Hot off the presses! Mar 18 Nature

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Latest Articles Include:

• Science in court
  - Nature 464(7287):325 (2010)
  Academics are too often at loggerheads with forensic scientists. A new framework for certification, accreditation and research could help to heal the breach.
• Handle with care
  - Nature 464(7287):325 (2010)
  Britain's Department of Health must respond to concerns about electronic medical records.
• Setting the bar
  - Nature 464(7287):326 (2010)
  Europe's chief science adviser must be given authority and support to deliver across the board.
• Geoscience: Wind-blown ice
  - Nature 464(7287):328 (2010)
  
• Materials science: Ultrathin fibres heat up
  - Nature 464(7287):328 (2010)
  
• Palaeontology: Egg-stracting DNA
  - Nature 464(7287):328 (2010)
  
• Neuroscience: Rats on the wagon
  - Nature 464(7287):328 (2010)
  
• Virology: Infectious inheritance
  - Nature 464(7287):328 (2010)
  
• Conservation: Heavy metal history
  - Nature 464(7287):329 (2010)
  
• Archaeology: Adoption or migration?
  - Nature 464(7287):329 (2010)
  
• Neuroscience: Memory reading
  - Nature 464(7287):329 (2010)
  
• Genomics: We are family
  - Nature 464(7287):329 (2010)
  
• Journal club
  - Nature 464(7287):329 (2010)
  
• News briefing: 18 March 2010
  - Nature 464(7287):330 (2010)
  The week in science This article is best viewed as a PDF Policy|Business|Research|Events|People|Business watch|The week ahead|Number crunch|Sound bites Faced with numerous criticisms and an acknowledged mistake in its last assessment in 2007, the Intergovernmental Panel on Climate Change (IPCC) appointed the InterAcademy Council to conduct an independent review of its procedures on 10 March. The council, an international organization representing national science academies worldwide, will itself appoint a team to conduct the review later this month. The team will target a range of IPCC procedures as well as larger questions of organization, resources and communications. The final report is expected by August. Legislation codifying US President Barack Obama's policy of allowing federal funding for human embryonic stem-cell research was introduced in Congress on 10 March. Representatives Diana DeGette (Democrat, Colorado) and Mike Castle (Republican, Delaware) sponsored the Stem Cell Research Advancement Act. The aim is to prevent the current presidential policy from being changed by future administrations. The proposed law, like Obama's policy, allows federal funding for research on stem-cell lines derived from embryos created for reproductive purposes that would otherwise be discarded. Israel's cabinet has approved a five-year plan to bring Israeli-born researchers back to the country. As part of the scheme, to which the cabinet has allocated US$121 million, 30 centres of excellence will from this September begin to be established at the country's universities, creating positions for young scientists, social scientists and humanities researchers. The universities will have to raise further (unspecified) funds from private sources. The US Environmental Protection Agency has agreed to develop guidance to help US states address the increase in ocean acidification caused by carbon dioxide absorption. The decision, spelled out in an 11 March federal court settlement with the Center for Biological Diversity, based in Tucson, Arizona, stops short of regulation but does not preclude such action in the future. India's coalition-led government has deferred introducing legislation that would have smoothed the way towards Indo-US trade in nuclear technology. The delayed bill would cap the liability of foreign nuclear reactor suppliers at 5 billion rupees (US$110 million), a clause that US companies would like as a precondition of selling nuclear equipment. Opposition parties in India protested that the cap would allow US companies to avoid responsibility for accidents. Countries such as France and Russia have already agreed to supply nuclear reactors to India, but an Indo-US nuclear deal signed in 2008 has still not resulted in trade. On 9 March, drug companies Merck and Sanofi-Aventis announced that they would merge their animal-health businesses. Merck, headquartered in Whitehouse Station, New Jersey, and Sanofi-Aventis, headquartered in Paris, will have equal ownership in the new venture, which would be the largest player in the US$19-billion animal-health market. SOURCE: TRU GROUP The appetite for lithium to supply batteries in mobile phones, laptops and electric cars is growing, but supplies are forecast to outstrip demand over the next decade. That would keep lithium prices low — and put eager new suppliers of the element out of business. TRU Group, a consultancy based in Toronto, Canada, says that demand for lithium purified sufficiently for use in batteries will more than double over the coming decade, thanks in part to electric cars. Mining firms are busily signing deals with car manufacturers to supply lithium, and a few dozen new entrants are proposing other production ventures. But TRU Group president Edward Anderson says that existing suppliers, mainly in South America, are fully capable of meeting demand (see chart). With the new proposals, the result is a nearly 50% oversupply in 2012 and significant surpluses through to the end of the decade. "Most of the money that's going into these [new] companies now is going to be lost to investors," Anderson says. Chris Hartshorn, an analyst with Lux Research in Boston, Massachusetts, says that the lithium supply glut could carry over into the lithium-battery market, resulting in an eventual shake-out of battery manufacturers. That is good for the market in the long run, he says, but there will be some carnage along the way. On its second attempt, commercial spaceflight company SpaceX has successfully test-fired all nine engines of its Falcon 9 rocket. The firm, based in Hawthorne, California, has a contract with NASA to take payloads to the International Space Station once the Shuttle retires. The 13 March static test precedes a full launch, which could happen within months. A pioneering underwater robot has been lost off the coast of Chile. First launched in 1995, the Autonomous Benthic Explorer, nicknamed 'ABE', was one of the earliest completely independent research submersibles, neither manned nor tethered to its research ship. It failed to resurface on its 222nd dive, perhaps because its buoyancy spheres imploded, the Woods Hole Oceanographic Institution in Massachusetts announced on 9 March. The US National Institute of Standards and Technology in Gaithersburg, Maryland, is to consolidate its national laboratories, says director Patrick Gallagher. He plans to reduce the number of agency labs from ten to six, putting researchers in larger, interdisciplinary groups aligned more with agency missions than individual scientific disciplines. Gallagher also wants to replace the deputy director position (currently vacant) with three associate directors — respectively managing research at the agency's labs; external industry programmes; and information technology, human resources and facilities. M. TEFRE/SVALBARD GLOBAL SEED VAULT The Svalbard Global Seed Vault (pictured), which opened two years ago, now holds more than 250 million seeds and 520,000 crop varieties — around a third of the world's known 1.5 million crop strains. The Global Crop Diversity Trust, which oversees the seed bank, announced the passing of the half-a-million landmark on 11 March. Installed in the side of a mountain at Longyearbyen, a town in the Norwegian archipelago of Svalbard, the bunker is designed to keep samples of the world's seeds safe at −18 °C, for backup in case disaster strikes global food production. Phil Charles, a leading astronomer who was suspended as director of the South African Astronomical Observatory in Cape Town, has been reinstated after a disciplinary hearing. The country's main funding agency, the National Research Foundation, removed Charles from his post in January, citing the leaking of confidential documents, but says that the hearing found him "not guilty on all charges". It did not explain what those charges were, and added that issues giving rise to the suspension might "still exist" and needed to be dealt with. J. RAPO/ACA D. FINLAND Human geneticist Leena Peltonen-Palotie (pictured) died on 11 March, aged 57. She pioneered the use of isolated populations to discover disease genes, analysing those in her native Finland to illuminate the genetic basis of at least 20 diseases. Deeply engaged in bioethical debates about genetics, Peltonen-Palotie was head of human genetics at the Wellcome Trust Sanger Institute near Cambridge, UK, and also headed research groups at the Institute for Molecular Medicine Finland and the National Institute for Health and Welfare, both in Helsinki. She was also an associate member at the Broad Institute in Cambridge, Massachusetts. Jean Fréchet, the high-profile organic polymer chemist at the University of California, Berkeley, has been appointed vice-president for research at the newly opened King Abdullah University of Science and Technology in Saudi Arabia. From June 2010 to June 2011, Fréchet will oversee education and science at the fledgling university's nine research centres, and will develop 'innovation and enterprise' strategies. The American Chemical Society holds its 2010 spring meeting in San Francisco, California. The conference's theme is green and sustainable chemistry. → go.nature.com/iLMbWg London's Royal Society holds a meeting to discuss how scientists deal with uncertainty in their particular field — and how to communicate it. → go.nature.com/ZhthnH Expect norms and guidelines for geoengineering experiments to emerge from a summit in Pacific Grove, California, where climate scientists are meeting to talk about the risks of climate intervention. → climateresponsefund.org Both the Global Fund to Fight AIDS, Tuberculosis and Malaria and the Global Alliance for Vaccines and Immunisation meet in The Hague, the Netherlands to discuss shortfalls in their finances (see Nature 463, 415; 2010, and page 338). → go.nature.com/HHUHcM Estimated decline in bluefin tuna in the West Atlantic between 1970 and 2007. Delegates at the Convention on International Trade in Endangered Species of Wild Fauna and Flora meeting in Doha, Qatar, are debating whether to ban international trade in the fish. William Brinkman, director of the US energy department's Office of Science, tells a departmental committee meeting there will be 'significant changes' to the management of ITER, the fusion project that has suffered cost overruns and delays (see Nature 463, 721; 2010). Source: Fusion Power Associates 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.
• Wildlife service plans for a warmer world
  - Nature 464(7287):332 (2010)
  Akikikis are small birds with limber tongues that are adept at pulling insects from the crevices in tree bark. The olive-and-white birds are also headed towards extinction. There are currently no comments.
