On the tiny 'optofluidic' microscope that Yang and his colleagues invented, the sample casts a shadow directly on to an array of commercial light sensors as it floats along a microfluidic channel (X. Cui et al. Proc. Natl Acad. Sci. USA 105, 10670–10675; 2008). The sensors feed the projection pattern to a computer, which constructs an image using relatively simple image-processing software. The device itself is assembled using semiconductor fabrication techniques and is smaller than an American dime. When mounted into a device with a USB port so that it can transfer information to a computer, it is still just 3 centimetres square. Yang says that his microscopes, which could cost as little as US$10 apiece, could have the same revolutionary impact on science that the integrated circuit has had on the electronics industry. "When people were building transistors individually, it was still a pretty expensive proposition to build circuits out of them," he says. "But the move to build integrated circuits moved the semiconductor industry forwards because you could build things comparably cheaply with high functionality. If we can start to put 10–100 microscopes on a single chip and link a bunch of them up to operate in parallel to do high-throughput processing of a large number of samples, this opens up the opportunity to do experiments you might not otherwise do." The optofluidic microscope.The optofluidic microscope.G. MARSHALL With cheap, high-throughput imaging, researchers could perform drug assays, genomic or proteomic screens and rapidly observe the outcome of hundreds or thousands of manipulations on the shape or behaviour of living cells. "It's very clever work," says Charles DiMarzio, director of the Optical Science Laboratory at Northeastern University in Boston, Massachusetts. "This is a way of making a [high-power] microscope that is very low cost, maybe even disposable, and that's something that we haven't had before." Yang recognized that it would be difficult to shrink the lens and other delicate optics in a high-end instrument — so his 'direct projection' technique did away with lenses altogether. Other scientists have worked out similar techniques before, but they couldn't resolve anything smaller than 5 micrometres, because that's as small as the pixels on most digital light-sensing chips get. Yang coated the sensing chips with a thin layer of metal, than punched 500-nanometre holes into the metal to create apertures that are smaller than a pixel and that are patterned along the path of the microfluidic channel (see graphic). As the sample floats along, the chip captures repeated but staggered snapshots of what is passing overhead. A nematode worm (above) as seen by the optofluidic microscope (shown en masse and slightly larger than life, opposite, and in schematic below).Click to enlarge.X. CUI With 500-nanometre holes, Yang's optofluidic microscope has a resolution that approaches that of a standard laboratory light microscope. He has already shown that it can capture images of the nematode worm Caenorhabditis elegans that are almost indistinguishable from those collected with a 20× objective lens on a conventional instrument. He is working to narrow the holes to 300 nanometres, a resolution capable of distinguishing the finer details of cells. Besides transforming research microscopy, Yang's microscope could boost low-cost science and medicine in developing nations. The scope is rugged, works with sunlight, needs only the amount of computational power found in an iPod and, Yang wrote in his paper last July, might be "a boon for a health worker who needs to travel from village to village". That statement struck home for Ricardo Leitão, a postdoctoral fellow at New York University School of Medicine, who is founding a non-profit group called Tek4Dev — Science & Technology for Sustainable Development — which is putting together a tool kit to enable 'telemedicine' (using networks such as the Internet to facilitate clinical care) in poor countries. Leitão wrote to Yang on the day the paper was published to propose a collaboration. Yang, Leitão and Ana Rodriguez, a malaria researcher also at New York University, are now testing the microscope's ability to diagnose malaria-infected red blood cells based on their sh ape and those of the parasites inside them. Microscopy is still the standard method for diagnosing malaria, but microscopes can be few and far between in malaria-endemic areas. "Having a diagnostic tool as powerful as Yang's integrated with our hardware and 'tele' ability would be of tremendous clinical value," says Leitão. ADVERTISEMENT Advertisement Yang admits that by trying to do more with less, he is thinking differently from many of his peers. "In the field of biomicroscopy, there is a very strong drive towards building more sophisticated microscopes, giving you ever better resolution," he says. "But I think there's another axis to pursue, which is if you're actually building this in a comparably low-cost fashion, it can create experimental formats that are currently not doable using a traditional microscope or any other high-end microscope that other research groups are pursuing." What is certain is that by making microscopes exceedingly small, Yang has actually been thinking very, very big. Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Microscopic marvels: The big and the bold
  - Nature 459(7247):634-635 (2009)
  Some say it looks like a rocket ready for take-off. Others say a pagoda.
