Hot off the presses! Sep 24 Nature

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Latest Articles Include:

• What's wrong with UNESCO
  - Nature 461(7263):447 (2009)
  The new director-general needs to buck all expectations and transform the agency.
• Earth's boundaries?
  - Nature 461(7263):447 (2009)
  An attempt to quantify the limits of humanity's load on our planet opens an important debate.
• Biobanks need pharma
  - Nature 461(7263):448 (2009)
  Which is why Europe's citizens need reassurance that their donations will be in the public interest.
• Glaciology: Getting thinner faster
  - Nature 461(7263):450 (2009)
  
• Immunology: Natural born killers
  - Nature 461(7263):450 (2009)
  
• Systems biology: Metabolic map
  - Nature 461(7263):450 (2009)
  
• Evolution: Armed and dangerous
  - Nature 461(7263):450 (2009)
  
• Behavioural science: Jelly shots and jackpots
  - Nature 461(7263):450 (2009)
  
• Neurobiology: Shocktopus
  - Nature 461(7263):451 (2009)
  
• Gene therapy: Panning for phage
  - Nature 461(7263):451 (2009)
  
• Evolutionary biology: Well endowed
  - Nature 461(7263):451 (2009)
  
• Analytical chemistry: Evaporating flesh
  - Nature 461(7263):451 (2009)
  
• Aquatic toxicology: Mixed-up fish
  - Nature 461(7263):451 (2009)
  
• Journal club
  - Nature 461(7263):451 (2009)
  
• Correction
  - Nature 461(7263):451 (2009)
  The Research Highlight 'Aluminium arches' (Nature 461, 318; 2009) incorrectly referred to an aluminium powder used in the experiment. In fact, an aluminium oxide powder, alumina, was used.
• News briefing: 24 September 2009
  - Nature 461(7263):452 (2009)
  The week in science This article is best viewed as a PDF. Policy|Business|Research|Events|Awards|The week ahead|News maker|Number crunch Europe will have a , European Commission President José Manuel Barroso has promised. He made the pledge in a 15 September speech at the opening of the newly elected European Parliament, which also voted to extend his presidency for a second term. Barroso added that he would review the way the commission uses scientific advice — a move welcomed by researchers. For more, see http://tinyurl.com/chiefscientist Hydrofluorocarbons (HFCs) inched closer to regulation as greenhouse gases under the , after the joined a growing movement to amend the treaty. HFCs, which are used as refrigerants, were introduced to replace chemicals that destroy stratospheric ozone. Their regulation falls under the United Nations climate framework, but many say they could be phased out faster and more cheaply using the Montreal ozone treaty. The issue could be decided as early as November, when Montreal Protocol delegates convene in Egypt for their annual meeting. For more, see http://tinyurl.com/hfccurb Nine countries have pledged to share up to 10% of their pandemic H1N1 flu vaccines with . Australia, Brazil, France, Italy, New Zealand, Norway, Switzerland, the United States and Britain all said they would make vaccines available through the World Health Organization, which has been asking for such donations. The US National Research Council called last week for a new inter-agency, multidisciplinary life-sciences programme that would tackle problems in the fields of food, environment, energy and health. The should be supported by new dedicated funding, not from existing agency research budgets, the report from the Board on Life Sciences urged. Report co-author Keith Yamamoto of the University of California, San Francisco, estimates that at least US$2 billion per year should be earmarked for the scheme. Details of a new way to assess the quality of research in UK universities were published for consultation on 23 September. The proposed will inform decisions on how to carve up around £1.76 billion (US$2.9 billion) per year between institutions, and will use bibliometrics — such as citation counts — to aid peer-reviewed judgements of work quality. It is due to come into force in 2013, replacing the Research Assessment Exercise. For more, see http://tinyurl.com/resframe. Ahead of United Nations climate meetings in preparation for the Copenhagen summit, a flurry of reports warned last week of the impact of climate change on the developing world. Alongside calls for strong political leadership came the World Bank 2010 Development Report , a biennial assessment which estimated that poor nations would need more than US$500 billion a year to adapt to climate change and develop low-carbon technology — in line with earlier UN estimates. And in a letter to the British Medical Journal and The Lancet, doctors warned of a "global health catastrophe" resulting from climate change — with effects ranging from widespread malnutrition to the spread of tropical diseases. The biotherapeutics firm in Rockville, Maryland, has received permission from the US Food and Drug Administration to inject neural stem cells into the spinal cords of 12 patients with amyotrophic lateral sclerosis (Lou Gehrig's disease). The trials — the first stem-cell approach for the condition — will focus on safety rather than efficacy, and are expected to take place at Emory University, Georgia, subject to approval from the university's patient-safety board. For more, see http://tinyurl.com/Neuralstem SOURCE: EIA The US geothermal industry is anticipating a boost in investment, as the Department of Energy prepares to announce recipients of US$400 million in stimulus grants for research and demonstration projects in the sector. Geothermal energy is a consistent source of clean power, but electricity investors are not used to risking the large up-front cost of exploratory drilling. The department's money will "help drill a lot of holes", says Ethan Zindler, of consultants New Energy Finance in London. Geothermal's contribution to US electricity generation (see chart) has been constant