Hot off the presses! Jul 01 Nat Rev Cancer

The Jul 01 issue of the Nat Rev Cancer is now up on Pubget (About Nat Rev Cancer): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• From the editors
  - Nat Rev Cancer 10(7):449 (2010)
  The American Society of Clinical Oncology held its annual meeting at the start of June and reported several findings from a number of clinical trials investigating new targeted agents. Among these was a Phase III trial of an antibody, ipilimumab, which inhibits cytotoxic T lymphocyte antigen 4 (CTLA4).
• Tumorigenesis: Hormonally driven
  - Nat Rev Cancer 10(7):451 (2010)
  The ovarian hormones oestrogen and progesterone are inextricably linked to breast cancer. Not only do their levels influence disease risk and prognosis, but manipulating their activity also forms the basis for gold standard treatments.
• Metastasis: Pushing on through
  - Nat Rev Cancer 10(7):452 (2010)
  Metastasis is a complex process of which we still understand little, but the parallels between metastasis and cell invasion during development can give us some clues. During the development of a connection between uterine cells and vulval cells in the nematode Caenorhabditis elegans, one cell, the anchor cell (AC), has to invade through a basement membrane.
• Melanoma: Don't let sleeping cells lie
  - Nat Rev Cancer 10(7):452 (2010)
  Melanomas are heterogenous tumours that are highly metastastic, but patients with this disease can be cured if they are treated at an early stage before tumour cells colonize distant organs. Therefore, keeping the growth of primary tumours and metastases under control is one possible route to successful therapy.
• Therapy: An unhelpful hand
  - Nat Rev Cancer 10(7):453 (2010)
  Increased signalling through the insulin-like growth factor (IGF) pathway has been implicated in the progression of several types of human cancer. The IGF2 ligand is frequently overexpressed in colon and breast cancers, and inhibitors of one its receptors, IGF1 receptor (IGF1R), are in clinical trials.
• Transcription: We bonded — now make a decision
  - Nat Rev Cancer 10(7):454 (2010)
  p53 regulates the expression of genes involved in cell cycle arrest and apoptosis by binding to a DNA consensus sequence. Two recent papers by the groups of Thorsten Stiewe and Joaquín Espinosa provide insight into the mechanisms that influence the decision making between these two events.
• Mutation: It's the CpG content that counts
  - Nat Rev Cancer 10(7):454 (2010)
  The rate of neutral mutations — those that are not subject to natural selection — shows substantial variation, but the factors contributing to mutational rate have remained elusive. Now, new evidence indicates that the CpG content of DNA can influence the mutation rate of non-CpG-containing sequences, suggesting that the intrinsic properties of DNA sequences may be more important than the chromosomal environment in determining mutation rates and genome integrity.
• Oncogenes: Adding more to the Myc story
  - Nat Rev Cancer 10(7):455 (2010)
  The Myc family of transcription factors are well-known oncoproteins and three new studies contribute important insights into mechanisms of MYC regulation and the roles of MYCN in tumorigenesis and progression.Richard Young and colleagues demonstrate that MYC plays a key part in regulating transcriptional elongation by RNA polymerase II (Pol II).
• Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers
  - Nat Rev Cancer 10(7):457 (2010)
  Post-translational modification of histones provides an important regulatory platform for processes such as gene transcription and DNA damage repair. It has become increasingly apparent that the misregulation of histone modification, which is caused by the deregulation of factors that mediate the modification installation, removal and/or interpretation, actively contributes to human cancer. In this Review, we summarize recent advances in understanding the interpretation of certain histone methylations by plant homeodomain finger-containing proteins, and how misreading, miswriting and mis-erasing of histone methylation marks can be associated with oncogenesis and progression. These observations provide us with a greater mechanistic understanding of epigenetic alterations in human cancers and might also help direct new therapeutic interventions in the future.
• Non-germline genetically engineered mouse models for translational cancer research
  - Nat Rev Cancer 10(7):470 (2010)
  Genetically engineered mouse models (GEMMs) of cancer have affected virtually all areas of cancer research. However, the accelerated discovery of new cancer genes emerging from large-scale cancer genomics and new chemical entities pouring from the drug discovery pipeline have strained the capacity of traditional germline mouse models to provide crucial insights. This Review introduces new approaches to modelling cancer, with emphasis on a growing collection of non-germline GEMMs (nGEMMs). These offer flexibility, speed and uniformity at reduced costs, thus paving the way for much needed throughput and practical preclinical therapeutic testing models.