• Sex bias blights drug studies
  - Nature 464(7287):332 (2010)
  Omission of females is skewing results. Diseases such as depression can disproportionately affect women.M. Constantini/Ès Photography/Corbis The typical patient with chronic pain is a 55-year-old woman — the typical chronic-pain study subject is an 8-week-old male mouse. To pain researcher Jeffrey Mogil at McGill University in Montreal, Canada, that discrepancy is a telling example of the problem that he and other neuroscientists discussed last week at a workshop held in San Francisco, California: the serious under-representation of females in biomedical studies. The lack of female participation, which extends from basic research in animals to clinical trials in humans, has obvious consequences for women, not least a paucity of effective drug treatments for diseases that predominantly affect them. But it also affects men, for example when drug candidates fail to get regulatory approval because they don't work in women in late-stage clinical trials, or have severe side effects in women that are not seen in men. Such failures might be spotted earlier if more preclinical work was done in female model animals, according to researchers at the Workshop on Sex Differences and Implications for Translational Neuroscience Research, convened on 8–9 March by the US Institute of Medicine's Forum on Neuroscience and Nervous System Disorders. "This is an issue of enormous importance," says biologist Irving Zucker at the University of California, Berkeley. "In a number of disciplines, researchers simply don't study females, and there is so much evidence for sex differences at all levels of biological organization that to only study males, and assume the results apply to females, is just wrong." Many diseases disproportionately affect one sex: chronic pain, depression and autoimmune disease, for instance, more often affect women, with addiction and cardiovascular disease disproportionately affecting men. The NIH Revitalization Act of 1993 attempted to take account of this by requiring clinical trials funded by the National Institutes of Health to include adequate numbers of women to detect differing treatment effects. The US Government Accountability Office reported in 2000 that participation of women in NIH-funded trials had increased substantially (see www.gao.gov/archive/2000/he00096.pdf). The following year, it noted similar progress in late-stage drug trials overseen by the Food and Drug Administration (see www.gao.gov/new.items/d01754.pdf). "To only study males, and assume the results apply to females, is just wrong." But data from clinical trials are often not analysed separately on the basis of sex. Such analyses could reveal whether a drug has different adverse effects in men and women, for example. And the accountability office also noted in 2001 that although women made up more than half of full-scale safety and efficacy trials, they formed just 22% of the participants in initial, small-scale safety studies. Back at the bench, lab animals are still predominantly male, even in studies of diseases that disproportionately affect women. Investigators tend to prefer male animals because it is thought that females might introduce variability through factors such as their oestrous cycles. But Mogil has reported that in common tests used to measure responses to pain, data from female mice are no more variable than those from males (J. S. Mogil and M. L. Chanda Pain 117, 1–5; 2005). The problem is particularly acute in neuroscience, in which the ratio of male- to female-only studies is 5.5 to 1. But under-representation of females occurs in most fields of basic research, according to an unpublished analysis by Zucker and postdoctoral researcher Annaliese Beery. They investigated the use of female and male animals in research published during 2009 in 10 fields across 42 journals. They found that studies in eight of the fields used only male animals more often than only females, and that the data were often not analysed by sex. In two journals that the researchers investigated back to 1909, the proportion of animal studies using only males had actually grown since the early twentieth century. The authors speculate that this is because oestrous cycles in guinea pigs, rats and mice were first clearly characterized only in the 1920s. Researchers such as Karen Berkley of Florida State University in Tallahassee have been trying to boost female representation for decades, and Berkley feels that some progress has been made, citing, for example, the launch of an online journal in the field, Biology of Sex Differences, and an overall growth in research on sex differences. ADVERTISEMENT But at the workshop, Berkley and other scientists agreed that further steps were needed to address the problem. Many endorsed the idea that journals should require their authors to report the sex of animals used in the research. The London-based National Centre for the Replacement, Refinement and Reduction of Animals in Research is developing a set of research reporting guidelines that will call for authors to disclose the sex of animals. Seán Murphy, chief editor of the Journal of Neurochemistry, says that there is "interest" in the guidelines among journal editors at its publisher, Wiley-Blackwell. Researchers at the workshop said that funding agencies, too, could ask grant applicants to specify the sex of the animals they propose studying and justify their decision whenever they chose only male animals. Funders could also change the status quo, the researchers claimed, by supporting more work on sex differences, although the NIH would not comment on whether this was under consideration. 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.
• Hunt for the sterile neutrino heats up
  - Nature 464(7287):334 (2010)
  The elusive particles, if they exist, could help solve some of the most pressing problems in astrophysics. Neutrinos like to keep to themselves. These ghostly particles are so reluctant to interact with ordinary matter that billions zip harmlessly through each person every day, and it takes giant, specialized detectors to capture even a handful of them. Now astronomers are finding hints of an even more elusive type of neutrino, one so shy that it could never be detected directly: the sterile neutrino. "The question of sterile neutrinos is absolutely crucial for nuclear particle physics and astrophysics." For more than a decade, this subatomic spectre has intrigued theorists and experimenters, but experimental efforts have had trouble catching them. Now, two observations in space — one in microwaves and the other in X-rays — are raising hopes again. If sterile neutrinos could be identified, they would provide the first glimpse of a new realm of physics beyond the tried-and-tested standard model. They could also help to explain a host of astronomical puzzles, and perhaps even account for the invisible dark matter that is thought to make up 85% of the Universe's mass. "The question of sterile neutrinos is absolutely crucial for nuclear particle physics and astrophysics," says William Louis of Los Alamos National Laboratory in New Mexico, who worked on a ground-based experiment in the mid-1990s that provided one of the first hints of sterile neutrinos. The three types of ordinary neutrinos (see graphic) are hard enough to detect. They interact with matter through the weak nuclear force, which means they can pass through huge volumes of material yet collide with atomic nuclei only rarely. To catch them, physicists build detectors using tanks of mineral oil or heavy water, and they improve the odds by focusing on the torrents of neutrinos coming from nuclear reactors, particle accelerators and the Sun. Unsociable particle In 1998, results from an accelerator at CERN, Europe's particle-physics facility near Geneva, Switzerland, indicated that only the three known families, or flavours, of neutrinos could be affected by the weak force. Any beyond these three families would have to be 'sterile' — that is, immune to the weak nuclear force. And that would mean that they would pass straight through existing neutrino detectors. Why would theorists invoke such an unsociable particle to begin with? Because of another surprising discovery made in 1998: that the three ordinary neutrinos have a small but definite mass. The result came as a shock, and not simply because the standard model assumes that neutrinos have no mass. The masses of the three neutrinos, determined from the way they oscillate, or switch, from one flavour into another, turned out to be incredibly small: the heaviest ordinary neutrino is at least seven orders of magnitude lighter than the electron. Theorists reasoned that some other particle — perhaps a sterile neutrino — should sit in between. Hints of such a missing link have emerged from the Wilkinson Microwave Anisotropy Probe (WMAP), a spacecraft that since 2001 has been mapping tiny fluctuations in the radiation left over from the Big Bang. The pattern of fluctuations holds clues to the stew of particles that existed shortly after the Big Bang. Results from the past seven years, which were released in January1, suggest that the most likely number of neutrino families in the early Universe was four — implying that one more neutrino type awaits discovery. "To say that there's something else is a major deal," says principal investigator Charles Bennett of Johns Hopkins University in Baltimore, Maryland. But he cautions that the error bars are still wide enough that three might still be the maximum number. "I would call this intriguing, but I'm not losing any sleep right now." A more recent clue has come from the orbiting Chandra X-ray Observatory. Sterile neutrinos, if they exist and if they are heavy enough, should emit faint pulses of X-rays as they decay into lighter neutrinos. Alexander Kusenko of the University of California, Los Angeles, has focused on regions of the sky thought to contain lots of dark matter but few stars or other light sources. Sure enough, he claims to have found2 the predicted X-ray signature in Willman 1, a dim dwarf galaxy that orbits the Milky Way. But, like Bennett, Kusenko says that it is still too early to be claiming a discovery. "Everything seems to fit together," he says, "and it's tantalizing." Kusenko's neutrinos would be heavy and plentiful enough to be the dark-matter particles themselves. But the WMAP data point in another direction, towards a sterile neutrino at the lighter end of the spectrum of possible masses. George Fuller, director of the Center for Astrophysics and Space Science at the University of California, San Diego, in La Jolla, would find this lighter mass agreeable, because it would help him to solve a long-standing problem with supernovae. These massive star explosions cause neutrons to fuse together, creating elements heavier than iron that end up in other stars and in planets. But they also produce inordinate numbers of neutrinos, which should, in theory, inhibit fusion because they kill off neutrons by changing them into protons and electrons. Sterile neutrinos could provide a way out. If some of the neutrinos created in supernovae morphed into sterile ones, they would fly off without interacting with neutrons, leaving many of them intact. "We're very interested in this, because the stakes are so high," says Fuller. Mixed messages Sobering news for the sterile-neutrino hunters came this month3 from the Main Injector Neutrino Oscillation Search (MINOS), an experiment that shoots a beam of neutrinos from an accelerator at the Fermi National Accelerator Laboratory (Fermilab) in Batavia, Illinois, underground to a detector 735 kilometres away in Minnesota to observe neutrino oscillations. The MINOS data show that one family of neutrinos does not have a high propensity for turning into sterile ones, although spokesman Robert Plunkett says that the results do leave room for sterile neutrinos. "We're limiting the parameter space for them." ADVERTISEMENT Another Fermilab experiment, built to follow up on the earliest clues to sterile neutrinos, potentially offers more encouragement. The original evidence came from an experiment at Los Alamos in which Louis took part. From 1993 to 1998, he and his colleagues used the Liquid Scintillator Neutrino Detector experiment to shoot antineutrinos — neutrinos' antimatter counterparts — into 167 tonnes of mineral oil. Their data on how antineutrinos switch from one species to another suggested four distinct flavours. A decade later, data from a follow-up test also at Fermilab — the Mini Booster Neutrino Experiment, or MiniBooNE — found no evidence of a fourth neutrino type. But the MiniBooNE had used a beam of neutrinos, making it difficult to compare its results with the antineutrino data from Los Alamos. Now, after collecting data for a year and a half with antineutrinos, the MiniBooNE experiment sees a different pattern (see 'Neutrino hunters'). When combined with other antin! eutrino experiments worldwide, says Louis, its data fit "beautifully" to a 3 + 1 model: three ordinary neutrinos plus a sterile one4. Louis, who is also a part of the MiniBooNE collaboration, says that the next batch of data, to be released this summer, should give a better idea of whether this fleeting interloper has finally been caught. * References * Komatsu, E.et al. Preprint at http://arxiv.org/abs/1001.4538v1 (2010). * Lowenstein, M. & Kusenko, A. Preprint at http://arxiv.org/abs/0912.0552 (2009). * Adamson, P.et al. Phys. Rev. D81, 052004 (2010). * Karagiorgi, G. , Djurcic, Z. , Conrad, J. M. , Shaevitz, M. H. & Sorel, M.Phys. Rev. D80, 073001 (2009). There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Hobbit origins pushed back
  - Nature 464(7287):335 (2010)
  Stone tools reveal that hominins lived on the Indonesian island of Flores a million years ago. When the remains of tiny hominins — nicknamed hobbits — were found on the isolated Indonesian island of Flores in 2003, it sparked an epic hunt to understand the origins of these diminutive cousins of modern humans. Now, discoveries of stone flakes used as primitive tools on the island suggest that the hobbit's ancestors were there a million years ago, at least 120,000 years earlier than previously thought (A. Brumm et al. Nature doi:10.1038/nature08844; 2010). "Whatever species made it to the island 1 million years ago, it was probably an ancestor of Homo floresiensis," says William Jungers, an anthropologist at Stony Brook University in New York. The metre-high H. floresiensis lived on the island until at least 17,000 years ago, and its small stature probably evolved in response to the island's sparse resources. The simple stone tools demonstrate the skills of its ancestors — people who must have hopscotched across islands from mainland Asia, traversing deep and swift ocean channels, before arriving on Flores. In 2005, Adam Brumm, an archaeologist at the University of Wollongong in Australia, found the first of about 45 stone tools while exploring a bowl-shaped gully on the island that was like "a hot, steamy wok". Three years later, researchers at Roskilde University in Denmark analysed the ratio of two isotopes of argon trapped in volcanic ash overlaying the tools to determine their age. ADVERTISEMENT Previous tool discoveries showed that hominins had arrived on Flores by 880,000 years ago, suggesting that the hobbit's ancestors might have wiped out some of the island's peculiar indigenous animals, such as the pygmy elephant-like Stegodon sondaari and giant tortoises (Geochelone spp.), which both disappeared at around the same time. The new finds imply that the hobbit's ancestors coexisted with the creatures for much longer, raising the possibility that a natural disaster was behind the disappearance of the animals. The team will return to Flores this summer, hoping to find older sediments that could hold earlier evidence of the island's first hominins. 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.