• Microscopic marvels: The naked microscope
  - Nature 459(7247):636-637 (2009)
  Download a PDF of this story Download a PDF of this story Sunney Xie's newest microscopes don't look like the latest in sophistication. Tucked away in his biochemistry lab at Harvard University, they seem to be ad hoc assemblies of lasers, objectives and electronics, surrounded by a thicket of optical equipment. "Don't worry about most of these," says graduate student Christian Freudiger, gesturing to the latest addition to Xie's microscope family. "You only need a few optics to use the microscope. The rest are just for us to play with." As he leans briefly on the table, which is designed to eliminate vibrations, it counterbalances his weight with a reproachful "shhhh". Freudiger and the other researchers 'playing' in Xie's lab have pioneered techniques to see biological molecules in their natural state. Based on Raman spectroscopy, the methods detect compounds from the characteristic vibrations of their chemical bonds, and they free the user from having to label molecules by attaching tags such as gold particles, antibodies or fluorescent proteins. Many researchers are unwilling to abandon labels because they offer an unparalleled ability to distinguish target molecules in a cell. But for others, who want to observe a molecule 'naked', without the interference of a molecular tag, it is proving to be hugely liberating. In traditional Raman microscopy, laser beams illuminate a sample and the characteristic shift in wavelength caused by chemical bonds helps researchers pinpoint the identity and location of certain molecules. The method is therefore best suited for imaging molecules with distinct spectroscopic properties, such as lipids. But in early Raman microscopes the signal was weak and the technique required long exposure times (sometimes more than a day), precluding the possibility of monitoring biological processes that happen in minutes, seconds or less. The microscopes also relied on powerful lasers, which fry delicate biological samples. Sunney Xie (left), Christian Freudiger and their label-free microscope, which has resolved (from bottom left) cellulose; lignin; water (blue), protein (red) and oil (green) in a soya drink; and lipids in brain tumours.Sunney Xie (left), Christian Freudiger and their label-free microscope.U. LOSTER About a decade ago, Xie's lab developed a method called coherent anti-Stokes Raman scattering (CARS) microscopy, which uses two laser beams to excite molecular vibrations and generates a stronger signal. This technique cut down on exposure time and laser power, but was plagued by a high background signal. Then in December last year, Freudiger together with postdoc Wei Min reported a further improvement1. Called stimulated Raman scattering microscopy (SRS), the method excites molecules with two laser beams that have been calibrated so that the difference between the frequencies of the beams matches the vibrational frequency of the molecule to be imaged. The result: only the target molecules are excited and the troublesome background is squelched. By eliminating the high background signal, the SRS technique promises to extend label-free microscopy to molecules that couldn't previously be detected. Biologists are already lining up to give Xie's microscopes a try, along with similar instruments being developed by other groups2,3. Biofuels researcher Shi-You Ding of the National Renewable Energy Laboratory in Golden, Colorado, wants to use SRS in his pursuit of techniques to degrade cellulose, a major component of plant cell walls, into smaller sugars that can be used for fuel. His research has been frustrated by the lack of a method to distinguish cellulose from lignin, another molecule found in plant cell walls, without having to stain cells with techniques that affect the distribution of the two compounds. "Even if you want to tear down a building, you need to know what the structure is," says Ding, "but in this case there was just no way to see it." "Biologists have never been able to get this kind of information before." Shi-You Ding Ding teamed up with Xie's graduate student Brian Saar to create movies of cellulose and lignin dynamics, allowing him to find chemical conditions that will break down lignin and leave the cellulose intact. "It's a very powerful tool," Ding says. "Biologists have never been able to get that kind of information before." Xie's group is also collaborating with researchers at the pharmaceutical company Pfizer in New York, who have already used the technique to track the acne-treatment retinoic acid as it is absorbed by skin. Scientists at Unilever based in the Netherlands and the United Kingdom want to use SRS to study the effects of cosmetics on skin and the distribution of fats and proteins in foods without having to attach bulky labels. ADVERTISEMENT Advertisement At the moment, an SRS microscope costs in the order of half a million dollars, but Xie hopes that technological improvements will reduce the cost and complexity of the set-up. Zeiss and Leica, two major microscope manufacturers, have just licensed the technology, and aficionados who have set up their own CARS systems can tweak their microscopes to accommodate SRS, he says. SRS still has a few kinks to iron out, says Jing Kang, a professor of medicine at Harvard Medical School. It should enable researchers to distinguish between different types of unsaturated fatty acids at biological concentrations within the cell — discerning heart-friendly omega-3 fatty acids from the less-healthy omega-6 fatty acids, for example. But so far, Kang and his collaborators in the Xie lab have not been able to do so. "In theory it should be okay," Kang says, "but whether it's really going to make it — that's another story." * References * Freudiger, C. W. et al. Science 322, 1857– 1861 (2008). * Ozeki, Y. , Dake, F. , Kajiyama, S. , Fukui, K. & Itoh, K. Opt. Express 17, 3651– 3658 (2009). * Nandakumar, P. , Kovalev, A. , & Volkmer, A. New J. Physics 11, 033026 (2009). Add your own comment You can be as critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Remember this is for feedback and discussion - not for publishing papers, press releases or advertisements, for example. If you ramble on in an annoying way too often, we may remove your posting privileges. You need to be registered with Nature to leave a comment. Please log in or register as a new user. You will be re-directed back to this page. * Log in / register
• Microscopic marvels: The glorious resolution
  - Nature 459(7247):638-639 (2009)
  "It's childish, but it still gives me great pleasure to see high-res pictures everyone told me would be impossible," says Stefan Hell of the razor-sharp silhouettes of mouse neurons on his screen. Hell can't resist a small gloat.