• Cartilage tumours and bone development: molecular pathology and possible therapeutic targets
  Bovée JV Hogendoorn PC Wunder JS Alman BA - Nat Rev Cancer 10(7):481 (2010)
  As a group, cartilage tumours are the most common primary bone lesions. They range from benign lesions, such as enchondromas and osteochondromas, to malignant chondrosarcoma. The benign lesions result from the deregulation of the hedgehog signalling pathway, which is involved in normal bone development. These lesions can be the precursors of malignant chondrosarcomas, which are notoriously resistant to conventional chemotherapy and radiotherapy. Cytogenetic studies and mouse models are beginning to identify genes and signalling pathways that have roles in tumour progression, such as hedgehog, p53, insulin-like growth factor, cyclin-dependent kinase 4, hypoxia-inducible factor, matrix metalloproteinases, SRC and AKT, suggesting potential new therapeutic approaches.
• Sphingosine 1-phosphate and cancer
  Pyne NJ Pyne S - Nat Rev Cancer 10(7):489 (2010)
  There is substantial evidence that sphingosine 1-phosphate (S1P) is involved in cancer. S1P regulates processes such as inflammation, which can drive tumorigenesis; neovascularization, which provides cancer cells with nutrients and oxygen; and cell growth and survival. This occurs at multiple levels and involves S1P receptors, sphingosine kinases, S1P phosphatases and S1P lyase. This Review summarizes current research findings and examines the potential for new therapeutics designed to alter S1P signalling and function in cancer.
• Targeting the tumour vasculature: insights from physiological angiogenesis
  - Nat Rev Cancer 10(7):505 (2010)
  The cardiovascular system ensures the delivery of nutrients, oxygen, and blood and immune cells to all organs and tissues: it is also responsible for the removal of waste metabolites. The vascular system develops and matures through two tightly regulated processes: vasculogenesis and angiogenesis. Angiogenesis is active only under specific physiological conditions in healthy adults but the vasculature can be aberrantly activated to generate new blood vessels during pathological conditions such as cancer and chronic inflammation. In this Opinion article we discuss the parallels and differences in the angiogenic process under either a physiological or a pathological state, especially tumorigenesis.
• Envisioning the future of early anticancer drug development
  Yap TA Sandhu SK Workman P de Bono JS - Nat Rev Cancer 10(7):514 (2010)
  The development of novel molecularly targeted cancer therapeutics remains slow and expensive with many late-stage failures. There is an urgent need to accelerate this process by improving early clinical anticancer drug evaluation through modern and rational trial designs that incorporate predictive, pharmacokinetic, pharmacodynamic, pharmacogenomic and intermediate end-point biomarkers. In this article, we discuss current approaches and propose strategies that will potentially maximize benefit to patients and expedite the regulatory approvals of new anticancer drugs.
• Correspondence: The ABC of glycosylation
  Perego P Gatti L Beretta GL - Nat Rev Cancer 10(7):523 (2010)
  We read with great interest the Opinion article by Jamie Fletcher and colleagues, ABC transporters in cancer: more than just drug efflux pumps. Nature Rev. Cancer. 10, 147–156 (2010)
• Correspondence: Breast and prostate cancer: familial associations
  - Nat Rev Cancer 10(7):523 (2010)
  In a recent Opinion article by Gail Risbridger and colleagues, Breast and prostate cancer: more similar than different (Nature Rev. Cancer 10, 205–212 (2010)), the extensive biological similarities of the hormone-dependant pathways of breast and prostate cancers were discussed1.
• Corrigendum: Genetic variation in microRNA networks: the implications for cancer research
  - Nat Rev Cancer 10(7):523 (2010)
  There were several mistakes in TABLES 1–3 of this article. In TABLE 1 on page 385, for rs2910164 in hepatocelluar carcinoma the odds ratio data refer to males only. For rs11614913 in lung cancer the odds ratio is for both sexes and not for males only. For rs11614913 in oesophageal cancer the reference genotype should be CC/CT and the analysed genotype should be TT. For rs11614913 in breast cancer the reference genotype should be CC and the analysed genotypes should be CT and then TT. For rs895819 in breast cancer the reference genotype should be CT. In TABLE 2 on page 396, for the SEDT8 alleles, the miRNA binds the derived alleles and not the ancestral alleles. For the BCTRP allele, the miRNA binds deletion alleles that are derived and not insertion alleles that are ancestral. For the BMPR1B allele, the miRNA binds the C allele and not the derived allele. For the CD86 allele, the miRNA binds the ancestral allele and not the derived allele. In TABLE 3 on page 398, the! odds ratio given for GEMIN4 rs7813 is for all cases of renal cell carcinoma, not just clear cell carcinoma as indicated. For GEMIN3 rs197414 the cancer site should be bladder and not renal cell carcinoma and the reference is 35 and not 111. This has been corrected online.