for more than a decade. But the country's 3 gigawatts of installed capacity — the largest of any nation — could double over the next ten years if projects already planned work out, says Karl Gawell, executive director of the Geothermal Energy Association in Washington DC. In July, Magma Energy, based in Vancouver, Canada, raised more than Can$110 million (US$103 million) in an initial public offering. Private geothermal developer Ram Power, in Reno, Nevada, raised Can$180 million by private subscriptions and is expecting to merge with three Canadian geothermal firms. But in California, a US$17-million project was halted earlier this month after operator AltaRock Energy in Sausalito encountered problems at its drilling site. The head of research at the (ETH), Zurich, has resigned over concerns that spectroscopic data published by his research group in 1999 and 2000 had been faked. Peter Chen, a physical organic chemist, stepped down as vice-president for research after a commission that he had requested in January concluded that two papers and a doctoral thesis contained falsified data. Chen denies any involvement in handling the data and is retaining his post as a professor. For more, see http://tinyurl.com/eth-resig The (NIH) began accepting applications on 21 September to evaluate which human embryonic stem cells will be eligible for federal dollars. A panel of nine scientists, lawyers and ethicists will check that the submissions meet new requirements for informed consent from embryo donors. The working group has not yet appraised any cell lines — including the 21 lines approved under former US President George W. Bush, which must be reassessed — and will start considering particular lines after scientists submit their petitions on the NIH website. A molecular geneticist at the died on 13 September after exposure to an attenuated strain of Yersinia pestis, the bacterium that causes plague. Malcolm Casadaban, 60, was working with a strain of the bacterium that has been used in vaccines in some countries and is approved by the US Centers for Disease Control and Prevention in Atlanta, Georgia, for laboratory studies. He died about 12 hours after being admitted to hospital. The bacterium was not identified as the cause of death until 18 September. The Planck telescope enjoyed a successful test run, said the (ESA), as it geared up to map the sky's cosmic microwave background. ESA reported on 17 September that preliminary results showed excellent data quality. are collaborating on stem-cell research. The California Institute for Regenerative Medicine and the German Federal Ministry of Education and Research announced plans last week to work together on joint research projects, focusing on immunology. The agreement makes it easier for researchers in both jurisdictions to apply for joint funding. The California stem-cell agency already has international collaborations with Australia, Canada, Japan, Spain and the United Kingdom. Gérard de Nazelle, a former global manager for research and innovation at Shell, has been appointed the first director of the European Institute of Innovation and Technology, at its Budapest headquarters. S. FLOOD/GETTY Arctic sea ice has reached its third-lowest level since satellite radar measurements began in 1979. Scientists with the University of Colorado's National Snow and Ice Data Center in Boulder announced on 17 September that the sea-ice extent of 5.1 million square kilometres observed on 12 September was the low point for the year. This year's minimum is higher than in both 2007 and 2008, but does not indicate any reversal in a marked 30-year decline in summertime ice extent, scientists said. For more, see http://tinyurl.com/seaicelow This year's winners, announced on 17 September, were , now at the University of Texas at Austin, and at Stanford University, California, and previously director of the Los Alamos National Laboratory in New Mexico. They share US$375,000. Goodenough developed cathode materials for the lithium-ion rechargeable battery; Hecker was cited for his research on plutonium metallurgy, and his leadership on global nuclear non-proliferation. The United Nations Framework convention on climate change holds its fourth round of international climate talks this year, this time in Bangkok. → http://tinyurl.com/climatetalks A US National Academy of Sciences panel releases a report on security and screening measures for labs working with biological agents and toxins. By the end of the US government's fiscal year, the National Institutes of Health will have allocated a considerable chunk of its allotted US$10.4 billion in stimulus funds. A rush of grant announcements is due. LAWRENCE BERKELEY NATL LAB. The director of the environmental energy department at Lawrence Berkeley National Laboratory in California has been nominated to head the US Advanced Research Projects Agency-Energy. The aviation industry pledged to halve its carbon dioxide emissions from 2005 levels by 2050 at the United Nations' climate summit in New York There are currently no comments.
• Buoy damage blurs El Niño forecasts
  - Nature 461(7263):455 (2009)
  More than half a dozen oceanographic buoys are missing in action in the eastern Pacific Ocean. The US National Oceanic and Atmospheric Administration (NOAA) has dispatched a ship to fix the malfunctioning buoys, which are part of the 55-strong Tropical Atmosphere Ocean (TAO) array that monitors the ocean and atmosphere. There are currently no comments.
• German science looks to new political players
  - Nature 461(7263):456 (2009)
  Science budgets in Germany have flourished under the current government led by Chancellor Angela Merkel. And despite the gloomy economic climate, the 27 September parliamentary elections seem unlikely to change that. There are currently no comments.