• Fair-use policies aim to balance access and cost of publishing
  - Nature 459(7247):641 (2009)
  Your News story 'Open-access policy flourishes at NIH' (Nature 458, 690–691; 2009) raises the related question for publishers about the challenges inherent in providing the widest and most cost-effective access to quality scientific literature.At the non-profit American Institute of Physics, we (like other publishers) are concerned about the inescapable realities of accomplishing this aim.
• Funding ban could break careers at the toss of a coin
  - Nature 459(7247):641 (2009)
  In your News story 'UK scientists get funding ban reprieve' (Nature 459, 20; 2009), you report the response of the UK Engineering and Physical Sciences Research Council (EPSRC) to criticism of proposed changes to grant-submission eligibility. In my view, the EPSRC response still fails to address the central issue.
• Cancer screening for women in developing countries
  - Nature 459(7247):641 (2009)
  SIR — Your Editorial 'Early warnings' (Nature 458, 679; 2009) points out some pitfalls in the effectiveness of cancer screening.
• A microscopic reality tale
  - Nature 459(7247):642-644 (2009)
  The earliest microscopes shed light on a once-invisible world. But, Patricia Fara explains, microscopists were uncertain about how well the images reflected reality — just as they are today.
• Keeping up scientific standards
  - Nature 459(7247):645-646 (2009)
  A journalistic account of the case of data manipulation by physicist Jan Hendrik Schön is rich in detail but draws the wrong conclusions about the self-correcting processes of science, argues Martin Blume.
• An Indian history of numbers
  - Nature 459(7247):646-647 (2009)
  
• Averting environmental crisis
  - Nature 459(7247):647-648 (2009)
  
• Q&A: Acting the part
  - Nature 459(7247):648 (2009)
  Actor and playwright Anna Deavere Smith has pioneered documentary theatre through her one-woman plays constructed from interviews. As she prepares to portray biologists Edward O. Wilson and James Watson at the World Science Festival in New York next week, Smith talks about life, death and the influence of science on her work.
• Photonics: How nanocrystals lost their blink
  - Nature 459(7247):649-650 (2009)
  Semiconducting nanocrystals emit light in many different colours, but they blink on and off at random. The latest nanocrystals emit photons steadily, thanks to the blending of their cores into their outer shells.
• Cosmology: Climbing up the cosmic ladder
  - Nature 459(7247):650-651 (2009)
  Study of an under-appreciated subclass of stars that brighten and dim periodically brings to light their potential use as cosmic yardsticks — out to distances of a few hundred million light years.
• Membrane-protein structure: Piercing insights
  - Nature 459(7247):651-652 (2009)
  Pore-forming proteins are deadly biological weapons that punch holes in target-cell membranes. The structure of the pore formed by a bacterial toxin suggests that diverse pore formers have similar assembly pathways.
• Geophysics: Magnetic ringing of the Earth
  - Nature 459(7247):652-653 (2009)
  The study of Earth's core is an exacting task that involves interpreting indirect evidence. An innovative approach to understanding decadal changes in the magnetic field provides a new probe of core dynamics.
• Quantum mechanics: Entanglement goes mechanical
  - Nature 459(7247):653-654 (2009)
  A neat experiment shows that the mechanical vibration of two ion pairs separated by a few hundred micrometres is entangled — their motions are intrinsically and inseparably connected in a quantum way.
• Developmental biology: The early heart remodelled
  - Nature 459(7247):654-655 (2009)
  What factors direct the formation of heart muscle in the developing embryo? Unexpectedly, a chromatin-remodelling protein complex turns out to be a crucial determinant of cardiac-cell fate.
• Attrition of memory CD8 T cells
  - Nature 459(7247):E3 (2009)
  Arising from: V. Vezys et al. Nature 457, 196–199 (2009); Vezys et al. reply An important role for the immune system is to maintain protective immunological memory to a wide variety of pathogens encountered over one's lifetime, while still leaving the host able to respond to newly encountered pathogens. Vezys et al. 1 make the interesting observation that it is possible to repeatedly immunize mice in ways that allow for development of high numbers of memory CD8 T cells without depleting pre-existing memory cells specific for other pathogens. This study, which offers promise in developing potent vaccination schemes, is seemingly at odds with work published by us in the 1990s showing a loss in CD8 memory cells after a series of infections2, 3. In their reply, Vezys et al. mention that we may have misinterpreted our data because we reported the putative loss of memory T cells as per cent rather than total number, but here we represent the data in those studies as total cell number2, 3, 4. We show here in Fig. 1 that a series of infections can indeed redu ce the total number of memory cells, indicating that vaccination strategies need to consider this issue.