Hot off the presses! Jun 24 Nature

The Jun 24 issue of the Nature is now up on Pubget (About Nature): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• A pandemic of hindsight?
  - Nature (London) 465(7301):985 (2010)
  Nature | Editorial A pandemic of hindsight? Journal name:NatureVolume:465,Page:985Date published:(24 June 2010)DOI:doi:10.1038/465985aPublished online23 June 2010 We must learn lessons from the handling of the flu pandemic to improve future research and public-health responses to emerging diseases, but retrospective hindsight and recriminations are not the answer. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Late this week, the Council of Europe's parliamentary assembly, a 47-member-state body that promotes democracy and human rights in Strasbourg, France, is scheduled to vote on a resolution expressing alarm over the World Health Organization's (WHO's) handling of the H1N1 influenza pandemic. The council should think twice. In conversations with more than a dozen flu researchers and public-health officials from Australia, the United States, the United Kingdom and several other countries, Nature heard many objections to the conclusions of the report on which the resolution is based. Angus Nicoll, a senior influenza expert at the European Centre for Disease Prevention and Control (ECDC) in Stockholm, says that in the ECDC's opinion: "The conclusions of the report do not fit the facts as we see them, and as are backed up by science." Certainly, the council's inquiry into the pandemic started off by taking a strong angle, with a December 2009 parliamentary motion entitled 'Faked pandemics — a threat for health'. The motion asserted that "to promote their patented drugs and vaccines against flu, pharmaceutical companies have influenced scientists and official agencies, responsible for public health standards, to alarm governments worldwide". Similar ideas are reiterated in the inquiry's draft final report, which was adopted on 4 June by the council's health committee, and which also contains the resolution to be voted on this week (see http://go.nature.com/txThYG). "Drug firms 'encouraged world health body to exaggerate swine flu threat'," declared Britain's Daily Mail newspaper that day, in a typical headline. It is this kind of response that the WHO's defenders find so potentially damaging — not least because it can only encourage the conspiracy theories that already swirl around the pandemic, and diminish public confidence in health authorities. It is indeed vital that health authorities are transparent in their dealings with industry. But the drug industry is a necessary partner in a pandemic response, as the producer of antivirals and vaccines. It would have been irresponsible to exclude top academic experts from the decision-making just because of industrial competing interests, which do not necessarily represent conflicts of interest. Critics also tend to forget that in spring 2009 the WHO and national officials were struggling with large scientific uncertainties, and the possibility that millions of people would die if the response was inadequate (a reality that the Council of Europe report does acknowledge). Paul Flynn, a UK Labour Member of Parliament and rapporteur of the inquiry, says he could not fully address Nature's queries as to the accuracy of the science of some statements in the report, given the short deadline, but says he feels that these are minor and do not significantly alter its conclusions. "I will, of course consider your comments, but our concerns remain unchallenged," he says, adding that he would have any errors corrected in the final report. He questions the criticism of the report, saying that he believes industry lobbyists are working to undermine it. The resolution states that the council is "alarmed" about the WHO's, the European Union's and national governments' handling of the pandemic, arguing that some decisions taken led to "distortion of priorities of public health services across Europe, waste of large sums of public money, and also unjustified scares and fears about health risks faced by the European public at large". It also affirms its concern over possible "undue influence" on decisions by the pharmaceutical industry. Some of its recommendations, such as calls for greater transparency, and creating a public fund for research and trials independent of industry, are sensible. But many researchers dispute its highly critical analysis of the pandemic response, which is expanded on in an accompanying 15-page explanatory memorandum. That said, however, there are plenty of lessons to be learned from the WHO's response to the pandemic. Fortunately, there is at least one independent review that seems to be looking for those lessons in the right way — slowly and impartially, and without indulging in 20/20 hindsight. The 29-member panel, chaired by Harvey Fineberg, the president of the US Institute of Medicine, is due to deliver its findings at next year's World Health Assembly. Meanwhile, several national investigations are also under way — as the flu pandemic played out, it was largely national governments, at least in the rich countries, not the WHO, that led the pandemic responses. And they have plenty of their own lessons to learn. Additional data
• A full accounting
  - Nature (London) 465(7301):985 (2010)