• Genomics shifts focus to rare diseases
  - Nature 461(7263):458 (2009)
  Disappointing genome-wide studies prompt researchers to tackle single-gene defects. Hugh Rienhoff sequenced family transcriptomes to try to diagnose his daughter Bea's genetic disease.H. RIENHOFF Genome sequencing may finally be living up to its promise of pinpointing genetic mutations that bear on treatment for individual patients. But the breakthroughs are not coming from the DNA analysis of common diseases with complex genetic origins, which has been the obsession of genomics for nearly the past decade. Instead, many genome scientists are turning back to study rare disorders that are traceable to defects in single genes, and whose causes have remained a mystery. The change is partly a result of frustration with the disappointing results of genome-wide association studies (GWAS). Rather than sequencing whole genomes, GWAS studies examine a subset of DNA variants in thousands of unrelated people with common diseases. Now, however, sequencing costs are dropping, and whole genome sequences can quickly provide in-depth information about individuals, enabling scientists to locate genetic mutations that underlie rare diseases by sequencing a handful of people. "Years ago, people were using families and mapping approaches to distil down to a region where they thought a causative gene was," says Elaine Mardis, a director of the Genome Sequencing Center at Washington University in St Louis, Missouri. "Fast-forward 12 years, and you've got sort of the same thing going on, except with new technology that gives us much higher resolution and speed." The change was showcased at the second Personal Genomes meeting, held in Cold Spring Harbor, New York, last week. At the same meeting last year, most speakers focused on the genome of scientist James Watson — one of only four fully sequenced individuals available at that time (see Nature 455, 1014; 2008). Now, about 50 individual genomes are published or in production, many of mostly anonymous patients with medical needs, estimates Richard Gibbs, director of the Human Genome Sequencing Center at Baylor College of Medicine in Houston, Texas. The first genomes of patients came in cancer, but scientists are now quickly moving into less high-profile diseases. For instance, together with Baylor's James Lupski, Gibbs reported that they had sequenced the genomes of patients in one family with a familial neuropathy — a disorder marked by muscle weakness and pain — and found defects in a single gene that could account for the family's condition. Matthew Bainbridge, a student in Gibbs's lab, reported that he had found a genetic glitch that is probably responsible for an inherited form of ataxia, a disorder affecting bodily coordination, by sequencing the exome, or set of all protein-coding genes, of two distant relatives with the disease. And Jay Shendure of the University of Washington in Seattle used a separate exome-sequencing strategy to find the gene that could be responsible for Miller syndrome, marked by head and facial abnormalities. Meanwhile, Richard Lifton of Yale University in New Haven, Connecticut, reported a striking example of how genome sequencing can help patients. A doctor asked Lifton to study a sickly infant who appeared to have a kidney disease. But Lifton's group sequenced the exomes of the infant and some family members and found a genetic variant in a gene, called SLC26A3, that causes congenital chloride diarrhoea, a treatable disease. Lifton informed the doctor, who reported that, indeed, the infant had had hourly bouts of diarrhoea. "I now think that we're going to get there by understanding a whole lot of these Mendelian diseases." The meeting also heard from bioentrepreneur Hugh Rienhoff, a California father who has sequenced his daughter's transcriptome — the readout of protein templates expressed in her cells — as well as his wife's and his own to find the cause of her undiagnosed genetic disease (see http://tinyurl.com/mf6oxs). The effort has yielded a list of mutated genes that could cause her unique collection of symptoms, including long hands and feet and a cleft uvula, says Rienhoff, who trained as a clinical geneticist. He argues that studies like his are promising first steps to understanding more complex diseases. "First, let's figure out the diseases that are 100% genetic and then go after the diseases that aren't 100% genetic," he says, pointing out that there are about 3,000 Mendelian diseases — inherited disorders caused by defects in single genes — of which the genetic causes are not known. "It's the new new thing, which is old: studying the rare stuff because it bears on the common stuff," he says. "The issue is how we're going to understand the architecture of common disorders," agrees Gibbs. "Three or four years ago I thought it was going to be because of GWAS studies, but I now think that we're going to get there by understanding a whole lot of these Mendelian diseases." Leslie Biesecker, who heads the ClinSeq study at the National Human Genome Research Institute in Bethesda, Maryland, is uncovering evidence to support that idea. ClinSeq has enrolled 725 patients and sequenced 251 of their genes, including two genes that, when mutated, cause familial hypercholesterolaemia (FH), a disease marked by high cholesterol levels. In seven patients with high cholesterol, Biesecker found mutations in the two FH genes, even though some of the patients had not been diagnosed with the condition. Biesecker estimates that 75–100 family members of these patients probably have undiagnosed FH, and is trying to contact them. "If we can leverage the finding to diagnose and treat 75–100 people for FH, I can go to bed at night feeling like our sequencing money has been well spent," he says. Plummeting prices Cost is still a roadblock to broader sequencing, however, so scientists at the meeting were interested in a report from collaborators of Complete Genomics, of Mountain View, California, which says it will dramatically cut the price of sequencing by offering human-genome sequences for US$5,000 next year. The company sequenced a family of four people for $20,000 apiece, including two children with undiagnosed symptoms, for the Institute for Systems Biology in Seattle, Washington, whose founder, Lee Hood, is on Complete Genomics' scientific advisory board. Lee Rowen, a researcher at the institute, said that its analysis of Complete Genomics' data has yielded three candidate genes for the children's disorders. "We were happy with what they gave us," Rowen says. However, she also estimates that there could be roughly 10–20 errors per megabase of DNA, which would translate to tens of thousands of errors per genome. The group is resequencing each error to try to pinpoint the error rate more closely. That left many in the audience unsatisfied. "What use is a $20,000 genome if you have to spend even more money to figure out if it's right or not?" Mardis said. Some contenders in the crowded sequencing field hope to ultimately push costs as low as hundreds of dollars per genome. Until then, the ultimate payoff on the promise of genomics — a true understanding of common diseases — remains over the horizon. But for now, a down payment appears to have been made. There are currently no comments.