• China debates university reform
  - Nature 464(7287):336 (2010)
  Academics lobby for more autonomy, but fear losing powerful connections with government. Could Tsinghua University's School of Life Sciences benefit from more freedom from government?Tsinghua University Most scientists in China agree that their university system is ripe for reform. They chafe under bureaucracy and targets that promote research quantity over quality. Now the government has asked them for ideas about how to achieve that reform — and sparked a heated debate. At issue is the desire of many academics to secure greater autonomy for their institutions, allowing them to hire more freely and develop unique research specialities. But some argue that this autonomy will go hand in hand with losing crucial connections — and influence — with powerful government departments. On 28 February, China revealed its National Outline for Medium and Long Term Educational Reform and Development, which will guide education over the next decade. The plan, open for public consultation until the end of March, says that annual investment in education should increase to 4% of gross domestic product (from 3.48% in 2008), and also calls for proposals for university reform that will make the higher-education sector more internationally competitive. On 5 March, Premier Wen Jiabao said that the plan should be implemented "promptly" once the consultation is over. "Universities should be cultivating their individual strengths." Rao Yi, dean of Peking University's School of Life Sciences, and Shi Yigong, dean of Tsinghua University's School of Life Sciences in Beijing, had already set out their own ideas for reform the previous week in an article in the Renmin Ribao (People's Daily), the Communist party's daily newspaper. It was an abbreviated version of a letter sent to the premier, with whom they had previously discussed the matter, suggesting that the same autonomy that had been bestowed on Chinese agriculture and businesses in the 1980s, and led to rapid economic success, should also be granted to education. The scientists — who both returned to China after successful careers abroad — argue that micromanagement by university administrators acting on instructions from central government forces all universities to chase the same targets, leading to a "monotony of purpose". "Evaluating schools without much research capacity, whose strengths might lie elsewhere, by the number of papers produced ! could lead to rushed and exaggerated results," Shi and Rao wrote. Instead, "different universities should be cultivating their individual strengths". By setting common targets regardless of size or resources, the Ministry of Education encourages a harmful standardization, agrees Rao Zihe, president of Nankai University in Tianjin. "Universities watch each other's success in living up to that standard. Sooner or later, they all start cloning each other," he says. The education ministry also determines how many students each university should admit, and the basic curricula. These decisions, too, should devolve to the universities, say Shi and Rao Yi, with a board of directors drawn from the faculty able to oversee the process. This board would also select the university's president — subject to ministry approval — and individual faculties should have the freedom to decide who to appoint as professors. China has the third-largest national science budget in the world, but most observers agree that results have not been commensurate with investment. A report released in February by the Institute of Scientific and Technical Information of China ranked its homeland 13th out of 19 countries assessed for their "global science influence". Some scientists contacted by Nature suggest that trimming the influence of university bureaucrats with close ties to the ministry could help to tame the obsession with publication targets. The question is how. ADVERTISEMENT One suggestion is to end the practice, started in 1999, of bestowing the administrative rank of vice-minister on the presidents of China's 31 leading universities. The titles are meant to recognize the importance of universities. "But some say it poisons the academic culture," says Xue Lan, a science-policy expert at Tsinghua University. "Professors come to think of rank rather than academic standards." Such a change would signal that universities were focusing more on teaching and research, and less on administrative targets. But in a society that lauds Confucianism, with its emphasis on social hierarchy, a vice-minister post is a mark of a university's importance. "For university presidents, it gives them some power to relate to those outside academia," says Rao Yi. Xue acknowledges that the status of vice-minister can be useful for university administrators. "No matter where you go in China, people pay attention to rank." 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.
• Cash crisis looms for vaccine drive
  - Nature 464(7287):338 (2010)
  Rising demand for immunization programmes in developing countries could outstrip funding. GAVI has immunized hundreds of millions of children.G. Pirozzi/PANOS Up to 4.2 million people, mostly young children, will die needlessly over the next 6 years unless donors fill a looming multibillion-dollar shortfall in the budget of the GAVI Alliance. The warning from GAVI, which focuses on getting vaccines into low-income countries, is contained in advocacy documents it sent to its donors last weekend, in the run up to an extraordinary meeting due to be held on 25–26 March in The Hague, the Netherlands. It is the first time that the global-health partnership, based in Geneva, Switzerland, has brought together all of its major donors — countries and philanthropic organizations — at a single fund-raising event. It is also a sign of the current woes at the organization, which since its creation in 2000 has taken vaccination rates in low-income countries to record highs. "The funding crisis at GAVI is acute," says Daniel Berman, deputy director of the Access to Essential Medicines Campaign at the medical charity Médecins Sans Frontières. According to the World Health Organization, GAVI has immunized more than 250 million children and prevented some 5.4 million premature deaths over the past decade. But it now risks becoming a victim of its own success, with demand for its immunization efforts outstripping donor contributions just as the financial crisis has begun to bite. The GAVI documents show that its projected spending for 2010–15 is US$7 billion, which, given existing and promised donations, leaves a $4.3-billion shortfall. If existing donors maintain their funding at current levels, the shortfall would shrink by $1.7 billion, leaving enough money to maintain existing programmes. But GAVI's future initiatives would stall. It had hoped to roll out two additional vaccines between now and 2015, spending $2.4 billion on a campaign against pneumococcal disease and $750 million to tackle rotavirus. Together, these would reduce pneumonia and diarrhoea, which are the top two vaccine-preventable causes of child deaths and account for around 40% of deaths in children under five — a key target in achieving the United Nations' Millennium Development Goals on global health. The fund-raising meeting will focus on soli­citing new donors to broaden GAVI's funding base. Around 80% of GAVI cash comes from a handful of country donors (see 'Few funders for vaccines'), which has left the alliance highly vulnerable during the global economic downturn to funding reductions by only a few nations. Click for larger image GAVI is hoping that one of its key financial innovations, the International Finance Facility for Immunisation, will prove particularly recession-proof. The facility does not require countries to put money on the table immediately, but rather to make 10–20-year legally binding commitments, which the facility then borrows against on capital markets. New long-term pledges by countries or foundations could help the alliance to free up cash in the short term, says Joelle Tanguy, a GAVI spokeswoman. The billion-dollar question is how much cash might be forthcoming from the Bill & Melinda Gates Foundation, a founder of GAVI that has pledged $1.55 billion to the alliance up to 2014. In January, the foundation promised $10 billion to support a ten-year effort to research, develop and deliver vaccines, but declined to comment on how much of that will go to GAVI. It will be difficult for donors at the Hague meeting to come to decisions without a firmer idea of any extra contribution by the foundation, says Berman. GAVI's activities are widely applauded, but even supporters say that it could be doing more to make its funds go further. Vaccines amount to 80% of its costs, and Médecins Sans Frontières, for example, has criticized as "too lucrative for the drug industry" an 'advance market commitment' deal that GAVI and its partners signed in June 2009 to secure lower prices for pneumococcal vaccines. GAVI promised to guarantee a $1.5-billion market as an initial incentive to roll out the vaccines; in exchange, drug companies including GlaxoSmithKline agreed to charge $7 per dose for the first batches of vaccine and $3.50 in the longer term, compared with the $70 per dose charged in rich countries. But GAVI should have got a better deal, says Berman. "The crisis is a good opportunity to make some reforms of how GAVI works," he says. He suggests that it needs to pursue more aggressive policies to promote greater competition between vaccine makers to further reduce prices. For example, the Meningitis Vaccine Project, funded by the Gates Foundation, is developing a meningitis vaccine that will be manufactured by the Serum Institute of India in Pune, and will cost just $0.40 per dose. Tanguy says that GAVI's $7-billion projected spending up to 2015 already takes into account its goal of saving $1 billion on vaccines, and that cutting vaccine prices is "one of our critical strategies". The US government should also help, according to Bill Gates, who testified at a US Senate committee hearing last week on President Barack Obama's global health plans. Although getting more US government money for global health would be an "uphill battle", he said, funding for GAVI should get high priority. ADVERTISEMENT The Obama administration intends to spend $9.7 billion on global health in its 2011 budget, 80% of which would go towards fighting AIDS (through the President's Emergency Plan for AIDS Relief) and malaria. The budget includes a modest increase in GAVI funding, from $78 million to $90 million. "An investment in GAVI will give American taxpayers the best bang for their buck," said Gates, "and the committee should consider increasing the level of funding beyond the administration's request." 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.