  Nature | Editorial A full accounting Journal name:NatureVolume:465,Pages:985–986Date published:(24 June 2010)DOI:doi:10.1038/465985bPublished online23 June 2010 The BP spill should help make the case for bringing ecosystem services into the economy. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg On 14 June, BP promised to put US$20 billion into an escrow account to pay for damage caused by the 22 April sinking of its Deepwater Horizon drilling platform off the coast of Louisiana — an event that has left a geyser of crude oil gushing into the Gulf of Mexico for two months, at a rate currently estimated as high as 60,000 barrels (9.5 million litres) a day. The beneficiaries of this fund are expected to be fishermen, hoteliers, charter-boat operators and other Gulf-coast business owners who have lost income, as well as states and other entities with clean-up costs. Left unclear, however, is whether payment will ever be made for the loss of 'ecosystem services' that benefit everyone but are owned by no one. One such service is the carbon sequestration provided by marsh plants and ocean plankton. How will BP make good the value lost if the oil kills enough of them to hasten climate change? Another service is the buffering that coastal marshes provide to nearby communities from the Gulf's many hurricanes. Who pays if the oil destroys the marshes entirely? The 1989 Exxon Valdez oil spill in Alaska raised similar questions, and sparked a flurry of research in the once-obscure discipline of ecological economics, which seeks to estimate quantities such as the 'replacement cost' of an ecosystem — or even an individual organism. (Killer whales cost $300,000 at the time; cormorants were a bargain at $310 apiece.) The Gulf oil spill seems likely to inspire another surge of research in this field. Indeed, ecological economist Robert Costanza at the University of Vermont in Burlington has already estimated a $34-billion to $670-billion price tag for the loss of Gulf ecosystem services. Costanza also has a suggestion for how to avoid such harm in the future: force companies that want to drill, dig or otherwise extract resources to take a more serious account of environmental risks before they start. He and his colleagues have argued that the best way to do this is to demand that each company put up an "assurance bond": a sum of money large enough to rectify damages if things go wrong (see http://go.nature.com/styAyz). The amount of the bond would be set by an independent government agency or government-chartered body, and be based on the total value of the ecosystems at risk. In BP's case, Constanza says, the company would have had to put up something like $50 billion to get permission to drill in the Gulf, or about two to three times the $20 billion they are having to pay now. The very size of that bond, in turn, might have made the company more likely to invest, say, $500,000 in a functional blowout preventer. Other experts favour a variant of this idea in which large, risky enterprises would be required to carry insurance against ecosystem services claims — an approach that would essentially put the insurance companies in charge of policing safety practices. These and other variants seem well worth exploring as a way to bring ownerless ecosystem services into the marketplace. Congress and the US administration should take the idea seriously. But the science behind putting a price on nature must also improve. After all, any attempt to extract a multi-billion-dollar compensation for ecosystem damage seems likely to wind up in court. So scientists' cost estimates will have to be sound enough to convince judges and juries, not just make for an interesting journal article. Such an increase in rigour is hardly bad news for research. If ecosystems services science gets a boost from the spill, that may be one of the few silver linings to the dark plume that continues to gush in the Gulf of Mexico. Additional data
• The right kind of elitism
  - Nature (London) 465(7301):986 (2010)
  Nature | Editorial The right kind of elitism Journal name:NatureVolume:465,Page:986Date published:(24 June 2010)DOI:doi:10.1038/465986aPublished online23 June 2010 National academies can be pivotal in speaking up for science, both to those in power and to the public. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Britain's Royal Society is 350 years old this year, and its track record is one worthy of celebration. It stands today as a relatively successful model of what an independent national academy can achieve, having made itself both highly regarded in the corridors of power and prominent in public debates on major science-related issues (see pages 1002 and 1009). Such success cannot be taken for granted. In many parts of the world, scientific academies either lack real independence from the state (as in China) or else struggle to make themselves heard within it (as in Italy). And even where academies have established an independent voice — other notable examples include those in the United States, the Netherlands and Sweden — they must still maintain the difficult balance between taking stances that are full-throated enough to make the news, yet not so rash as to tarnish their reputation for impartiality. As the Royal Society has demonstrated, however, scientific academies able to navigate these treacherous