• Vezys et al. reply
  - Nature 459(7247):E4 (2009)
  Replying to: R. M. Welsh and L. K. Selin Nature 459, 10.1038/nature08091 (2009) We reported that it is possible to increase the total number of memory CD8 T cells within an organism, and to establish preternatural numbers of vaccine-specific effector memory CD8 T cells while preserving naive CD8 T cells and most pre-existing memory CD8 T cells specific for a previously encountered infection 1. These findings raise new questions regarding the regulation and limits of generating CD8 T cell immunity. Our discussion highlighted three points related to the issue of attrition. First, that it is possible to over-estimate perceived attrition by only examining percentages (see Fig. 1 of ref. 1)2. Second, our vaccine regimen resulted predominantly in the generation of effector memory CD8 T cells located outside of lymph nodes. It remains possible that the number of lymph node central memory T cells remains tightly regulated. Third, we noted that our data did not refute that attrition could happen under a variety of circumstances. However, our data demonstrate tha t attrition is not an axiomatic property of immunization, mandated by stringent regulation of the size of the total memory CD8 T-cell compartment. Indeed, we saw no evidence of attrition after single infections with a virus (vaccinia), an intracellular bacteria (Listeria monocytogenes) and a parasite that induces massive splenomegaly (Plasmodium yoelii), and observed comparatively little attrition after a heterologous prime–boost regimen involving successive immunization with three viruses1.
• Evolution of pathogenicity and sexual reproduction in eight Candida genomes
  - Nature 459(7247):657-662 (2009)
  Candida species are the most common cause of opportunistic fungal infection worldwide. Here we report the genome sequences of six Candida species and compare these and related pathogens and non-pathogens. There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence. Large genomic tracts are homozygous in three diploid species, possibly resulting from recent recombination events. Surprisingly, key components of the mating and meiosis pathways are missing from several species. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/alpha2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Lastly, we rev ise the Candida albicans gene catalogue, identifying many new genes.
• Driving fast-spiking cells induces gamma rhythm and controls sensory responses
  - Nature 459(7247):663-667 (2009)
  Cortical gamma oscillations (20-80 Hz) predict increases in focused attention, and failure in gamma regulation is a hallmark of neurological and psychiatric disease. Current theory predicts that gamma oscillations are generated by synchronous activity of fast-spiking inhibitory interneurons, with the resulting rhythmic inhibition producing neural ensemble synchrony by generating a narrow window for effective excitation. We causally tested these hypotheses in barrel cortex in vivo by targeting optogenetic manipulation selectively to fast-spiking interneurons. Here we show that light-driven activation of fast-spiking interneurons at varied frequencies (8-200 Hz) selectively amplifies gamma oscillations. In contrast, pyramidal neuron activation amplifies only lower frequency oscillations, a cell-type-specific double dissociation. We found that the timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses. Our data direct ly support the fast-spiking-gamma hypothesis and provide the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.
• Chaperonin overexpression promotes genetic variation and enzyme evolution
  - Nature 459(7247):668-673 (2009)
  Most protein mutations, and mutations that alter protein functions in particular, undermine stability and are therefore deleterious. Chaperones, or heat-shock proteins, are often implicated in buffering mutations, and could thus facilitate the acquisition of neutral genetic diversity and the rate of adaptation. We examined the ability of the Escherichia coli GroEL/GroES chaperonins to buffer destabilizing and adaptive mutations. Here we show that mutational drifts performed in vitro with four different enzymes indicated that GroEL/GroES overexpression doubled the number of accumulating mutations, and promoted the folding of enzyme variants carrying mutations in the protein core and/or mutations with higher destabilizing effects (destabilization energies of >3.5 kcal mol- 1, on average, versus approx1 kcal mol- 1 in the absence of GroEL/GroES). The divergence of modified enzymatic specificity occurred much faster under GroEL/GroES overexpression, in terms of the number o f adapted variants (greater than or equal to2-fold) and their improved specificity and activity (greater than or equal to10-fold). These results indicate that protein stability is a major constraint in protein evolution, and buffering mechanisms such as chaperonins are key in alleviating this constraint.
• A low-energy core-collapse supernova without a hydrogen envelope
  - Nature 459(7247):674-677 (2009)
  The final fate of massive stars depends on many factors. Theory suggests that some with initial masses greater than 25 to 30 solar masses end up as Wolf–Rayet stars, which are deficient in hydrogen in their outer layers because of mass loss through strong stellar winds. The most massive of these stars have cores which may form a black hole and theory predicts that the resulting explosion of some of them produces ejecta of low kinetic energy, a faint optical luminosity and a small mass fraction of radioactive nickel1, 2, 3. An alternative origin for low-energy supernovae is the collapse of the oxygen–neon core of a star of 7–9 solar masses4, 5. No weak, hydrogen-deficient, core-collapse supernovae have hitherto been seen. Here we report that SN 2008ha is a faint hydrogen-poor supernova. We propose that other similar events have been observed but have been misclassified as peculiar thermonuclear supernovae (sometimes labelled SN 2002cx-like events6). This discovery could link these faint supernovae to some long-duration gamma-ray bursts, because extremely faint, hydrogen-stripped core-collapse supernovae have been proposed to produce such long gamma-ray bursts, the afterglows of which do not show evidence of associated supernovae7, 8, 9.