• The elephant and the neutrino
  - Nature 461(7263):459 (2009)
  Conservationists challenge physics observatory in Indian wildlife reserve. Big hurdles for India's neutrino-detection lab.T. & P. LEESON/ARDEA.COM India's environment minister Jairam Ramesh will visit the site of a proposed underground neutrino laboratory next month, to try to break the impasse between physicists and environmentalists over its construction. The US$160-million India-based Neutrino Observatory (INO) was to have been completed by 2012 to study the elusive particles known as neutrinos (see Nature 450, 13; 2007). But its construction is mired in controversy over the wisdom of locating the facility in prime elephant and tiger habitat at Singara in the Nilgiri Biosphere Reserve, 250 kilometres south of Bangalore. The observatory applied for permission to begin construction at the Singara site in 2006; "there has been no reply to date," says project spokesman Naba Mondal, a physicist at the Tata Institute of Fundamental Research in Mumbai. "All I know is we have not cleared it," says A. S. Balanathan, principal chief conservator of forest for the state of Tamil Nadu, who declined to comment further. Last month, 11 leading physicists, including Nobel laureates Sheldon Glashow and Masatoshi Koshiba, wrote to India's prime minister Manmohan Singh urging that the project move forward. "The INO will bring more big science to India and enhance India's role as an important player in front-line science," they wrote. Meanwhile, prominent Indian conservationists are circulating and signing a letter laying out their concerns and asking that the observatory be sited elsewhere. The Nilgiri reserve includes more than 5,500 square kilometres of continuous forest cover and six protected areas. The proposed location for the INO comes as close as 7 kilometres to the edge of one of the sanctuaries. The project involves digging out a 120-metre-long cavern at the end of a 2-kilometre-long tunnel inside a mountain. The cavern will house a magnetized iron calorimeter to detect the muons that are produced occasionally when neutrinos interact with matter. The controversy stems from disagreements over the impact of the tunnelling and the increased human population on the fragile ecosystem. "Transporting the estimated 630,000 tonnes of debris and 147,000 tonnes of construction material would require about 156,000 truck trips through 35 kilometres of forest — and two tiger reserves," says the NBR Alliance, a group of Indian organizations concerned about the reserve. This means 468,000 hours of disturbance to animal movement routes, the alliance estimates. The INO team "could hardly have picked a site in India more likely to damage wildlife," says John Seed, an Australian environmentalist who has researched elephant habitats in India. "As well as being home to the largest single population of Asian elephants in the world," he says, "the Nilgiri is also one of the most important tiger habitats in the country." Mondal disputes the tally of construction debris and says that the project will limit the number of daily truck trips and restrict them to daytime. But Priya Davidar, an ecologist at Pondicherry University, says that the environmental impact assessment the project submitted to state officials is seriously flawed. Davidar is president of the Association for Tropical Biology and Conservation, based in Washington DC, which passed its own resolution urging the Indian government not to permit construction and to look for an alternative site. Davidar criticizes the project for limiting its search to only two sites; a better location, she says, would have been the Kolar gold mine in neighbouring Karnataka state, used for neutrino detection in 1965. But the Kolar mine is now closed and filled with water, and is not suitable for lowering heavy materials down, says Mondal. He says that after considering other sites, his team, along with the Geological Survey of India, identified Singara as "the best available site for locating the INO, based on safety, seismicity, as well as year-round accessibility". The minister will visit on 10 October. If a construction permit is denied, INO may have to start looking for another site.
• Gold rush for algae
  - Nature 461(7263):460 (2009)
  No longer lowly pond scum, algae have rocketed in status to what some say is the most promising 'green' fuel source of the future. With the likes of Bill Gates, the US military and ExxonMobil trumpeting their potential, "it's hard to find someone on the sidewalk in New York who hasn't heard about the idea of using algae for energy," says Harrison Dillon, president and chief technology officer of Solazyme, a biotechnology company in South San Francisco, California. There are currently no comments.
• Correction
  - Nature 461(7263):461 (2009)
  The Editorial 'Data's shameful neglect' (Nature 461, 145; 2009) stated that the Joint Information Systems Committee was established by the seven UK research councils. It was, in fact, established by the three Higher Education Funding Councils. There are currently no comments.
• Physics: The edge of physics
  - Nature 461(7263):462 (2009)
  Working at the Perimeter Institute for Theoretical Physics comes with certain perquisites. Whenever recruits arrive at the Toronto airport, for example, they are met by a limousine and driven west along Canada's Route 401 into the rich farmlands of Ontario. There are currently no comments.
• Atmospheric science: Cloudy, with a chance of science
  - Nature 461(7263):466 (2009)
  The meteorological bureau in the sleepy town of Shouxian in eastern China was buzzing with excitement. It was May 2008, and the spacious courtyard was littered with sophisticated remote-sensing instruments that had just arrived on loan from the United States Department of Energy (DoE). There are currently no comments.
• Luxury bushmeat trade threatens lemur conservation
  - Nature 461(7263):470 (2009)
  Shocking new proof of an emerging trade in lemur bushmeat in Madagascar (see http://tinyurl.com/mqsx7w) is refocusing attention on the conservation and health challenges in one of the world's most important biodiversity hotspots.
• A communication wipeout by gabbling presenters
  - Nature 461(7263):470 (2009)
  I have noticed a trend among speakers at scientific conferences to speed up their oral presentations so that they can compress as much information as possible into their allocated time slots. Talking so fast can create a problem for those in the audience whose native language is not the one being used by the speaker — almost invariably English on today's stage.
• Politics and priorities behind Greek research reforms
  - Nature 461(7263):470 (2009)
  In your News story 'Greek scientists fight research shake-up' (Nature460, 671; 2009), you indicate that research at the National Hellenic Research Foundation (NHRF) was judged to be generally poor during government-backed evaluations in 2001 and 2005. This is not the case.
• Overzealous use of decimal places has wrong kind of impact
  - Nature 461(7263):470 (2009)
  Scientists teach students to evaluate critically the significance of their measurements, and to eschew meaningless decimal places thrown up when pocket calculators work out a quotient of two integers. So what are we to make of the recently released impact factors, including Nature's much advertised rating of '31.