waters can offer authoritative input on contentious public-policy issues such as climate change, or the regulation of human embryonic stem-cell research, and can thus enrich public debate by ensuring that science is properly heard. Sometimes that input will be articulated through technical reports, such as those produced in large numbers by the US National Academy of Sciences through its operating arm, the National Research Council. Academies also exert influence through informal consultation with government officials, and by influencing the selection of their government's scientific advisers. But these traditional avenues are only part of what academies can do to exert influence today. They can also issue more concise statements for wider audiences. And they can proactively engage with the public and the media in the same way that corporations and environmental pressure groups do — by anticipating or responding rapidly to events, and making sure that science's voice is heard amid the general cacophony. The Royal Society has, in recent years, used this kind of engagement to good effect. Academies that are seeking similar impact, such as new and reconstituted ones in Africa and the Leopoldina, which assumed the official status of Germany's national academy only three years ago, need to be similarly bold and outward-looking in their approach. Their memberships should note, however, that in order to have an independent voice, at least some of their funding must come from non-government sources. To exert influence, they must also carefully nurture connections with people and institutions inside government who genuinely want independent scientific input — and who can tell the difference between such advice and propaganda. Without that audience, no amount of earnest objectivity will establish a place for a scientific academy inside the framework of a state. And even successful academies need to keep an eye on their own processes, and resist the opaqueness and cliquishness that can afflict any self-appointed club. Ten years ago, for example, the US National Academy of Sciences staunchly resisted what it now concedes were positive advances in the transparency of its processes. And just recently it has noticed that Asian-Americans, who have become ubiquitous in American universities, are largely absent from its own ranks. Academies can still have a crucial role in taking scientific truth to the public, and to the heart of government. But to do so, they must constantly strive to properly represent an increasingly diverse scientific community. And they must adapt their processes and actions to a political and media landscape that doesn't sit still for 350 minutes, never mind 350 years. Additional data
• Evolutionary biology: Heat on for bills
  - Nature (London) 465(7301):988 (2010)
  Nature | Research Highlights Evolutionary biology: Heat on for bills Journal name:NatureVolume:465,Page:988Date published:(24 June 2010)DOI:doi:10.1038/465988aPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cited research: Am. Nat. doi:10.1086/653666 (2010) In 1877, American zoologist Joel Asaph Allen posited that animals that regulate their own body temperatures have smaller appendages relative to their body size if they live in colder environments to reduce heat loss. For birds, bills are important heat exchangers (pictured: infrared thermal images). To see whether birds' bills conform to Allen's rule, Matthew Symonds at the University of Melbourne in Australia and Glenn Tattersall at Brock University in St Catharines, Canada, compared bill lengths and evolutionary relationships in 214 species. These included African tinkerbirds, Antarctic penguins and South American toucans. They found that bill length across species correlated strongly with temperature and latitude or altitude, with birds in colder climes sporting shorter bills. This suggests that temperature regulation helped to shape the evolution of birds' bills. UNIV. CHICAGO Additional data
• Applied physics: The dark side of the laser
  - Nature (London) 465(7301):988 (2010)
  Nature | Research Highlights Applied physics: The dark side of the laser Journal name:NatureVolume:465,Page:988Date published:(24 June 2010)DOI:doi:10.1038/465988bPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cited research: Opt. Exp.18, 13385–13395 (2010) Laser beams are usually hard to miss, but a new laser is notable for its lack of light. Steven Cundiff at the University of Colorado in Boulder and his colleagues built the device by modifying a standard quantum-dot diode laser. Normally, lasers are amplified using two mirrors that reflect light between them, but Cundiff's group deposited light-absorbing material onto one of the mirrors. The laser still emitted light, but it flickered off at an extremely rapid and predictable rate. The 'dark' pulses verify existing theories of lasing and could prove useful in encoding information in long-distance fibre-optic communications. Additional data
• Geoscience: No shelter from storms
  - Nature (London) 465(7301):988 (2010)