• Global circulation as the main source of cloud activity on Titan
  - Nature 459(7247):678-682 (2009)
  Clouds on Titan result from the condensation of methane and ethane and, as on other planets, are primarily structured by circulation of the atmosphere1, 2, 3, 4. At present, cloud activity mainly occurs in the southern (summer) hemisphere, arising near the pole5, 6, 7, 8, 9, 10, 11, 12 and at mid-latitudes7, 8, 13, 14, 15 from cumulus updrafts triggered by surface heating and/or local methane sources, and at the north (winter) pole16, 17, resulting from the subsidence and condensation of ethane-rich air into the colder troposphere. General circulation models1, 2, 3 predict that this distribution should change with the seasons on a 15-year timescale, and that clouds should develop under certain circumstances at temperate latitudes (approx40°) in the winter hemisphere2. The models, however, have hitherto been poorly constrained and their long-term predictions have not yet been observationally verified. Here we report that the global spatial cloud coverage on Titan is in general agreement with the models, confirming that cloud activity is mainly controlled by the global circulation. The non-detection of clouds at latitude approx40° N and the persistence of the southern clouds while the southern summer is ending are, however, both contrary to predictions. This suggests that Titan's equator-to-pole thermal contrast is overestimated in the models and that its atmosphere responds to the seasonal forcing with a greater inertia than expected.
• Entangled mechanical oscillators
  - Nature 459(7247):683-685 (2009)
  Hallmarks of quantum mechanics include superposition and entanglement. In the context of large complex systems, these features should lead to situations as envisaged in the 'Schrödinger's cat'1 thought experiment (where the cat exists in a superposition of alive and dead states entangled with a radioactive nucleus). Such situations are not observed in nature. This may be simply due to our inability to sufficiently isolate the system of interest from the surrounding environment2, 3—a technical limitation. Another possibility is some as-yet-undiscovered mechanism that prevents the formation of macroscopic entangled states4. Such a limitation might depend on the number of elementary constituents in the system5 or on the types of degrees of freedom that are entangled. Tests of the latter possibility have been made with photons, atoms and condensed matter devices6, 7. One system ubiquitous to nature where entanglement has not been previously demonstrated consists of disti nct mechanical oscillators. Here we demonstrate deterministic entanglement of separated mechanical oscillators, consisting of the vibrational states of two pairs of atomic ions held in different locations. We also demonstrate entanglement of the internal states of an atomic ion with a distant mechanical oscillator. These results show quantum entanglement in a degree of freedom that pervades the classical world. Such experiments may lead to the generation of entangled states of larger-scale mechanical oscillators8, 9, 10, and offer possibilities for testing non-locality with mesoscopic systems11. In addition, the control developed here is an important ingredient for scaling-up quantum information processing with trapped atomic ions12, 13, 14.
• Non-blinking semiconductor nanocrystals
  - Nature 459(7247):686-689 (2009)
  The photoluminescence from a variety of individual molecules1 and nanometre-sized crystallites2 is defined by large intensity fluctuations, known as 'blinking', whereby their photoluminescence turns 'on' and 'off' intermittently, even under continuous photoexcitation2. For semiconductor nanocrystals, it was originally proposed3 that these 'off' periods corresponded to a nanocrystal with an extra charge. A charged nanocrystal could have its photoluminescence temporarily quenched owing to the high efficiency of non-radiative (for example, Auger) recombination processes between the extra charge and a subsequently excited electron–hole pair; photoluminescence would resume only after the nanocrystal becomes neutralized again. Despite over a decade of research, completely non-blinking nanocrystals4, 5 have not been synthesized and an understanding of the blinking phenomenon6 remains elusive. Here we report ternary core/shell CdZnSe/ZnSe semiconductor nanocrystals that indiv idually exhibit continuous, non-blinking photoluminescence. Unexpectedly, these nanocrystals strongly photoluminesce despite being charged, as indicated by a multi-peaked photoluminescence spectral shape and short lifetime. To model the unusual photoluminescence properties of the CdZnSe/ZnSe nanocrystals, we softened the abrupt confinement potential of a typical core/shell nanocrystal, suggesting that the structure is a radially graded alloy of CdZnSe into ZnSe. As photoluminescence blinking severely limits the usefulness of nanocrystals in applications requiring a continuous output of single photons, these non-blinking nanocrystals may enable substantial advances in fields ranging from single-molecule biological labelling7 to low-threshold lasers8.
• The Gamburtsev mountains and the origin and early evolution of the Antarctic Ice Sheet
  - Nature 459(7247):690-693 (2009)
  Ice-sheet development in Antarctica was a result of significant and rapid global climate change about 34 million years ago1. Ice-sheet and climate modelling suggest reductions in atmospheric carbon dioxide (less than three times the pre-industrial level of 280 parts per million by volume) that, in conjunction with the development of the Antarctic Circumpolar Current, led to cooling and glaciation paced by changes in Earth's orbit2. Based on the present subglacial topography, numerical models point to ice-sheet genesis on mountain massifs of Antarctica, including the Gamburtsev mountains at Dome A, the centre of the present ice sheet2, 3. Our lack of knowledge of the present-day topography of the Gamburtsev mountains4 means, however, that the nature of early glaciation and subsequent development of a continental-sized ice sheet are uncertain. Here we present radar information about the base of the ice at Dome A, revealing classic Alpine topography with pre-existing river valleys overdeepened by valley glaciers formed when the mean summer surface temperature was around 3 °C. This landscape is likely to have developed during the initial phases of Antarctic glaciation. According to Antarctic climate history (estimated from offshore sediment records) the Gamburtsev mountains are probably older than 34 million years and were the main centre for ice-sheet growth. Moreover, the landscape has most probably been preserved beneath the present ice sheet for around 14 million years.