• A safe operating space for humanity
  - Nature 461(7263):472 (2009)
  Identifying and quantifying planetary boundaries that must not be transgressed could help prevent human activities from causing unacceptable environmental change, argue Johan Rockström and colleagues.
• The younger Oppenheimer
  - Nature 461(7263):476 (2009)
  Frank Oppenheimer founded the San Francisco Exploratorium: his charisma and passion for science education made him as influential, if not as famous, as his brother, explains Robert Crease.
• Howard's end at Perimeter
  - Nature 461(7263):477 (2009)
  The goal of First Principles is good: Howard Burton, founding director of the Perimeter Institute for Theoretical Physics, relates the setting up of the institute in Waterloo, Ontario, Canada, following a donation exceeding Can$100 million by Mike Lazaridis, creator of the BlackBerry, in 1999. But the book's self-congratulatory tone is a major snag.
• A floating island of sustainability
  - Nature 461(7263):478 (2009)
  In 1970, the artist Robert Smithson proposed his Floating Island, a commercial shipping barge full of earth and covered in trees that he wanted to have towed around Manhattan island as if to mock its giddy, man-made skyline. In New York this summer, the artist Mary Mattingly turned the idea into reality on a rented barge almost 300 metres square.
• Correction
  - Nature 461(7263):478 (2009)
  The Book Review 'Like minds can be small minds' (Nature 461, 40–41; 2009) incorrectly stated that US voters are now more likely to declare themselves Independents than they were "a century ago".
• Archaeology: Maya, Khmer and Inca
  - Nature 461(7263):479 (2009)
  Past societies have struggled against environmental problems similar to those that beset us today. Three publications illuminate the outcomes for three different tropical civilizations during the period AD 700–1600.
• Developmental biology: Rise of the source–sink model
  - Nature 461(7263):480 (2009)
  Gradients of signalling molecules dictate where specific cell types form in developing tissues, but how these gradients are set up is much debated. A model proposed 40 years ago by Francis Crick may provide an answer.
• Climate change: The El Niño with a difference
  - Nature 461(7263):481 (2009)
  Patterns of sea-surface warming and cooling in the tropical Pacific seem to be changing, as do the associated atmospheric effects. Increased global warming is implicated in these shifts in El Niño phenomena.
• Chemical biology: Caught in the activation
  - Nature 461(7263):484 (2009)
  A crystal structure reveals how a protein kinase is activated by the binding of a small molecule at a pocket far from the catalytic site. This opens the door to the design of modulators of protein phosphorylation.
• Astrophysics: Inner workings of a star
  - Nature 461(7263):485 (2009)
  By borrowing a technique used by seismologists to investigate Earth's interior, astronomers have probed the hitherto-unknown interior rotation profile of a white-dwarf star.
• Developmental biology: A bad boy comes good
  - Nature 461(7263):486 (2009)
  Reactive oxygen species are often blamed for the development of cancer and other diseases. Contrary to their 'bad boy' reputation, these species seem to be essential for the development of immune cells, at least in the fly.
• Human genetics: Tracing India's invisible threads
  - Nature 461(7263):487 (2009)
  One measure of the extraordinary level of human diversity found in India is the use of 15 languages on its banknotes. The genetic underpinnings of that population diversity are yielding to whole-genome analysis.
• Reconstructing Indian population history
  - Nature 461(7263):489 (2009)
  India has been underrepresented in genome-wide surveys of human variation. We analyse 25 diverse groups in India to provide strong evidence for two ancient populations, genetically divergent, that are ancestral to most Indians today. One, the 'Ancestral North Indians' (ANI), is genetically close to Middle Easterners, Central Asians, and Europeans, whereas the other, the 'Ancestral South Indians' (ASI), is as distinct from ANI and East Asians as they are from each other. By introducing methods that can estimate ancestry without accurate ancestral populations, we show that ANI ancestry ranges from 39–71% in most Indian groups, and is higher in traditionally upper caste and Indo-European speakers. Groups with only ASI ancestry may no longer exist in mainland India. However, the indigenous Andaman Islanders are unique in being ASI-related groups without ANI ancestry. Allele frequency differences between groups in India are larger than in Europe, reflecting strong founder! effects whose signatures have been maintained for thousands of years owing to endogamy. We therefore predict that there will be an excess of recessive diseases in India, which should be possible to screen and map genetically.
• A luminal epithelial stem cell that is a cell of origin for prostate cancer
  - Nature 461(7263):495 (2009)
  In epithelial tissues, the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer has been poorly understood. Here we show that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3-1, marks a stem cell population that functions during prostate regeneration. Genetic lineage-marking demonstrates that rare luminal cells that express Nkx3-1 in the absence of testicular androgens (castration-resistant Nkx3-1-expressing cells, CARNs) are bipotential and can self-renew in vivo, and single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3-1 mutant mice in serial prostate regeneration suggest that Nkx3-1 is required for stem cell maintenance. Furthermore, targeted deletion of the Pten tumour suppressor gene in CARNs results in rapid carcinoma formation after androgen-mediated regeneration. These observations indicate that CARNs represent a new lum! inal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.
• Seismic evidence for the loss of stellar angular momentum before the white-dwarf stage
  - Nature 461(7263):501 (2009)
  White-dwarf stars represent the final products of the evolution of some 95% of all stars1. If stars were to keep their angular momentum throughout their evolution, their white-dwarf descendants, owing to their compact nature, should all rotate relatively rapidly, with typical periods of the order of a few seconds. Observations of their photospheres show, in contrast, that they rotate much more slowly, with periods ranging from hours to tens of years2, 3, 4, 5. It is not known, however, whether a white dwarf could 'hide' some of its original angular momentum below the superficial layers, perhaps spinning much more rapidly inside than at its surface. Here we report a determination of the internal rotation profile of a white dwarf using a method based on asteroseismology. We show that the pulsating white dwarf PG 1159-035 rotates as a solid body (encompassing more than 97.5% of its mass) with the relatively long period of 33.61 0.59 h. This implies that it has lost essen! tially all of its angular momentum, thus favouring theories which suggest important angular momentum transfer and loss in evolutionary phases before the white-dwarf stage6, 7.