  Nature | Research Highlights Geoscience: No shelter from storms Journal name:NatureVolume:465,Page:988Date published:(24 June 2010)DOI:doi:10.1038/465988cPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cited research: Geophys. Res. Lett. doi:10.1029/2010GL043124 (2010) Major hurricanes can churn up sea-floor sediments at depths of up to 90 metres, which can trigger underwater mudslides, and damage oil and gas pipelines. Hemantha Wijesekera and his colleagues at the Naval Research Laboratory of the Stennis Space Center in Mississippi analysed a rare set of data collected from instruments that measure current and wave properties in the Gulf of Mexico as Hurricane Ivan passed directly overhead in 2004. Using a wave–current model to calculate friction and sea-floor stresses, the team found that these stresses correlated with wind speed. Extreme surface waves and elevated currents produced damaging forces at the sea floor during the storm and for about one week after Hurricane Ivan's passage. The Gulf of Mexico, which provides almost 30% of the United States' oil supply, hosts some 50,000 kilometres of sea-floor pipelines. Hurricane-induced stress should be considered in the engineering design of pipelines in shallow shelf regions, the researchers suggest. Additional data
• Neuroscience: Stressed out females
  - Nature (London) 465(7301):988 (2010)
  Nature | Research Highlights Neuroscience: Stressed out females Journal name:NatureVolume:465,Page:988Date published:(24 June 2010)DOI:doi:10.1038/465988dPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cited research: Mol. Psychiatry doi:10.1038/mp.2010.66 (2010) Stress-related psychiatric disorders such as depression affect more women than men, and researchers have discovered a possible molecular basis for this in rats. Debra Bangasser at the Children's Hospital of Philadelphia in Pennsylvania and her colleagues put male and female rats through stressful swim tests. They then looked at changes in signalling by the receptor for corticotropin-releasing factor (CRF), which mediates stress responses in the brain. Excessive CRF activity is thought to contribute to depression and post-traumatic stress disorder. In unstressed females, the team found greater coupling of the receptor to a key protein — an important step in CRF signalling — than in unstressed males. Moreover, female rats' neurons did not internalize these receptors in response to stress — a mechanism for lowering the cells' sensitivity to stress signals — whereas those in males did. These findings, the authors say, are consistent with previous work suggesting that females are more sensitive to low levels of CRF. Additional data
• Nanotechnology: Graphene touch
  - Nature (London) 465(7301):988 (2010)
  Nature | Research Highlights Nanotechnology: Graphene touch Journal name:NatureVolume:465,Page:988Date published:(24 June 2010)DOI:doi:10.1038/465988ePublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cited research: Nature Nano. doi:10.1038/nnano.2010.132 (2010) A touch-screen with transparent electrodes made from graphene — single layers of carbon atoms — could be thinner, cheaper and more durable than today's devices that use indium tin oxide. But it has proved hard to manufacture these transparent films efficiently on a large scale. Now Byung Hee Hong, Jong-Hyun Ahn at Sungkyunkwan University in Suwon, South Korea, and their colleagues have made such films (pictured) using a scalable industrial manufacturing process and incorporated them into a touch screen. They created 30-inch graphene films by depositing carbon atoms onto copper, which is later etched away. Additional data
• Microbiology: Hitching a ride
  - Nature (London) 465(7301):989 (2010)
  Nature | Research Highlights Microbiology: Hitching a ride Journal name:NatureVolume:465,Page:989Date published:(24 June 2010)DOI:doi:10.1038/465989aPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cited research: Proc. Natl Acad. Sci. USA doi:10.1073/pnas.1000668107 (2010) Aquatic bacteria can access new environments by zipping around on larger organisms. Hans-Peter Grossart of the Leibniz-Institute of Freshwater Ecology and Inland Fisheries in Stechlin, Germany, and his colleagues labelled three species of bacterium with a fluorescent protein. They then tracked the microbes' movements in laboratory water columns with and without the water flea Daphnia magna, which usually travels up and down the water column each day. When water fleas migrated towards a light, the bacteria moved along with them, either by attaching to the surface of their bodies, or by being ingested and defecated by the water fleas. Similar behaviour was observed in a German lake, suggesting that bacteria hitchhike on zooplankton in natural settings as well — a phenomenon that could influence aquatic ecology. Additional data
• Imaging: Cell-wall secrets
  - Nature (London) 465(7301):989 (2010)
  Nature | Research Highlights Imaging: Cell-wall secrets Journal name:NatureVolume:465,Page:989Date published:(24 June 2010)DOI:doi:10.1038/465989bPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cited research: Nature Commun. doi:10.1038/ncomms1027 (2010) Researchers have imaged the structure of an enigmatic cell-wall component in living bacteria. Yves Dufrêne at the Catholic University of Louven in Belgium and his colleagues used atomic force microscopy to capture nanometre-scale images of the surface of Lactococcus lactis cells. The authors focused on a major constituent of bacterial cell walls called peptidoglycan because it is the target of many antibiotics, but its spatial organization is unclear. They imaged normal bacteria and mutants lacking cell-wall sugars that ordinarily coat the peptidoglycan and obscure it from view. Whereas normal bacteria appeared smooth, the mutants had 25-nanometre-wide bands of peptidoglycan running parallel to the short axis of the cell. The researchers say that their method could be used to help visualize peptidoglycan–drug interactions in other bacteria. Additional data