• Kinematic variables and water transport control the formation and location of arc volcanoes
  - Nature 459(7247):694-697 (2009)
  The processes that give rise to arc magmas at convergent plate margins have long been a subject of scientific research and debate1, 2, 3, 4, 5, 6. A consensus has developed that the mantle wedge overlying the subducting slab3, 4 and fluids and/or melts from the subducting slab itself6, 7, 8, 9, 10, 11 are involved in the melting process. However, the role of kinematic variables such as slab dip and convergence rate in the formation of arc magmas is still unclear. The depth to the top of the subducting slab beneath volcanic arcs, usually approx110 plusminus 20 km, was previously thought to be constant among arcs3, 6, 12. Recent studies13, 14 revealed that the depth of intermediate-depth earthquakes underneath volcanic arcs, presumably marking the slab–wedge interface, varies systematically between approx60 and 173 km and correlates with slab dip and convergence rate. Water-rich magmas (over 4–6 wt% H2O) are found in subduction zones with very different subduction par ameters, including those with a shallow-dipping slab (north Japan), or steeply dipping slab (Marianas). Here we propose a simple model to address how kinematic parameters of plate subduction relate to the location of mantle melting at subduction zones. We demonstrate that the location of arc volcanoes is controlled by a combination of conditions: melting in the wedge is induced at the overlap of regions in the wedge that are hotter than the melting curve (solidus) of vapour-saturated peridotite and regions where hydrous minerals both in the wedge and in the subducting slab break down. These two limits for melt generation, when combined with the kinematic parameters of slab dip and convergence rate, provide independent constraints on the thermal structure of the wedge and accurately predict the location of mantle wedge melting and the position of arc volcanoes.
• Parvalbumin neurons and gamma rhythms enhance cortical circuit performance
  - Nature 459(7247):698-702 (2009)
  Synchronized oscillations and inhibitory interneurons have important and interconnected roles within cortical microcircuits. In particular, interneurons defined by the fast-spiking phenotype and expression of the calcium-binding protein parvalbumin1, 2 have been suggested to be involved in gamma (30–80 Hz) oscillations3, 4, 5, 6, 7, which are hypothesized to enhance information processing8, 9. However, because parvalbumin interneurons cannot be selectively controlled, definitive tests of their functional significance in gamma oscillations, and quantitative assessment of the impact of parvalbumin interneurons and gamma oscillations on cortical circuits, have been lacking despite potentially enormous significance (for example, abnormalities in parvalbumin interneurons may underlie altered gamma-frequency synchronization and cognition in schizophrenia10 and autism11). Here we use a panel of optogenetic technologies12, 13, 14 in mice to selectively modulate multiple disti nct circuit elements in neocortex, alone or in combination. We find that inhibiting parvalbumin interneurons suppresses gamma oscillations in vivo, whereas driving these interneurons (even by means of non-rhythmic principal cell activity) is sufficient to generate emergent gamma-frequency rhythmicity. Moreover, gamma-frequency modulation of excitatory input in turn was found to enhance signal transmission in neocortex by reducing circuit noise and amplifying circuit signals, including inputs to parvalbumin interneurons. As demonstrated here, optogenetics opens the door to a new kind of informational analysis of brain function, permitting quantitative delineation of the functional significance of individual elements in the emergent operation and function of intact neural circuitry.
• Mechanism of differential control of NMDA receptor activity by NR2 subunits
  - Nature 459(7247):703-707 (2009)
  N-methyl-d-aspartate (NMDA) receptors (NMDARs) are a major class of excitatory neurotransmitter receptors in the central nervous system. They form glutamate-gated ion channels that are highly permeable to calcium and mediate activity-dependent synaptic plasticity1. NMDAR dysfunction is implicated in multiple brain disorders, including stroke, chronic pain and schizophrenia2. NMDARs exist as multiple subtypes with distinct pharmacological and biophysical properties that are largely determined by the type of NR2 subunit (NR2A to NR2D) incorporated in the heteromeric NR1/NR2 complex1, 3, 4. A fundamental difference between NMDAR subtypes is their channel maximal open probability (P o), which spans a 50-fold range from about 0.5 for NR2A-containing receptors to about 0.01 for receptors containing NR2C and NR2D; NR2B-containing receptors have an intermediate value (about 0.1)5, 6, 7, 8, 9. These differences in P o confer unique charge transfer capacities and signalling prope rties on each receptor subtype4, 6, 10, 11. The molecular basis for this profound difference in activity between NMDAR subtypes is unknown. Here we show that the subunit-specific gating of NMDARs is controlled by the region formed by the NR2 amino-terminal domain (NTD), an extracellular clamshell-like domain previously shown to bind allosteric inhibitors12, 13, 14, 15, and the short linker connecting the NTD to the agonist-binding domain (ABD). The subtype specificity of NMDAR P o largely reflects differences in the spontaneous (ligand-independent) equilibrium between open-cleft and closed-cleft conformations of the NR2-NTD. This NTD-driven gating control also affects pharmacological properties by setting the sensitivity to the endogenous inhibitors zinc and protons. Our results provide a proof of concept for a drug-based bidirectional control of NMDAR activity by using molecules acting either as NR2-NTD 'closers' or 'openers' promoting receptor inhibition or potentiation, r espectively.
• Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors
  Takeuchi JK Bruneau BG - Nature 459(7247):708-711 (2009)
  Heart disease is the leading cause of mortality and morbidity in the western world. The heart has little regenerative capacity after damage, leading to much interest in understanding the factors required to produce new cardiac myocytes. Despite a robust understanding of the molecular networks regulating cardiac differentiation1, 2, no single transcription factor or combination of factors has been shown to activate the cardiac gene program de novo in mammalian cells or tissues. Here we define the minimal requirements for transdifferentiation of mouse mesoderm to cardiac myocytes. We show that two cardiac transcription factors, Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatin-remodelling complexes, Baf60c (also called Smarcd3), can direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes, including the normally non-cardiogenic posterior mesoderm and the extraembryonic mesoderm of the amnion. Gata4 with Baf60c initiated ectopic cardiac ge ne expression. Addition of Tbx5 allowed differentiation into contracting cardiomyocytes and repression of non-cardiac mesodermal genes. Baf60c was essential for the ectopic cardiogenic activity of Gata4 and Tbx5, partly by permitting binding of Gata4 to cardiac genes, indicating a novel instructive role for BAF complexes in tissue-specific regulation. The combined function of these factors establishes a robust mechanism for controlling cellular differentiation, and may allow reprogramming of new cardiomyocytes for regenerative purposes.
• Frequent inactivation of A20 in B-cell lymphomas
  - Nature 459(7247):712-716 (2009)
  A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation1. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli2, 3, 4, 5, 6, 7; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk8, 9. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma- derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.
• Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma
  - Nature 459(7247):717-721 (2009)
  Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL1. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kappaB transcription complex2. However, except for a small fraction of cases3, it remains unclear whether NF-kappaB activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-kappaB. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-kappaB responses, is mo st commonly affected, with approx30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kappaB. Thus, our results demonstrate that NF-kappaB activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappaB responses.
• F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage
  Santra MK Wajapeyee N Green MR - Nature 459(7247):722-725 (2009)
  In response to DNA damage, eukaryotic cells initiate a complex signalling pathway, termed the DNA damage response (DDR), which coordinates cell cycle arrest with DNA repair. Studies have shown that oncogene-induced senescence, which provides a barrier to tumour development, involves activation of the DDR1, 2, 3. Using a genome-wide RNA interference (RNAi) screen, we have identified 17 factors required for oncogenic BRAF to induce senescence in primary fibroblasts and melanocytes4. One of these factors is an F-box protein, FBXO31, a candidate tumour suppressor encoded in 16q24.3, a region in which there is loss of heterozygosity in breast, ovarian, hepatocellular and prostate cancers5, 6, 7, 8, 9. Here we study the cellular role of FBXO31, identify its target substrate and determine the basis for its growth inhibitory activity. We show that ectopic expression of FBXO31 acts through a proteasome-directed pathway to mediate the degradation of cyclin D1, an important regula tor of progression from G1 to S phase, resulting in arrest in G1. Cyclin D1 degradation results from a direct interaction with FBXO31 and is dependent on the F-box motif of FBXO31 and phosphorylation of cyclin D1 at Thr 286, which is known to be required for cyclin D1 proteolysis. The involvement of the DDR in oncogene-induced senescence prompted us to investigate the role of FBXO31 in DNA repair. We find that DNA damage induced by gamma-irradiation results in increased FBXO31 levels, which requires phosphorylation of FBXO31 by the DDR-initiating kinase ATM. RNAi-mediated knockdown of FBXO31 prevents cells from undergoing efficient arrest in G1 after gamma-irradiation and markedly increases sensitivity to DNA damage. Finally, we show that a variety of DNA damaging agents all result in a large increase in FBXO31 levels, indicating that induction of FBXO31 is a general response to genotoxic stress. Our results reveal FBXO31 as a regulator of the G1/S transition that is specifi cally required for DNA damage-induced growth arrest.