• Science in court: Head case
  - Nature 464(7287):340 (2010)
  Last year, functional magnetic resonance imaging made its debut in court. Virginia Hughes asks whether the technique is ready to weigh in on the fate of murderers. Download a PDF of this story Brian Dugan, dressed in an orange jumpsuit and shackles, shuffled to the door of Northwestern Memorial Hospital in downtown Chicago, accompanied by four sheriff deputies. It was the first time that Dugan, 52, had been anywhere near a city in 20 years. Serving two life sentences for a pair of murders he had committed in the 1980s, he was now facing the prospect of the death penalty for an earlier killing. Dugan was here on a Saturday this past September to meet one of the few people who might help him to avoid that fate: Kent Kiehl, a neuroscientist at the University of New Mexico in Albuquerque. Dugan, Kiehl and the rest of the entourage walked the length of the hospital, crossed a walkway to another building, and took the lift down to a basement-level facility where researchers would scan Dugan's brain using functional magnetic resonance imaging (fMRI). Todd Parrish, the imaging centre's director, offered plastic zip ties to replace the shackles — no metal is allowed in the same room as the scanner's powerful magnet — but the guards said they weren't necessary. Dugan entered the machine without restraints, and Parrish locked the door — as much to keep the guards and their weapons out as to keep Dugan in. Dugan lay still inside the scanner for about 90 minutes, performing a series of cognitive control, attention and moral decision-making tests. Afterwards he ate a hamburger, sat through an extensive psychiatric interview and rode back to DuPage county jail, about 50 kilometres west of Chicago. Kiehl has been amassing data on men such as Dugan for 16 years. Their crimes are often impulsive, violent, committed in cold blood and recalled without the slightest twinge of remorse. They are psychopaths, and they are estimated to make up as much as 1% of the adult male population, and 25% of male prisoners. To date, Kiehl has used fMRI to scan more than 1,000 inmates, many from a mobile scanner set up in the courtyard of a New Mexico prison. He says that the brains of psychopaths tend to show distinct defects in the paralimbic system, a network of brain regions important for memory and regulating emotion. Mitigating circumstances The purpose of the work, Kiehl says, is to eliminate the stigma against psychopaths and find them treatments so they can stop committing crimes. But Dugan's lawyers saw another purpose. During sentencing for capital crimes, the defence may present just about anything as a mitigating factor, from accounts of the defendant being abused as a child to evidence of extreme emotional disturbance. Kiehl's research could offer a persuasive argument that Dugan is a psychopath and could not control his killer impulses. After reading about Kiehl's work in The New Yorker, Dugan's lawyers asked Kiehl to testify and offered him the chance to scan the brain of a notorious criminal. Kiehl agreed and Dugan's case became what is thought to be the first in the world to admit fMRI as evidence. Kiehl's decision has put him at odds with many in his profession, and stirred debate among neuroscientists and lawyers. "It is a dangerous distortion of science that sets dangerous precedents for the field," says Helen Mayberg, a neurologist at Emory University School of Medicine in Atlanta, Georgia. Mayberg, who uses brain imaging to study depression, has testified against the use of several kinds of brain scan in dozens of cases since 1992. Although other brain-imaging techniques have been used in court, it is especially hard to argue that fMRI should be, argue critics. The technique reveals changes in blood flow within the brain, thought to correlate with brain activity, and it has become popular in research. But most fMRI studies are small, unreplicated and compare differences in the average brain activity of groups, rather than individuals, making it difficult to interpret for single cases. It is rarely used in diagnosis. Moreover, a recent scan, say some critics, wouldn't necessarily indicate Dugan's mental state when he committed his crimes. "It is a dangerous distortion of science that sets dangerous precedents for the field." In 1983, Dugan kidnapped 10-year-old Jeanine Nicarico, of Naperville, Illinois. He raped her in the back seat of his car and beat her to death. In 1984, he saw a 27-year-old nurse waiting at a stop light on a deserted road. He rammed into her car, raped her and drowned her in a quarry. A year later, he plucked a 7-year-old girl from her bicycle, raped her, killed her and left her body in a drainage ditch, weighed down with rocks. Plea bargaining Police charged Dugan with the third murder three weeks after it happened and listed him as a suspect in the nurse's death. Through his lawyers, Dugan offered to confess to all three killings, but only if prosecutors took the death penalty off the table. Authorities, deeming some of Dugan's statements on the Nicarico murder to be unreliable, wouldn't negotiate.One reason for their reluctance was that two men had already been sent to death row for killing Nicarico. But more than ten years later the two convicted men were finally exonerated. With constituents demanding justice for Nicarico, local authorities used DNA evidence to link Dugan to the crime in 2002. In July last year, he formally pleaded guilty. It was a high-profile case for the area, and local media accounts depict a community haunted by the girl's death. The defence lawyers knew that they would have a tough time arguing for leniency. They were willing to try anything, including the latest that neuroscience could offer. Above: criminal psychopaths show less activity than non-criminal control subjects in specific emotion-processing areas of the brain, according to Kent Kiehl's testing. Right: Brian Dugan in 1985.K. A. KIEHL Brain imaging has a long history in legal cases. Lawyers have often used scans as a way to tip the scale in the perpetual battle between opposing expert psychiatric witnesses. You can't control your brain waves, the theory goes, and scans are an objective measure of mental state. "The psychiatric diagnosis is still soft data — it's behaviour," notes Ruben Gur, director of the Brain Behavior Center at the University of Pennsylvania in Philadelphia. "The brain scan doesn't lie. If there is tissue missing from your brain, there is no way you could have manufactured it for the purpose of the trial." Brain imaging played into the 1982 trial of John Hinckley Jr, who had attempted to assassinate US President Ronald Reagan. Lawyers presented a computed tomography X-ray scan of his head, arguing that it showed slight brain shrinkage and abnormally large ventricles, indicating a mental defect. The prosecution's expert witnesses said the scans looked normal. Whether imaging influenced the verdict is not known, but Hinckley was found not guilty by reason of insanity. Over the next decade, lawyers gradually switched to positron emission tomography (PET), which can be used to give a measure of metabolic activity in the brain. Gur's research team has scanned dozens of patients with mental illness and hundreds of healthy volunteers using PET and structural MRI — a technique that looks at the static structure of the brain and is more established for diagnosis than fMRI. Through his research, he has developed algorithms that can predict whether a person has schizophrenia, for example, from structural MRI alone with about 80% accuracy1. Gur has testified in roughly 30 criminal cases on behalf of defendants alleged to have schizophrenic or brain-damage. "We determine whether the values are normal or abnormal," Gur says. "It's a challenge to explain that to a jury, but when they understand, basically all I'm telling them is that this is not someone who's operating with a full deck. And so, they may not be eligible for the harshest punishment possible." Gur gets so many requests to testify that he has a team of psychology residents and interns to vet them. Still, he doesn't think that fMRI is reliable enough for legal settings. "If somebody asked me to debunk an fMRI testimony, it wouldn't be too hard," Gur says. That's mainly because fMRI studies deal in average differences between groups. For example, Kiehl's work has shown that when processing abstract words, psychopathic prisoners have lower activity in some brain regions than non-psychopathic prisoners and non-prisoners. But there's bound to be overlap. He has not shown, for example, that any one person showing a specific brain signature is guaranteed, with some per cent certainty, to be a psychopath or behave like one. For Kiehl, the scan is just part of the picture and he conducts extensive interviews to determine a diagnosis of psychopathy. "It's just one bit of information that helps us understand brain function," he says. Taking the stand On 29 October, Kiehl participated in a 'Frye hearing' for Dugan's case. Based on a 1923 ruling, the hearing determines whether scientific evidence is robust enough to be admitted. Joseph Birkett, the lead prosecutor in the Dugan case, argued that allowing the scans — the bright colours and statistical parameters of which are chosen by the researchers — might bias the jury. Some studies, prosecutors argued, have shown that neuroscientific explanations can be particularly seductive to the layperson2. The judge ultimately "cut the baby in half", says Birkett. He ruled that the jury would not be allowed to see Dugan's actual brain scans, but that Kiehl could describe them and how he interpreted them based on his research. On 5 November, Kiehl took the stand for about six hours. He described the findings of two, three-hour psychiatric interviews with Dugan. Dugan had scored 38 out of a possible 40 on the Hare Psychopathy Checklist, which evaluates 20 aspects of personality and behaviour through a semi-structured interview. (It was developed by Kiehl's graduate-school mentor, Robert Hare.) That puts him in the 99.5th percentile of all inmates, Kiehl says. Using PowerPoint slides of bar graphs and cartoon brains — but not the scans — Kiehl testified that Dugan's brain, like those of psychopaths in his other studies3, showed decreased levels of activity in specific areas. Prosecutors, Kiehl says, went to great lengths to sow confusion about the data. At one point during Kiehl's testimony, he showed a cartoon brain with Xs marked on various regions, to illustrate where Dugan's activity was aberrant. The prosecutor, Kiehl recalls, "asked me on cross examination, 'Are there really Xs in this guy's brain?' It's the adversarial system — they were just out to make it look like nothing made sense." Kent Kiehl outside the mobile scanner he has used to look at the brains of inmates at a New Mexico prison. The next day, the prosecution brought a rebuttal witness: Jonathan Brodie, a psychiatrist at New York University. He refuted the imaging evidence on several grounds. First, there was timing: Kiehl scanned Dugan 26 years after he killed Nicarico. It was impossible to know what was going on in Dugan's brain while he was committing the act, and it was perhaps not surprising that his brain would look like a murderer's after committing murder. Second, Brodie said, there was the issue with average versus individual differences. If you look at professional basketball players, most of them are tall, he told the jury, but not everyone over six foot six is a basketball player. From a technical perspective, Kiehl's work is expertly done, says Brodie. "I have no issue with his science. I have an issue with what he did with it. I think it was just a terrible leap." Even if fMRI could reliably diagnose psychopathy, it wouldn't necessarily reduce a defendant's culpability in the eyes of a judge or jury. Ultimately, the law is based on an individual's rational, intentional action, not brain anatomy or blood flow, says Stephen Morse, professor of law and psychiatry at the University of Pennsylvania. "Brains don't kill people. People kill people," says Morse, who also co-directs the MacArthur Foundation's Law and Neuroscience Project, which brings together scientists, lawyers and judges to debate how brain technology should be used in legal settings. Change of heart Dugan's sentencing proceedings ended four days after Brodie's testimony. The jury deliberated for less than an hour before coming back with a verdict: ten for the death