• Violation of Bell's inequality in Josephson phase qubits
  - Nature 461(7263):504 (2009)
  The measurement process plays an awkward role in quantum mechanics, because measurement forces a system to 'choose' between possible outcomes in a fundamentally unpredictable manner. Therefore, hidden classical processes have been considered as possibly predetermining measurement outcomes while preserving their statistical distributions1. However, a quantitative measure that can distinguish classically determined correlations from stronger quantum correlations exists in the form of the Bell inequalities, measurements of which provide strong experimental evidence that quantum mechanics provides a complete description2, 3, 4. Here we demonstrate the violation of a Bell inequality in a solid-state system. We use a pair of Josephson phase qubits5, 6, 7 acting as spin-1/2 particles, and show that the qubits can be entangled8, 9 and measured so as to violate the Clauser–Horne–Shimony–Holt (CHSH) version of the Bell inequality10. We measure a Bell signal of 2.0732 0.00! 03, exceeding the maximum amplitude of 2 for a classical system by 244 standard deviations. In the experiment, we deterministically generate the entangled state, and measure both qubits in a single-shot manner, closing the detection loophole11. Because the Bell inequality was designed to test for non-classical behaviour without assuming the applicability of quantum mechanics to the system in question, this experiment provides further strong evidence that a macroscopic electrical circuit is really a quantum system7.
• Stable isotope constraints on Holocene carbon cycle changes from an Antarctic ice core
  - Nature 461(7263):507 (2009)
  Reconstructions of atmospheric CO2 concentrations based on Antarctic ice cores1, 2 reveal significant changes during the Holocene epoch, but the processes responsible for these changes in CO2 concentrations have not been unambiguously identified. Distinct characteristics in the carbon isotope signatures of the major carbon reservoirs (ocean, biosphere, sediments and atmosphere) constrain variations in the CO2 fluxes between those reservoirs. Here we present a highly resolved atmospheric 13C record for the past 11,000 years from measurements on atmospheric CO2 trapped in an Antarctic ice core. From mass-balance inverse model calculations3, 4 performed with a simplified carbon cycle model, we show that the decrease in atmospheric CO2 of about 5 parts per million by volume (p.p.m.v.). The increase in 13C of about 0.25 during the early Holocene is most probably the result of a combination of carbon uptake of about 290 gigatonnes of carbon by the land biosphere and carbon r! elease from the ocean in response to carbonate compensation of the terrestrial uptake during the termination of the last ice age. The 20 p.p.m.v. increase of atmospheric CO2 and the small decrease in 13C of about 0.05 during the later Holocene can mostly be explained by contributions from carbonate compensation of earlier land-biosphere uptake and coral reef formation, with only a minor contribution from a small decrease of the land-biosphere carbon inventory.
• El Niño in a changing climate
  - Nature 461(7263):511 (2009)
  El Niño events, characterized by anomalous warming in the eastern equatorial Pacific Ocean, have global climatic teleconnections and are the most dominant feature of cyclic climate variability on subdecadal timescales. Understanding changes in the frequency or characteristics of El Niño events in a changing climate is therefore of broad scientific and socioeconomic interest. Recent studies1, 2, 3, 4, 5 show that the canonical El Niño has become less frequent and that a different kind of El Niño has become more common during the late twentieth century, in which warm sea surface temperatures (SSTs) in the central Pacific are flanked on the east and west by cooler SSTs. This type of El Niño, termed the central Pacific El Niño (CP-El Niño; also termed the dateline El Niño2, El Niño Modoki3 or warm pool El Niño5), differs from the canonical eastern Pacific El Niño (EP-El Niño) in both the location of maximum SST anomalies and tropical–midlatitude teleconnectio! ns. Here we show changes in the ratio of CP-El Niño to EP-El Niño under projected global warming scenarios from the Coupled Model Intercomparison Project phase 3 multi-model data set6. Using calculations based on historical El Niño indices, we find that projections of anthropogenic climate change are associated with an increased frequency of the CP-El Niño compared to the EP-El Niño. When restricted to the six climate models with the best representation of the twentieth-century ratio of CP-El Niño to EP-El Niño, the occurrence ratio of CP-El Niño/EP-El Niño is projected to increase as much as five times under global warming. The change is related to a flattening of the thermocline in the equatorial Pacific.
• An epistatic ratchet constrains the direction of glucocorticoid receptor evolution
  - Nature 461(7263):515 (2009)
  The extent to which evolution is reversible has long fascinated biologists1, 2, 3, 4, 5, 6, 7, 8. Most previous work on the reversibility of morphological and life-history evolution9, 10, 11, 12, 13 has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters14, 15. Further, despite theoretical work on the factors that could contribute to irreversibility1, 8, 16, there is little empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available3, 8, 17. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in the vertebrate glucocorticoid receptor as a case-study, that the evolutionary path by which this protein acquired its new function soon became inaccessible to reverse exploration. Using anc! estral gene reconstruction, protein engineering and X-ray crystallography, we demonstrate that five subsequent 'restrictive' mutations, which optimized the new specificity of the glucocorticoid receptor, also destabilized elements of the protein structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key function-switching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution.