• The structure of a cytolytic alpha-helical toxin pore reveals its assembly mechanism
  - Nature 459(7247):726-730 (2009)
  Pore-forming toxins (PFTs) are a class of potent virulence factors that convert from a soluble form to a membrane-integrated pore1. They exhibit their toxic effect either by destruction of the membrane permeability barrier or by delivery of toxic components through the pores. Among the group of bacterial PFTs are some of the most dangerous toxins, such as diphtheria and anthrax toxin. Examples of eukaryotic PFTs are perforin and the membrane-attack complex, proteins of the immune system2. PFTs can be subdivided into two classes, alpha-PFTs and beta-PFTs, depending on the suspected mode of membrane integration, either by alpha-helical or beta-sheet elements3. The only high-resolution structure of a transmembrane PFT pore is available for a beta-PFT—alpha-haemolysin from Staphylococcus aureus 4. Cytolysin A (ClyA, also known as HlyE), an alpha-PFT, is a cytolytic alpha-helical toxin responsible for the haemolytic phenotype of several Escherichia coli and Salmonella ente rica strains5, 6, 7, 8. ClyA is cytotoxic towards cultured mammalian cells, induces apoptosis of macrophages and promotes tissue pervasion9, 10, 11. Electron microscopic reconstructions demonstrated that the soluble monomer of ClyA12 must undergo large conformational changes to form the transmembrane pore13, 14. Here we report the 3.3 Å crystal structure of the 400 kDa dodecameric transmembrane pore formed by ClyA. The tertiary structure of ClyA protomers in the pore is substantially different from that in the soluble monomer. The conversion involves more than half of all residues. It results in large rearrangements, up to 140 Å, of parts of the monomer, reorganization of the hydrophobic core, and transitions of beta-sheets and loop regions to alpha-helices. The large extent of interdependent conformational changes indicates a sequential mechanism for membrane insertion and pore formation.
• Metamorphic enzyme assembly in polyketide diversification
  - Nature 459(7247):731-735 (2009)
  Natural product chemical diversity is fuelled by the emergence and ongoing evolution of biosynthetic pathways in secondary metabolism1. However, co-evolution of enzymes for metabolic diversification is not well understood, especially at the biochemical level. Here, two parallel assemblies with an extraordinarily high sequence identity from Lyngbya majuscula form a beta-branched cyclopropane in the curacin A pathway (Cur), and a vinyl chloride group in the jamaicamide pathway (Jam). The components include a halogenase, a 3-hydroxy-3-methylglutaryl enzyme cassette for polyketide beta-branching, and an enoyl reductase domain. The halogenase from CurA, and the dehydratases (ECH1s), decarboxylases (ECH2s) and enoyl reductase domains from both Cur and Jam, were assessed biochemically to determine the mechanisms of cyclopropane and vinyl chloride formation. Unexpectedly, the polyketide beta-branching pathway was modified by introduction of a gamma-chlorination step on (S)-3-hy droxy-3-methylglutaryl mediated by Cur halogenase, a non-haem Fe(ii), alpha-ketoglutarate-dependent enzyme2. In a divergent scheme, Cur ECH2 was found to catalyse formation of the alpha,beta enoyl thioester, whereas Jam ECH2 formed a vinyl chloride moiety by selectively generating the corresponding beta,gamma enoyl thioester of the 3-methyl-4-chloroglutaconyl decarboxylation product. Finally, the enoyl reductase domain of CurF specifically catalysed an unprecedented cyclopropanation on the chlorinated product of Cur ECH2 instead of the canonical alpha,beta C = C saturation reaction. Thus, the combination of chlorination and polyketide beta-branching, coupled with mechanistic diversification of ECH2 and enoyl reductase, leads to the formation of cyclopropane and vinyl chloride moieties. These results reveal a parallel interplay of evolutionary events in multienzyme systems leading to functional group diversity in secondary metabolites.
• The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks
  - Nature 459(7247):736 (2009)
  Nature 447, 730–734 (2007) In this Letter, an alternative symbol for NBS1 was incorrectly listed as NLRP2. The authors are in fact referring to nibrin, the official protein symbol of which is NBN.
• Millennial-scale trends in west Pacific warm pool hydrology since the Last Glacial Maximum
  - Nature 459(7247):736 (2009)
  Nature 449, 452–455 (2007) A recalibration of the Caltech 236U and 229Th spike has determined that the original spike value used for the stalagmite chronologies yielded U–Th ages that were too old by a margin of approx2–3%. U–Th ages and subsequent age models have been recalculated using the new spike value for all stalagmites. The new age models alter the absolute timing of certain events, but do not alter any major conclusions of the original manuscript. The highest delta18O values (inferred driest conditions) now occur at 16.0 plusminus 0.3 kyr ago. A late deglacial delta18O plateau in the Borneo stalagmite records is now centred at 13.0 plusminus 0.2 kyr ago. The lowest delta18O values (inferred wettest conditions) now occur at 5.0 plusminus 0.1 kyr ago. Examples of original and adjusted dates, respectively, at 5 kyr intervals are as follows: 5280 versus 5141 (SSC01); 10581 versus 10293 (SSC01); 15673 versus 15231 (BA04); 20937 versus 20322 (BA04); and 26387 versus 25602 (SCH02). Revised chro nologies are available at: ftp://ftp.ncdc.noaa.gov/pub/data/paleo/speleothem/pacific/gunung-buda2007.xls
• UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals
  - Nature 459(7247):736 (2009)
  Nature 454, 846–851 (2008) In Fig. 3a and b of this Article, the pAMPK samples were spliced. Images of the uninterrupted AMPK together with the uninterrupted pAMPK samples are now provided in the Supplementary Information, together with the proper loading sequence of the primary data and the original blots.
• To all sister capsules
  - Nature 459(7247):744 (2009)
  There's something out there.