• Biogeochemistry: Faecal fertilization
  - Nature (London) 465(7301):989 (2010)
  Nature | Research Highlights Biogeochemistry: Faecal fertilization Journal name:NatureVolume:465,Page:989Date published:(24 June 2010)DOI:doi:10.1038/465989cPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cited research: Proc. R. Soc. B doi:10.1098/rspb.2010.0863 (2010) Sperm whales in the Southern Ocean are helping to reduce atmospheric carbon dioxide levels, rather than adding to them as marine mammals have been assumed to do. H. MINAKUCHI/MINDEN PICTURES/FLPA Trish Lavery at Flinders University in Adelaide, Australia, and her co-workers calculated that the 12,000 or so sperm whales (pictured) inhabiting the Southern Ocean facilitate the removal of 240,000 tonnes more carbon from the atmosphere per year than they add through respiration. The whales' iron-rich faeces fertilize iron-starved waters and stimulate the growth of phytoplankton. As these microscopic marine organisms sink to the ocean floor, it is thought that they take with them 20–40% of the carbon they have fixed through photosynthesis. The authors say that other whale species may be having the same effect and warn that the hunting of sperm and other whales has probably decreased the removal of carbon from the atmosphere. Additional data
• Cognitive neuroscience: Mapped from birth
  - Nature (London) 465(7301):989 (2010)
  Nature | Research Highlights Cognitive neuroscience: Mapped from birth Journal name:NatureVolume:465,Page:989Date published:(24 June 2010)DOI:doi:10.1038/465989dPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Cited research: Science328, 1573–1576; 1576–1580 (2010) How do newborn rats find their way around? Easily, it seems: two groups report that some basic elements of spatial representation don't require any experience. Researchers recorded the activity of three types of neuron in the brains of rat pups as they explored their environment for the first time. Tom Wills, Francesca Cacucci and their colleagues at University College London report that head-direction neurons — which are tuned to fire according to the direction in which the animal points its head — are already fully developed by the time a pup first ventures from the nest. The basic properties of place cells, which respond to particular locations, are also established by then. Conversely, a third type of cell for spatial orientation, the grid cell, doesn't begin firing stably until later. Edvard Moser and his colleagues at the Norwegian University of Science and Technology in Trondheim largely agree, but say that rudimentary grid-cell properties are also present during the pups' first explorations. Both studies underscore that the animals may be born with spatial cognitive abilities. Additional data
• Journal club
  - Nature (London) 465(7301):989 (2010)
  Nature | Journal Club Journal club * Nicola Clayton1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:989Date published:(24 June 2010)DOI:doi:10.1038/465989ePublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg It is well established that an excessive intake of high-calorie foods, unless coupled with plenty of exercise, leads to obesity, which is a growing public-health concern. As a dancer and a scientist, I am well aware of the intimate connection between the body and the brain, and not at all surprised by the recent accumulation of evidence showing that a high-calorie diet leads to a suite of cognitive impairments, particularly in memory. What is striking, however, is how quickly the effects can occur and how selective they are. Scott Kanoski and Terry Davidson at Purdue University in West Lafayette, Indiana, studied the effects of a high-energy diet on the memory performance of rats trained in a radial-arm maze (S. E. Kanoski and T. L. DavidsonJ. Exp. Psychol. Anim. Behav. Proc.36, 313–319; 2010). They found that maintaining rats on a high-energy diet for just 72 hours was sufficient to result in a marked impairment in spatial memory. Deficits in non-spatial memory took much longer to detect, emerging only after 30 days. Spatial skills are therefore particularly vulnerable. This finding has important implications for our own lifestyle. Clearly, consuming an excessively high-calorie diet can result in marked decreases in cognitive abilities, especially in spatial memory. The fact that this occurs in such a short space of time, prior to any significant gain in body weight, suggests that diet-induced cognitive impairments could contribute to, rather than simply be a consequence of, obesity. So hide the high-calorie foods — if out of sight is out of mind, it might just save your brain! View the archive at Author information * Author information * Comments Affiliations * University of Cambridge, UK * Nicola Clayton Additional data
• News briefing: 18–24 June 2010
  - Nature (London) 465(7301):990 (2010)