penalty and two for life in prison — a death sentence requires a unanimous vote. But while waiting for the Nicarico family to return to the courtroom, one of the jurors asked for more time and the judge agreed. The jury asked for copies of several transcripts of testimony, including Kiehl's, and went back into deliberation. The next day, all 12 jurors voted to send Dugan to his death. "Kiehl got a lot of criticism, but I think what he did is perfectly reasonable." Even with the unfavourable final verdict, Kiehl's testimony "turned it from a slam dunk for the prosecution into a much tougher case", says Steve Greenberg, Dugan's lawyer. The switched verdict will definitely be brought up in the appeal to the state supreme court, says Greenberg, as will the fact that the jurors weren't allowed to see Dugan's brain scans. Since November, Kiehl says he has been contacted by about a dozen lawyers asking for similar services. In February, he and Parrish scanned another man on trial using the same fMRI scanner at Northwestern Memorial Hospital. For Kiehl the motivations for scanning Dugan were twofold. "It gave me an opportunity to study one of the classic psychopaths in American history," he says. That included privileged access to Dugan and his massive case file. Kiehl also says he feels a "moral obligation" to help educate the jury, and the public, about psychopathy, a disorder that is often maligned in the popular press. "You can live in the ivory tower for your whole career, and never really have a practical influence. This was a chance to help," says Kiehl. Many of his peers are unimpressed. The witness stand, says Mayberg, is "not a soapbox". "What you might believe to drive your own research is very different from being a spokesperson for science," she says, adding that people who take the stand should not use the platform as a way to meet their own scientific agenda. Others are less critical. When DuPage county prosecutors discovered that Dugan's defence team would be using brain imaging, they contacted Scott Grafton, director of the Brain Imaging Center at the University of California, Santa Barbara. Grafton has testified against imaging in many cases, but this time he declined, saying that even potentially shaky scientific evidence should be allowed during the sentencing phase of a trial. "Kiehl got a lot of criticism, but I think what he did is perfectly reasonable," says Grafton. "I've had judges tell me, 'Look, everything else everybody's bringing into a mitigation hearing is extremely unreliable, so why should we hold scans to a different standard?'" ADVERTISEMENT Whatever standards fMRI scans should be held to, neuroscientists and the legal system are under pressure to work them out fast. Although a fledgling technology, fMRI has been knocking at the doors of the courts for a while. Since at least 2007, two US companies, Cephos in Tyngsboro, Massachusetts, and No Lie MRI in San Diego, California, have been selling 'deception detection' services based on fMRI scans. The technology has almost certainly been used in plea bargains (like its older cousin, the polygraph), and is expected to debut in court within a few years. Use of fMRI for diagnosing mental disorders, as was the case for Dugan, will improve and more scans will probably show up in court, says Gur. "That's only a question of time." What matters, though, is how the jury perceives the evidence and the testimony — and in Dugan's case, it's not clear how much weight it carried. For Michael Euringer, a juror in the trial and a retired stockbroker, it didn't mean much at all. "I don't think that they were able to present that idea that he had a brain defect. He was a psychopath, but he was not psychotic," he says. "But it all depends on the jury." Virginia Hughes is a freelance writer in New York City. * References * Davatzikos, C.et al. Arch. Gen. Psychiatry62, 1218-1227 (2005). * Weisberg, D. S. , Keil, F. C. , Goodstein, J. , Rawson, E. & Gray, J. R.J. Cogn. Neurosci.20, 470-477 (2008). * Kiehl, K. A.et al. Psychiatry Res.130, 297-312 (2004). 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.
• Science in court: The fine print
  - Nature 464(7287):344 (2010)
  A single incriminating fingerprint can land someone in jail. But, Laura Spinney finds, there is little empirical basis for such decisions. Download a PDF of this story The terrorist explosions that ripped through Madrid's crowded commuter trains on the morning of 11 March 2004 killed 191 people, wounded some 2,000 more and prompted an international manhunt for the perpetrators. Soon after, Spanish investigators searching the area near one of the blasts discovered an abandoned set of detonator caps inside a plastic bag that bore a single, incomplete fingerprint. They immediately shared the clue with law-enforcement colleagues around the world. And on 6 May 2004, the US Federal Bureau of Investigation (FBI) arrested Oregon lawyer Brandon Mayfield, proclaiming that his print was a match. Two and a half weeks later, a chagrined FBI was forced to release Mayfield after Spanish police arrested an Algerian national — one of several terrorists later charged with the crime — and found one of his fingerprints to be a much better match. The FBI eventually admitted that it had made multiple errors in its fingerprint analysis1. The Mayfield case is a textbook example of 'false positive' fingerprint identification, in which an innocent person is singled out erroneously. But the case is hardly unique. Psychologist Erin Morris, who works with the Los Angeles County Public Defender's Office, has compiled a list of 25 false positives, going back several decades, that is now being used to challenge fingerprint evidence in US courts. Those challenges, in turn, are being fed by a growing unease among fingerprint examiners and researchers alike. They are beginning to recognize that the century-old fingerprint-identification process rests on assumptions that have never been tested empirically, and that it does little to safeguard against unconscious biases of the examiners. That unease culminated last year in a stinging report by the US National Academy of Sciences (NAS)2, which acknowledged that fingerprints contain valuable information — but found that long-standing claims of zero error rates were "not scientifically plausible". Since then, fingerprint examiners have found themselves in an uncomfortable situation. "How do you explain to the court that what you've been saying for 100 years was exaggerated, but you still have something meaningful to say?" asks Simon Cole, a science historian at the University of California, Irvine. The only way out of the dilemma is data, says Cole: do the research that will put fingerprinting on solid ground. And that is what researchers are starting to do. In January, for example, the US Department of Justice's research branch, the National Institute of Justice, launched the first large-scale research programme to classify fingerprints according to their visual complexity — including incomplete and unclear prints — and to determine how likely examiners are to make errors in each class. "The vast majority of fingerprints are not a problem," says Itiel Dror, a cognitive psychologist at University College London who is involved in the study. "But even if only 1% are, that's thousands of potential errors each year." Leaving a mark Even fingerprinting's harshest critics concede that the technique is probably more accurate than identification methods based on hair, blood type, ear prints or anything else except DNA. Granted, no one has ever tested its underlying premise, which is that every print on every finger is unique. But no one seriously doubts it, either. The ridges and furrows on any given fingertip develop in the womb, shaped by such a complex combination of genetic and environmental factors that not even identical twins share prints. Barring damage, moreover, the pattern is fixed for life. And thanks to the skin's natural oiliness, it will leave an impression on almost any surface the fingertip touches. The concerns start with what happens after a fingerprint, or 'mark', is found at a crime scene and sent to the examiners. The problem lies not so much with the individual examiners, most of whom have undergone several years of specialist training, but more with the ACE-V identification procedure they follow in most countries (see graphic). The acronym stands for the four sequential steps of analysis, comparison, evaluation and verification — the hyphen signifying that the last step is carried out by a different individual, who repeats the first three. Click for larger image. The analysis phase starts at the gross level, where there are three main patterns — loops, whorls and arches — that can be used to classify prints or to rapidly exclude suspects. Then comes a second level of analysis, which focuses on finer details, such as bifurcations and ridge endings (see graphic), which are highly discriminating between individuals. If necessary, the examiner can bore down to a third level of detail, related to the shape of ridge edges and the pattern of pores. Having analysed a mark and noted its distinctive features, the examiner then goes to the comparison step: checking for similarities or differences with a reference fingerprint, or 'exemplar', retrieved from law-enforcement files or taken from a suspect. This part of the process has become increasingly automated, first with the development of automatic fingerprint identification systems (AFIS) in the 1980s, then with the advent of digital print-capture technology in the 1990s. Today's AFIS technology can scan though the vast fingerprint databases compiled by the FBI and other agencies and automatically filter out all but a handful of candidate matches to present to the examiner. The examiner will then winnow the candidates down by eye. According to the ACE-V protocol, the third step, evaluation, can lead the examiner to one of three conclusions: 'identification', meaning that mark and exemplar came from the same finger; 'exclusion', meaning that they did not, as there is at least one significant difference that cannot be explained by factors such as smearing; and 'inconclusive', meaning that the mark is not clear enough for the examiner to be sure. "The system as it's designed purposely produces false negatives," says legal scholar Jennifer Mnookin of the University of California, Los Angeles. Because the protocol makes it possible to have one difference and exclude a match, but a lot of similarities and still not be sure, it builds in a preference for missing the identification of a criminal rather than risking the conviction of an innocent person. "The system as it's designed purposely produces false negatives." Yet, as the Mayfield case illustrates, false positives can slip through the net. In Scotland, for example, an ongoing inquiry is trying to understand how a fingerprint found at a murder scene was wrongly attributed to police officer Shirley McKie, leading her to be falsely accused of perjury. Such errors may not come to light until some other, incontrovertible piece of evidence trumps the fingerprint, or until the prints are reanalysed in an internal review. But for examiners and researchers alike, the urgent question is why they happen at all. One of the problems with the ACE-V procedure lies in sloppy execution. For example, the protocol calls for the analysis and comparison steps to be separated, with a detailed description of the mark being made before an examiner ever sees an exemplar. This is to prevent circular reasoning, in which the presence of the exemplar inspires the 'discovery' of previously unnoticed features in the mark. But this separation doesn't always happen, says forensic-science consultant Lyn Haber, who together with her husband, psychologist Ralph Haber, co-authored the 2009 book Challenges to Fingerprints. To save time, she says, many examiners do the analysis and comparison simultaneously. The FBI highlighted this as a factor contributing to the Mayfield error. Misprints Another problem is that the ACE-V protocol itself is sloppy, at least by academic standards. For example, it calls for the final verification step to be independent of the initial analysis, but does not lay down strict guidelines for what that means. So in practice, the verifier often works in the same department as the first examiner and knows whose work he or she is checking — not a form of 'independence' with which many scientists would be comfortable. Nor is ACE-V