• Population context determines cell-to-cell variability in endocytosis and virus infection
  - Nature 461(7263):520 (2009)
  Single-cell heterogeneity in cell populations arises from a combination of intrinsic and extrinsic factors1, 2, 3. This heterogeneity has been measured for gene transcription, phosphorylation, cell morphology and drug perturbations, and used to explain various aspects of cellular physiology4, 5, 6. In all cases, however, the causes of heterogeneity were not studied. Here we analyse, for the first time, the heterogeneous patterns of related cellular activities, namely virus infection, endocytosis and membrane lipid composition in adherent human cells. We reveal correlations with specific cellular states that are defined by the population context of a cell, and we derive probabilistic models that can explain and predict most cellular heterogeneity of these activities, solely on the basis of each cell's population context. We find that accounting for population-determined heterogeneity is essential for interpreting differences between the activity levels of cell populatio! ns. Finally, we reveal that synergy between two molecular components, focal adhesion kinase and the sphingolipid GM1, enhances the population-determined pattern of simian virus 40 (SV40) infection. Our findings provide an explanation for the origin of heterogeneity patterns of cellular activities in adherent cell populations.
• Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling
  - Nature 461(7263):524 (2009)
  The cerebral cortex is a laminated sheet of neurons composed of the arrays of intersecting radial columns1, 2, 3. During development, excitatory projection neurons originating from the proliferative units at the ventricular surface of the embryonic cerebral vesicles migrate along elongated radial glial fibres4 to form a cellular infrastructure of radial (vertical) ontogenetic columns in the overlaying cortical plate5. However, a subpopulation of these clonally related neurons also undergoes a short lateral shift and transfers from their parental to the neighbouring radial glial fibres6, and intermixes with neurons originating from neighbouring proliferative units5, 7. This columnar organization acts as the primary information processing unit in the cortex1, 8, 9. The molecular mechanisms, role and significance of this lateral dispersion for cortical development are not understood. Here we show that an Eph receptor A (EphA) and ephrin A (Efna) signalling-dependent shift! in the allocation of clonally related neurons is essential for the proper assembly of cortical columns. In contrast to the relatively uniform labelling of the developing cortical plate by various molecular markers and retrograde tracers in wild-type mice, we found alternating labelling of columnar compartments in Efna knockout mice that are caused by impaired lateral dispersion of migrating neurons rather than by altered cell production or death. Furthermore, in utero electroporation showed that lateral dispersion depends on the expression levels of EphAs and ephrin-As during neuronal migration. This so far unrecognized mechanism for lateral neuronal dispersion seems to be essential for the proper intermixing of neuronal types in the cortical columns, which, when disrupted, might contribute to neuropsychiatric disorders associated with abnormal columnar organization8, 10.
• Asymptomatic deer excrete infectious prions in faeces
  - Nature 461(7263):529 (2009)
  Infectious prion diseases1—scrapie of sheep2 and chronic wasting disease (CWD) of several species in the deer family3, 4—are transmitted naturally within affected host populations. Although several possible sources of contagion have been identified in excretions and secretions from symptomatic animals5, 6, 7, 8, the biological importance of these sources in sustaining epidemics remains unclear. Here we show that asymptomatic CWD-infected mule deer (Odocoileus hemionus) excrete CWD prions in their faeces long before they develop clinical signs of prion disease. Intracerebral inoculation of irradiated deer faeces into transgenic mice overexpressing cervid prion protein (PrP) revealed infectivity in 14 of 15 faecal samples collected from five deer at 7–11 months before the onset of neurological disease. Although prion concentrations in deer faeces were considerably lower than in brain tissue from the same deer collected at the end of the disease, the estimated total! infectious dose excreted in faeces by an infected deer over the disease course may approximate the total contained in a brain. Prolonged faecal prion excretion by infected deer provides a plausible natural mechanism that might explain the high incidence and efficient horizontal transmission of CWD within deer herds3, 4, 9, as well as prion transmission among other susceptible cervids.
• Fgf8 morphogen gradient forms by a source-sink mechanism with freely diffusing molecules
  - Nature 461(7263):533 (2009)
  It is widely accepted that tissue differentiation and morphogenesis in multicellular organisms are regulated by tightly controlled concentration gradients of morphogens1, 2. How exactly these gradients are formed, however, remains unclear3, 4, 5, 6, 7, 8, 9, 10, 11, 12. Here we show that Fgf8 morphogen gradients in living zebrafish embryos are established and maintained by two essential factors: fast, free diffusion of single molecules away from the source through extracellular space, and a sink function of the receiving cells, regulated by receptor-mediated endocytosis. Evidence is provided by directly examining single molecules of Fgf8 in living tissue by fluorescence correlation spectroscopy, quantifying their local mobility and concentration with high precision. By changing the degree of uptake of Fgf8 into its target cells, we are able to alter the shape of the Fgf8 gradient. Our results demonstrate that a freely diffusing morphogen can set up concentration gradie! nts in a complex multicellular tissue by a simple source-sink mechanism.
• Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation
  Owusu-Ansah E Banerjee U - Nature 461(7263):537 (2009)
  Reactive oxygen species (ROS), produced during various electron transfer reactions in vivo, are generally considered to be deleterious to cells1. In the mammalian haematopoietic system, haematopoietic stem cells contain low levels of ROS. However, unexpectedly, the common myeloid progenitors (CMPs) produce significantly increased levels of ROS2. The functional significance of this difference in ROS level in the two progenitor types remains unresolved2, 3. Here we show that Drosophila multipotent haematopoietic progenitors, which are largely akin to the mammalian myeloid progenitors4, display increased levels of ROS under in vivo physiological conditions, which are downregulated on differentiation. Scavenging the ROS from these haematopoietic progenitors by using in vivo genetic tools retards their differentiation into mature blood cells. Conversely, increasing the haematopoietic progenitor ROS beyond their basal level triggers precocious differentiation into all three ! mature blood cell types found in Drosophila, through a signalling pathway that involves JNK and FoxO activation as well as Polycomb downregulation. We conclude that the developmentally regulated, moderately high ROS level in the progenitor population sensitizes them to differentiation, and establishes a signalling role for ROS in the regulation of haematopoietic cell fate. Our results lead to a model that could be extended to reveal a probable signalling role for ROS in the differentiation of CMPs in mammalian haematopoietic development and oxidative stress response.
• A dimerization-dependent mechanism drives RAF catalytic activation
  Rajakulendran T Sahmi M Lefrançois M Sicheri F Therrien M - Nature 461(7263):542 (2009)
  The ERK (extracellular signal-regulated kinase) pathway is an evolutionarily conserved signal transduction module that controls cellular growth, differentiation and survival1. Activation of receptor tyrosine kinases (RTKs) by the binding of growth factors initiates GTP loading of RAS, which triggers the initial steps in the activation of the ERK pathway by modulating RAF family kinase function. Once activated, RAF participates in a sequential cascade of phosphorylation events that activate MEK, and in turn ERK. Unbridled signalling through the ERK pathway caused by activating mutations in RTKs, RAS or RAF has been linked to several human cancers2. Of note, one member of the RAF family, BRAF, is the most frequently mutated oncogene in the kinase superfamily3. Not surprisingly, there has been a colossal effort to understand the underlying regulation of this family of kinases. In particular, the process by which the RAF kinase domain becomes activated towards its substrat! e MEK remains of topical interest. Here, using Drosophila Schneider S2 cells, we demonstrate that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which we term the side-to-side dimer. Moreover, we find that the RAF-related pseudo-kinase KSR (kinase suppressor of Ras) also participates in forming side-to-side heterodimers with RAF and can thereby trigger RAF activation. This mechanism provides an elegant explanation for the longstanding conundrum about RAF catalytic activation, and also provides an explanation for the capacity of KSR, despite lacking catalytic function, to directly mediate RAF activation. We also show that RAF side-to-side dimer formation is essential for aberrant signalling by oncogenic BRAF mutants, and identify an oncogenic mutation that acts specifically by promoting side-to-side dimerization. Together, our data identify the side-to-side dimer interface of RAF as a potential therapeutic target for ! intervention in BRAF-dependent tumorigenesis.
• Active turnover modulates mature microRNA activity in Caenorhabditis elegans
  - Nature 461(7263):546 (2009)
  MicroRNAs (miRNAs) constitute a large class of regulatory RNAs that repress target messenger RNAs to control various biological processes1. Accordingly, miRNA biogenesis is highly regulated, controlled at both transcriptional and post-transcriptional levels2, and overexpression and underexpression of miRNAs are linked to various human diseases, particularly cancers1, 3. As RNA concentrations are generally a function of biogenesis and turnover, active miRNA degradation might also modulate miRNA accumulation, and the plant 3'5' exonuclease SDN1 has been implicated in miRNA turnover4. Here we report that degradation of mature miRNAs in the nematode Caenorhabditis elegans, mediated by the 5'3' exoribonuclease XRN-2, affects functional miRNA homeostasis in vivo. We recapitulate XRN-2-dependent miRNA turnover in larval lysates, where processing of precursor-miRNA (pre-miRNA) by Dicer, unannealing of the miRNA duplex and loading of the mature miRNA into the Argonaute protein ! of the miRNA-induced silencing complex (miRISC) are coupled processes that precede degradation of the mature miRNA. Although Argonaute:miRNA complexes are highly resistant to salt, larval lysate promotes efficient release of the miRNA, exposing it to degradation by XRN-2. Release and degradation can both be blocked by the addition of miRNA target RNA. Our results therefore suggest the presence of an additional layer of regulation of animal miRNA activity that might be important for rapid changes of miRNA expression profiles during developmental transitions and for the maintenance of steady-state concentrations of miRNAs. This pathway might represent a potential target for therapeutic intervention on miRNA expression.
• The nature of the globular- to fibrous-actin transition
  - Nature 461(7263):550 (2009)
  Nature 457, 441–445 (2009) In this Article, Figure 4a was incorrect. The correct figure is shown below. The results and conclusions of the Article are not affected.
• Reptilian heart development and the molecular basis of cardiac chamber evolution
  - Nature 461(7263):550 (2009)
  Nature 461, 95–98 (2009) In this Letter, author Laurel Beck was incorrectly listed as Laural Beck.
• Structural basis for leucine-rich nuclear export signal recognition by CRM1
  - Nature 461(7263):550 (2009)
  Nature 458, 1136–1141 (2009) In the first paragraph of this Article, Leu was incorrectly listed as Lys. The correct sentence is: "Several mutagenesis and computational studies have led to a consensus sequence -X(2–3)--X(2–3)--X- (in which is Leu, Val, Ile, Phe or Met, X is any amino acid, and the numbers in parentheses denote the number of repeats) that matches most known LR-NESs, but it is so broad that it is found in most helix-containing proteins17,18,19,20,21."
• A kiss isn't just a kiss
  - Nature 461(7263):558 (2009)
  Mouth-to-mouth resuscitation.