especially strict about what examiners can and cannot know about the case on which they are working. This is especially worrying in light of a study3 published in 2006 in which Dror and his colleagues showed that both experienced and novice fingerprint examiners can be swayed by contextual information. In one experiment, the researchers presented six examiners with marks that, unbeknown to them, they had analysed before. This time, the examiners were furnished with certain details about the case — that the suspect had confessed to the crime, for example, or that the suspect was in police custody at the time the crime was committed. In 17% of their examinations, they changed their decision in the direction suggested by the information. This point is emphasized by the conclusion in last year's NAS report that "ACE-V does not guard against bias; is too broad to ensure repeatability and transparency; and does not guarantee that two analysts following it will obtai! n the same results." For many critics this is the central issue: fingerprint analysis is fundamentally subjective. Examiners often have to work with incomplete or distorted prints — where a finger slid across a surface, for example — and they have to select the relevant features from what is available. What is judged relevant therefore changes from case to case and examiner to examiner. Several research groups are now looking at this problem, with a view to understanding and improving the way that experts make a judgement. The FBI has an ongoing study looking at the quantity and quality of information needed to make a correct decision. Dror's group is doing a controlled study of the errors made by examiners in which they are given marks, told they have been taken from a crime scene — they were actually made by Dror — and asked to identify them. Expert testimony Other critics have wondered whether any examiner truly qualifies as an expert. As the Habers point out in their book, examiners rarely find out whether their decision was correct, because the truth about a crime is often not known. As a result, they write, "even years of experience may not improve [an examiner's] accuracy". Some fingerprint examiners have simply rejected these criticisms. In 2007, for example, the chairman of Britain's Fingerprint Society, Martin Leadbetter, wrote in the society's magazine4 that examiners who allow themselves to be swayed by outside information are either incompetent or so immature they "should seek employment at Disneyland". But others have taken the criticisms to heart. After hearing about Dror's research on bias, Kevin Kershaw, head of forensic identification services at Greater Manchester Police, one of Britain's largest police forces, decided to buffer his examiners from potentially biasing information by preventing investigating officers from coming on-site to wait for results, and potentially talking to the examiners about the case. This is made easier by the fact that in Manchester, as in many British police forces, the forensic division is separated from the others. In the United States, by contrast, most of the fingerprint work is done inside police departments — a situation that the NAS report recommended be changed. Brandon Mayfield was falsely accused of terrorism on the basis of a fingerprint found at the scene.D. RYAN/AP PHOTO Kershaw also invited Dror to come and teach his examiners about the dangers of bias, and he changed his service so that the verifier no longer knows whose work he or she is checking. Finally, as Dror's research indicated that the decisions that are most susceptible to bias are those in which the mark is unclear or hard to interpret, Kershaw introduced blind arbitration in cases in which examiners disagree. Safeguards against bias are relatively easy to put in place, but another potential source of error might be harder to eliminate. It has to do with how faithfully the pattern on a finger is reproduced when it is inked or scanned to create an exemplar. No reproduction is perfect, notes Christophe Champod, an expert in forensic identification at the University of Lausanne in Switzerland. So a mark recovered from a crime scene could match exemplars from more than one person, or vice versa, he says. Exacerbating the problem is the continued growth in the exemplar databases that AFIS have to search. Champod thinks that the language of certainty that examiners are forced to use hides this uncertainty from the court. He proposes that fingerprint evidence be interpreted in probabilistic terms — bringing it in line with other forensic domains — and that examiners should be free to talk about probable or possible matches. In a criminal case, this would mean that an examiner could testify that there was, say, a 95% chance of a match if the defendant left the mark, but a one in a billion chance of a match if someone else left it. "This is all about adding a culture of science to the forensic-science community." To be able to quote such odds, however, examiners would need to refer to surveys showing how fingerprint patterns vary across populations and how often various components or combinations of components crop up. For example, is a particular configuration of bifurcations, ridge endings and the like found in 40% of a given population or in 0.4%? Some research has been done on this issue, but not on a sufficiently large or systematic scale. Nevertheless, Champod is optimistic that a probabilistic system is within reach. Unlike with DNA, he says, which has strong subpopulation effects, fingerprint patterns vary little between populations, simplifying the task. A probabilistic approach would not replace the examiner or address bias, but it would render the decision-making process less opaque. "Once certainty is quantified, it becomes transparent," says Champod. Ultimately, however, it is for the courts to decide how much weight they accord to fingerprint evidence. The fact that courts still routinely treat it as infallible — which means a single incriminating fingerprint can still send someone to jail — strikes Mnookin as "distressing jurisprudence". Champod, too, would like to see its importance downgraded. "Fingerprint evidence should be expressed by fingerprint examiners only as corroborative evidence," he says. If other strands of evidence limit the pool of suspects, then a fingerprint is much less likely to be misattributed. ADVERTISEMENT To date, judges haven't shown much inclination to alter the status quo. But to be fair, says Barry Scheck, co-director of the Innocence Project — a group in New York that campaigns to overturn wrongful convictions — they haven't been given a viable alternative. The probabilistic approach is not yet ready for court. But that may be about to change if researchers can come up with ways to help fingerprinting profession re-establish itself on a more scientific footing. A cultural change will also be needed, within both the fingerprint community and the legal system. "This is all about adding a culture of science to the forensic-science community," says Harry Edwards, a senior judge on the District of Columbia circuit and co-chair of the NAS committee that produced last year's report. "From what I have seen, we still have a long way to go." Laura Spinney is a freelance writer based in Lausanne, Switzerland. * References * A Review of the FBI's Handling of the Brandon Mayfield Case (Office of the Inspector General Oversight and Review Division, 2006). * Strengthening Forensic Science in the United States: A Path Forward (National Academies, 2009). * Dror, I. E. & Charlton, D. J.Forensic Identification56, 600-616 (2006). * Leadbetter, M.Fingerprint Whorld33, 231 (2007). 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.
• Science in court: DNA's identity crisis
  - Nature 464(7287):347 (2010)
  When Peter Hoe was found stabbed to death in his home in North Yorkshire, UK, in the afternoon of 13 October 2006, investigators were able to connect the murder to brothers Terence and David Reed on the basis of a small amount of DNA lifted from shards of plastic found near the body. The men were convicted the next year. There are currently no comments.
• World view: What can little Europe do?
  - Nature 464(7287):349 (2010)
  The research component of the European Union (EU) budget — known as the framework programme, now in its seventh iteration (FP7) — has experienced only incremental change each time the union has set its budget. The outcome is a set of activities, under FP7, of limited strategic impact. There are currently no comments.
• Tsunami: unexpected blow foils flawless warning system
  - Nature 464(7287):350 (2010)
  The trans-Pacific tsunami generated by the magnitude-8.8 Chile earthquake on 27 February exposed a problem with Australia's tsunami early-warning system.
• Tsunami: time for models to be tested in warning centres
  - Nature 464(7287):350 (2010)
  You highlight, in a News story, the controversy over the reliance of tsunami early-warning systems on model-based forecasts (Nature 464, 14–15; 2010).
• Researchers' petition aims to simplify European funding
  - Nature 464(7287):350 (2010)
  Your call for simplification of European research funding (Nature 463, 999; 2010) is timely.
• Smoking out the big tobacco-users — and they're not in China
  - Nature 464(7287):350 (2010)
  The photograph of an Asian person puffing on a cigarette and the map of the top cigarette-consuming countries, both shown in J. M.
• Waterfall is the clue to a case of mistaken identity
  - Nature 464(7287):350 (2010)
  A photograph (Nature 463, 1007; 2010) captioned to imply that it shows the coastline of Monterey Bay actually shows the cove at the mouth of McWay Canyon, about 50 km south of Monterey Bay.
• Making forensic science more scientific
  - Nature 464(7287):351 (2010)
  The US Congress should create an office to study, standardize and certify those who apply science to crime as well as the techniques they use, urge Peter Neufeld and Barry Scheck.
• Tales from the climate-change crossroads
  - Nature 464(7287):352 (2010)
  Four books by prominent global-warming pundits illustrate that exhortation and authority are not enough to solve the climate crisis — it is time for some humility, concludes Roger Pielke Jr.
• A misguided attack on evolution
  - Nature 464(7287):353 (2010)
  On the heels of last year's anniversary celebrations of Charles Darwin's On the Origin of Species and C. P.
• A macromolecular history
  - Nature 464(7287):354 (2010)
  The study of large molecules follows two strands that have alternately diverged and intertwined over the subject's history. The first strand explores the natural macromolecules of biology, including proteins, polysaccharides and nucleic acids.
• Q&A: Hervé This on flavour and perception
  - Nature 464(7287):355 (2010)
  French chemist Hervé This is a pioneer of the field of molecular gastronomy, the science of cooking. From perfecting the boiled egg to making custards with meat proteins, he has advised top chefs worldwide. He tells Nature why he is moving on to 'note-by-note' cuisine using compounds to build taste and smells, and why turkey is best cooked in the dishwasher.
• Correction
  - Nature 464(7287):355 (2010)
  The brief review of William Langewiesche's book Fly By Wire (Nature 463, 882; 10.1038/463882b2010) incorrectly spelled the first name of Captain Sullenberger as "Chelsey". It should have read "Chesley".
• Spectroscopy: Expanding versatility
  - Nature 464(7287):357 (2010)
  Gold nanoparticles coated with a thin layer of an oxide allow molecules adsorbed on surfaces as diverse as those of platinum, yeast cells or citrus fruits to be characterized routinely in the laboratory.
• Drug discovery: Inhibitors that activate
  - Nature 464(7287):358 (2010)
  Inhibitors of RAF enzymes can suppress or activate the same signalling pathway. The details of how this happens provide a cautionary note for those targeting the pathway for anticancer drug discovery.
• Astrophysics: First generation of quasars
  - Nature 464(7287):359 (2010)
  The discovery of two quasars in the distant Universe that apparently have no hot dust in their environments provides evidence that these systems represent the first generation of their family.
• Multiple sclerosis: Closing in on an oral treatment
  - Nature 464(7287):360 (2010)
  At present, only injectable drugs are available for treating multiple sclerosis. So clinical trials indicating that the drug fingolimod might be a step towards an oral treatment for the disease are exciting indeed.
• 50 & 100 years ago
  - Nature 464(7287):361 (2010)
  The first hovercraft has begun the hard task of practical development ... The experimental version now flying, the 'SR-NI', is an oval dish on top of which are mounted the propulsion and control systems, and the air compressor ... A reasonably flat operational surface is required and early applications may well be over surfaces which existing vehicles find difficult, for example, marsh, snow, sand, ice and shallow rivers. Serious consideration has been given to a 400-ton car ferry capable of carrying eight hundred passengers and eighty cars across the channel at a speed of 90 knots ... If the hovercraft can prove its worth with modest payloads over short distances, then serious thought could be given to developing a trans-ocean hovercraft capable of crossing the Atlantic in 24 hr.
• Solid-state physics: Golden ratio seen in a magnet
  - Nature 464(7287):362 (2010)
  The golden ratio — an exact 'magic' number often claimed to be observed when taking ratios of distances in ancient and modern architecture, sculpture and painting — has been spotted in a magnetic compound.
• Cancer: A lower bar for senescence
  - Nature 464(7287):363 (2010)
  Cellular senescence is a physiological mechanism for thwarting the proliferation of tumour cells. Encouraging cancer-prone cells to senesce might therefore be a way to nip this disease in the bud.
• Evolutionary biology: Pregnant fathers in charge
  - Nature 464(7287):364 (2010)
  Pipefish and related species provide rare examples of extreme male parental care. Controlled breeding experiments allow the resulting conflicts of interest between female, male and offspring to be explored.
• Cell biology: Actin filaments up against a wall
  - Nature 464(7287):365 (2010)
  The front of motile cells is thought to be pushed out by branched filaments of actin protein abutting the cell membrane. New work challenges this textbook view, showing that actin branches grow away from, or obliquely to, a surface.
• Inorganic chemistry: Pores off the peg
  - Nature 464(7287):366 (2010)
  Abstract
• Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium
  - Nature 464(7287):367 (2010)
  Fusarium species are among the most important phytopathogenic and toxigenic fungi. To understand the molecular underpinnings of pathogenicity in the genus Fusarium, we compared the genomes of three phenotypically diverse species: Fusariumgraminearum, Fusariumverticillioides and Fusariumoxysporum f. sp. lycopersici. Our analysis revealed lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity, indicative of horizontal acquisition. Experimentally, we demonstrate the transfer of two LS chromosomes between strains of F. oxysporum, converting a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in F. oxysporum. These findi! ngs put the evolution of fungal pathogenicity into a new perspective.
• Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence
  - Nature 464(7287):374 (2010)
  Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the p19Arf–p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the p19Arf–p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19Arf–p53 response i! s impaired, whereas a Skp2–SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy.
• Dust-free quasars in the early Universe
  - Nature 464(7287):380 (2010)
  The most distant quasars known, at redshifts z ≈ 6, generally have properties indistinguishable from those of lower-redshift quasars in the rest-frame ultraviolet/optical and X-ray bands1, 2, 3. This puzzling result suggests that these distant quasars are evolved objects even though the Universe was only seven per cent of its current age at these redshifts. Recently one z ≈ 6 quasar was shown not to have any detectable emission from hot dust4, but it was unclear whether that indicated different hot-dust properties at high redshift or if it is simply an outlier. Here we report the discovery of a second quasar without hot-dust emission in a sample of 21 z ≈ 6 quasars. Such apparently hot-dust-free quasars have no counterparts at low redshift. Moreover, we demonstrate that the hot-dust abundance in the 21 quasars builds up in tandem with the growth of the central black hole, whereas at low redshift it is almost independent of the black hole mass. Thus z�! ��≈ 6 quasars are indeed at an early evolutionary stage, with rapid mass accretion and dust formation. The two hot-dust-free quasars are likely to be first-generation quasars born in dust-free environments and are too young to have formed a detectable amount of hot dust around them.
• A transiting giant planet with a temperature between 250 K and 430 K
  - Nature 464(7287):384 (2010)
  Of the over 400 known1 exoplanets, there are about 70 planets that transit their central star, a situation that permits the derivation of their basic parameters and facilitates investigations of their atmospheres. Some short-period planets2, including the first terrestrial exoplanet3, 4 (CoRoT-7b), have been discovered using a space mission5 designed to find smaller and more distant planets than can be seen from the ground. Here we report transit observations of CoRoT-9b, which orbits with a period of 95.274 days on a low eccentricity of 0.11 ± 0.04 around a solar-like star. Its periastron distance of 0.36 astronomical units is by far the largest of all transiting planets, yielding a 'temperate' photospheric temperature estimated to be between 250 and 430 K. Unlike previously known transiting planets, the present size of CoRoT-9b should not have been affected by tidal heat dissipation processes. Indeed, the planet is found to be well described by standard ! evolution models6 with an inferred interior composition consistent with that of Jupiter and Saturn.
• A trapped single ion inside a Bose–Einstein condensate
  - Nature 464(7287):388 (2010)
  Improved control of the motional and internal quantum states of ultracold neutral atoms and ions has opened intriguing possibilities for quantum simulation and quantum computation. Many-body effects have been explored with hundreds of thousands of quantum-degenerate neutral atoms1, and coherent light–matter interfaces have been built2, 3. Systems of single or a few trapped ions have been used to demonstrate universal quantum computing algorithms4 and to search for variations of fundamental constants in precision atomic clocks5. Until now, atomic quantum gases and single trapped ions have been treated separately in experiments. Here we investigate whether they can be advantageously combined into one hybrid system, by exploring the immersion of a single trapped ion into a Bose–Einstein condensate of neutral atoms. We demonstrate independent control over the two components of the hybrid system, study the fundamental interaction processes and observe sympathetic coolin! g of the single ion by the condensate. Our experiment calls for further research into the possibility of using this technique for the continuous cooling of quantum computers6. We also anticipate that it will lead to explorations of entanglement in hybrid quantum systems and to fundamental studies of the decoherence of a single, locally controlled impurity particle coupled to a quantum environment7, 8.
• Shell-isolated nanoparticle-enhanced Raman spectroscopy
  - Nature 464(7287):392 (2010)
  Surface-enhanced Raman scattering (SERS) is a powerful spectroscopy technique that can provide non-destructive and ultra-sensitive characterization down to single molecular level, comparable to single-molecule fluorescence spectroscopy1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. However, generally substrates based on metals such as Ag, Au and Cu, either with roughened surfaces or in the form of nanoparticles, are required to realise a substantial SERS effect, and this has severely limited the breadth of practical applications of SERS. A number of approaches have extended the technique to non-traditional substrates14, 16, 17, most notably tip-enhanced Raman spectroscopy (TERS)18, 19, 20 where the probed substance (molecule or material surface) can be on a generic substrate and where a nanoscale gold tip above the substrate acts as the Raman signal amplifier. The drawback is that the total Raman scattering signal from the tip area is rather weak, thus limiting TERS! studies to molecules with large Raman cross-sections. Here, we report an approach, which we name shell-isolated nanoparticle-enhanced Raman spectroscopy, in which the Raman signal amplification is provided by gold nanoparticles with an ultrathin silica or alumina shell. A monolayer of such nanoparticles is spread as 'smart dust' over the surface that is to be probed. The ultrathin coating keeps the nanoparticles from agglomerating, separates them from direct contact with the probed material and allows the nanoparticles to conform to different contours of substrates. High-quality Raman spectra were obtained on various molecules adsorbed at Pt and Au single-crystal surfaces and from Si surfaces with hydrogen monolayers. These measurements and our studies on yeast cells and citrus fruits with pesticide residues illustrate that our method significantly expands the flexibility of SERS for useful applications in the materials and life sciences, as well as for the inspection ! of food safety, drugs, explosives and environment pollutants.
• Isotope fractionation in silicate melts by thermal diffusion
  - Nature 464(7287):396 (2010)
  The phenomenon of thermal diffusion (mass diffusion driven by a temperature gradient, known as the Ludwig–Soret effect1, 2) has been investigated for over 150 years, but an understanding of its underlying physical basis remains elusive. A significant hurdle in studying thermal diffusion has been the difficulty of characterizing it. Extensive experiments over the past century have established that the Soret coefficient, ST (a single parameter that describes the steady-state result of thermal diffusion), is highly sensitive to many factors3, 4, 5, 6, 7, 8, 9. This sensitivity makes it very difficult to obtain a robust characterization of thermal diffusion, even for a single material. Here we show that for thermal diffusion experiments that span a wide range in composition and temperature, the difference in ST between isotopes of diffusing elements that are network modifiers (iron, calcium and magnesium) is independent of the composition and temperature. On the basis of! this finding, we propose an additive decomposition for the functional form of ST and argue that a theoretical approach based on local thermodynamic equilibrium3, 5, 10 holds promise for describing thermal diffusion in silicate melts and other complex solutions. Our results lead to a simple and robust framework for characterizing isotope fractionation by thermal diffusion in natural and synthetic systems.
• Post-copulatory sexual selection and sexual conflict in the evolution of male pregnancy
  - Nature 464(7287):401 (2010)
  Male pregnancy in seahorses, pipefishes and sea dragons (family Syngnathidae) represents a striking reproductive adaptation that has shaped the evolution of behaviour and morphology in this group of fishes1, 2, 3, 4. In many syngnathid species, males brood their offspring in a specialized pouch, which presumably evolved to facilitate male parental care5, 6. However, an unexplored possibility is that brood pouch evolution was partly shaped by parent–offspring or sexual conflict, processes that would result in trade-offs between current and future pregnancies. Here we report a controlled breeding experiment using the sexually dimorphic Gulf pipefish, Syngnathus scovelli, to test for post-copulatory sexual selection within broods and for trade-offs between successive male pregnancies as functions of female attractiveness. Offspring survivorship within a pregnancy was affected by the size of a male's mate, the number of eggs transferred and the male's sexual responsi! veness. Significantly, we also found that embryo survivorship in a current pregnancy was negatively related to survivorship in the prior pregnancy, clearly demonstrating fitness trade-offs between broods. Overall, our data indicate that post-copulatory sexual selection and sexual conflict occur in Gulf pipefishes. The conflict seems to be mediated by a strategy of cryptic choice in which males increase rates of offspring abortion in pregnancies from unattractive mothers to retain resources for future reproductive opportunities. Hence, the male brood pouch of syngnathid fishes, which nurtures offspring7, 8, 9, also seems to have an important role as an arbiter of conflict between the sexes.
• ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C
  Fellay J Thompson AJ Ge D Gumbs CE Urban TJ Shianna KV Little LD Qiu P Bertelsen AH Watson M Warner A Muir AJ Brass C Albrecht J Sulkowski M McHutchison JG Goldstein DB - Nature 464(7287):405 (2010)
  Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality1. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects2. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.
• Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice
  Visel A Zhu Y May D Afzal V Gong E Attanasio C Blow MJ Cohen JC Rubin EM Pennacchio LA - Nature 464(7287):409 (2010)
  Sequence polymorphisms in a 58-kilobase (kb) interval on chromosome 9p21 confer a markedly increased risk of coronary artery disease (CAD), the leading cause of death worldwide1, 2. The variants have a substantial effect on the epidemiology of CAD and other life-threatening vascular conditions because nearly one-quarter of Caucasians are homozygous for risk alleles. However, the risk interval is devoid of protein-coding genes and the mechanism linking the region to CAD risk has remained enigmatic. Here we show that deletion of the orthologous 70-kb non-coding interval on mouse chromosome 4 affects cardiac expression of neighbouring genes, as well as proliferation properties of vascular cells. Chr4Δ70kb/Δ70kb mice are viable, but show increased mortality both during development and as adults. Cardiac expression of two genes near the non-coding interval, Cdkn2a and Cdkn2b, is severely reduced in chr4Δ70kb/Δ70kb mice, indicating that distant-acting gene regulatory f! unctions are located in the non-coding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of chr4Δ70kb/Δ70kb aortic smooth muscle cells exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Taken together, our results provide direct evidence that the CAD risk interval has a pivotal role in regulation of cardiac Cdkn2a/b expression, and suggest that this region affects CAD progression by altering the dynamics of vascular cell proliferation.
• An intrinsic vasopressin system in the olfactory bulb is involved in social recognition
  Tobin VA Hashimoto H Wacker DW Takayanagi Y Langnaese K Caquineau C Noack J Landgraf R Onaka T Leng G Meddle SL Engelmann M Ludwig M - Nature 464(7287):413 (2010)
  Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours1. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader–Willi syndrome, affective disorders and obsessive–compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism2, 3. Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The ! findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.
• Differential innate immune signalling via Ca2+ sensor protein kinases
  Boudsocq M Willmann MR McCormack M Lee H Shan L He P Bush J Cheng SH Sheen J - Nature 464(7287):418 (2010)
  Innate immunity represents the first line of inducible defence against microbial infection in plants and animals1, 2, 3. In both kingdoms, recognition of pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs, respectively), such as flagellin, initiates convergent signalling pathways involving mitogen-activated protein kinase (MAPK) cascades and global transcriptional changes to boost immunity1, 2, 3, 4. Although Ca2+ has long been recognized as an essential and conserved primary mediator in plant defence responses, how Ca2+ signals are sensed and relayed into early MAMP signalling is unknown5, 6. Using a functional genomic screen and genome-wide gene expression profiling, here we show that four calcium-dependent protein kinases (CDPKs) are Ca2+-sensor protein kinases critical for transcriptional reprogramming in plant innate immune signalling. Unexpectedly, CDPKs and MAPK cascades act differentially in four MAMP-mediated regulatory programs to control earl! y genes involved in the synthesis of defence peptides and metabolites, cell wall modifications and redox signalling. Transcriptome profile comparison suggests that CDPKs are the convergence point of signalling triggered by most MAMPs. Double, triple and quadruple cpk mutant plants display progressively diminished oxidative burst and gene activation induced by the 22-amino-acid peptide flg22, as well as compromised pathogen defence. In contrast to negative roles of calmodulin and a calmodulin-activated transcription factor in plant defence7, 8, the present study reveals Ca2+ signalling complexity and demonstrates key positive roles of specific CDPKs in initial MAMP signalling.
• Control of Arabidopsis apical–basal embryo polarity by antagonistic transcription factors
  Smith ZR Long JA - Nature 464(7287):423 (2010)
  Plants, similarly to animals, form polarized axes during embryogenesis on which cell differentiation and organ patterning programs are orchestrated. During Arabidopsis embryogenesis, establishment of the shoot and root stem cell populations occurs at opposite ends of an apical–basal axis. Recent work has identified the PLETHORA (PLT) genes as master regulators of basal/root fate1, 2, 3, whereas the master regulators of apical/shoot fate have remained elusive. Here we show that the PLT1 and PLT2 genes are direct targets of the transcriptional co-repressor TOPLESS (TPL) and that PLT1/2 are necessary for the homeotic conversion of shoots to roots in tpl-1 mutants. Using tpl-1 as a genetic tool, we identify the CLASS III HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIP III) transcription factors as master regulators of embryonic apical fate, and show they are sufficient to drive the conversion of the embryonic root pole into a second shoot pole. Furthermore, genetic and misexpression ! studies show an antagonistic relationship between the PLT and HD-ZIP III genes in specifying the root and shoot poles.
• RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
  Poulikakos PI Zhang C Bollag G Shokat KM Rosen N - Nature 464(7287):427 (2010)
  Tumours with mutant BRAF are dependent on the RAF–MEK–ERK signalling pathway for their growth1, 2, 3. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF–CRAF) or heterodimers (CRAF–BRAF) inhibits one protomer, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that ! RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation of wild-type RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS.
• RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
  Hatzivassiliou G Song K Yen I Brandhuber BJ Anderson DJ Alvarado R Ludlam MJ Stokoe D Gloor SL Vigers G Morales T Aliagas I Liu B Sideris S Hoeflich KP Jaiswal BS Seshagiri S Koeppen H Belvin M Friedman LS Malek S - Nature 464(7287):431 (2010)
  Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects1. Small molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK2, 3. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF–MEK–ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor! binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS–GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.
• Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal
  Sotillo R Schvartzman JM Socci ND Benezra R - Nature 464(7287):436 (2010)
  Inhibition of an initiating oncogene often leads to extensive tumour cell death, a phenomenon known as oncogene addiction1. This has led to the search for compounds that specifically target and inhibit oncogenes as anticancer agents. However, there has been no systematic exploration of whether chromosomal instability generated as a result of deregulation of the mitotic checkpoint pathway2, 3, a frequent characteristic of solid tumours, has any effect on oncogene addiction. Here we show that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 in mice does not affect the regression of Kras-driven lung tumours when Kras is inhibited. However, tumours that experience transient Mad2 overexpression and consequent chromosome instability recur at markedly elevated rates. The recurrent tumours are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early chromosomal instability may be responsible for tumour rela! pse after seemingly effective anticancer treatments.
• Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome
  Neumann H Wang K Davis L Garcia-Alai M Chin JW - Nature 464(7287):441 (2010)
  The in vivo, genetically programmed incorporation of designer amino acids allows the properties of proteins to be tailored with molecular precision1. The Methanococcus jannaschii tyrosyl-transfer-RNA synthetase–tRNACUA (MjTyrRS–tRNACUA)2, 3 and the Methanosarcina barkeri pyrrolysyl-tRNA synthetase–tRNACUA (MbPylRS–tRNACUA)4, 5, 6 orthogonal pairs have been evolved to incorporate a range of unnatural amino acids in response to the amber codon in Escherichia coli1, 6, 7. However, the potential of synthetic genetic code expansion is generally limited to the low efficiency incorporation of a single type of unnatural amino acid at a time, because every triplet codon in the universal genetic code is used in encoding the synthesis of the proteome. To encode efficiently many distinct unnatural amino acids into proteins we require blank codons and mutually orthogonal aminoacyl-tRNA synthetase–tRNA pairs that recognize unnatural amino acids and decode the new codons. H! ere we synthetically evolve an orthogonal ribosome8, 9 (ribo-Q1) that efficiently decodes a series of quadruplet codons and the amber codon, providing several blank codons on an orthogonal messenger RNA, which it specifically translates8. By creating mutually orthogonal aminoacyl-tRNA synthetase–tRNA pairs and combining them with ribo-Q1 we direct the incorporation of distinct unnatural amino acids in response to two of the new blank codons on the orthogonal mRNA. Using this code, we genetically direct the formation of a specific, redox-insensitive, nanoscale protein cross-link by the bio-orthogonal cycloaddition of encoded azide- and alkyne-containing amino acids10. Because the synthetase–tRNA pairs used have been evolved to incorporate numerous unnatural amino acids1, 6, 7, it will be possible to encode more than 200 unnatural amino acid combinations using this approach. As ribo-Q1 independently decodes a series of quadruplet codons, this work provides foundational te! chnologies for the encoded synthesis and synthetic evolution o! f unnatural polymers in cells.
• Structural basis for receptor recognition of vitamin-B12–intrinsic factor complexes
  - Nature 464(7287):445 (2010)
  Cobalamin (Cbl, vitamin B12) is a bacterial organic compound and an essential coenzyme in mammals, which take it up from the diet. This occurs by the combined action of the gastric intrinsic factor (IF) and the ileal endocytic cubam receptor formed by the 460-kilodalton (kDa) protein cubilin and the 45-kDa transmembrane protein amnionless1, 2. Loss of function of any of these proteins ultimately leads to Cbl deficiency in man3, 4. Here we present the crystal structure of the complex between IF–Cbl and the cubilin IF–Cbl-binding-region (CUB5–8)5 determined at 3.3 Å resolution. The structure provides insight into how several CUB (for 'complement C1r/C1s, Uegf, Bmp1') domains collectively function as modular ligand-binding regions, and how two distant CUB domains embrace the Cbl molecule by binding the two IF domains in a Ca2+-dependent manner. This dual-point model provides a probable explanation of how Cbl indirectly induces ligand–receptor coupling. Fina! lly, the comparison of Ca2+-binding CUB domains and the low-density lipoprotein (LDL) receptor-type A modules suggests that the electrostatic pairing of a basic ligand arginine/lysine residue with Ca2+-coordinating acidic aspartates/glutamates is a common theme of Ca2+-dependent ligand–receptor interactions.
• Expectancy theory
  - Nature 464(7287):456 (2010)
  Wishful thinking.