  The week in science. This article is best viewed as a PDF. Policy|Business|Business watch|Events|People|Research|The week ahead|News maker|Number crunch| The US National Institutes of Health and the London-based Wellcome Trust announced plans on 22 June to use genome-wide scanning and sequencing technologies to study genetic and environmental underpinnings of chronic diseases in Africa. The five-year, US$38-million project, called Human Heredity and Health in Africa (H3 Africa), will award grants to African researchers after two working groups decide on the programme's parameters, such as which populations and diseases to study, and which technologies to use. European leaders formally adopted 'Europe 2020' — a ten-year economic strategy for the region — at a meeting on 17–18 June. The document maintains a goal to raise spending on research and development to 3% of the region's gross domestic product by 2020. See also Nature 464, 142; 2010. On 17 June, Sweden's parliament narrowly approved the overturning of a 30-year ban on building new nuclear power plants. The nuclear-reactor replacement policy, proposed by the coalition government in February 2009, annuls a phase-out of existing plants and allows the construction of replacements — although only for the ten existing reactors, which are at three sites and supply the country with nearly half of its electricity. However, Sweden's centre-left opposition has vowed to reverse the legislation if it wins September's general election. The American Chemical Society (ACS), the world's biggest scientific society, has lost its appeal over legal action which may cost it nearly US$40 million. It had argued that the founders of chemical-information company Leadscope in Columbus, Ohio — former ACS employees — had used intellectual property belonging to the ACS (see Nature, 459, 17; 2009). On 20 June, an Ohio district appeals court upheld a county-court ruling in favour of Leadscope, who had counterclaimed. As Nature went to press, the ACS had not yet decided whether to appeal to a higher court. Commercial space-flight company SpaceX, of Hawthorne, California, has signed a US$492-million deal with satellite-phone company Iridium, of McLean, Virginia, to launch a fleet of next-generation satellites. The contract follows SpaceX's 4 June debut launch of its Falcon 9 rocket, and Iridium's 2 June awarding of a contract to Thales Alenia Space, headquartered in Cannes, France, to build 81 communications satellites. GTC Biotherapeutics, which sells the only approved drug made in transgenic animals, will lay off 50 employees and replace some senior management, including its chief executive Geoffrey Cox. The company, in Framingham, Massachusetts, announced the move on 16 June. In March, GTC said it had only enough cash to last to the end of June and was delisted from the Nasdaq stock exchange, but has now secured a further $7 million of financing. The company's anti-clotting drug antithrombin (ATryn) is produced in goat's milk and is approved in the United States and Europe — but only for the treatment of a rare hereditary clotting disorder. On 21 June, the US Supreme Court overturned a ban on genetically modified herbicide-resistant alfalfa, ruling in favour of the agricultural company Monsanto, based in St Louis, Missouri. A federal district judge had mandated the nationwide ban in 2007 after farmers argued that the US Department of Agriculture (USDA) hadn't fully assessed the crop's environmental impact before permitting its use. The Supreme Court said that did not warrant a complete ban. The USDA may now approve limited planting of the seed; however, unrestricted planting will await the completion of an environmental assessment. A drug intended to boost sexual desire in women was unanimously voted down by a US Food and Drug Administration (FDA) advisory committee on 18 June. Widely called 'female Viagra', flibanserin was put forward by German drug-maker Boehringer Ingelheim as a treatment for 'hypoactive sexual desire disorder' in premenopausal women. An earlier report by FDA staff expressed concerns that the drug failed to increase desire in two studies, yet caused numerous side effects. The FDA usually follows its advisory committees, but has yet to announce a final decision. European pharmaceutical companies do more than their US counterparts to ensure that medicines reach people in developing countries, but their lead is shrinking. A ranking of 20 drug-makers was released on 21 June by the non-profit Access to Medicine Foundation, based in Haarlem, the Netherlands. GlaxoSmithKline, headquartered in London, topped the list, which ranks companies on criteria such as investment in research and development for neglected diseases, intellectual-property sharing, and their stance on patenting and drug pricing. Click for a larger version.SOURCE: IEA In a roadmap on nuclear energy published on 16 June, the International Energy Agency (IEA) in Paris asserted that almost a quarter of global electricity could be generated from nuclear power by 2050. The pace of new nuclear-plant construction is now slowly increasing, the roadmap showed (see chart). But in order to meet the IEA's 2050 target, around 30 new 1-gigawatt nuclear plants (or 20 larger ones) would need to enter operation each year during 2010–50, says the report. That building rate was reached only briefly in the 1970s. Adrian Bull of US nuclear supplier Westinghouse thinks this average rate is realistic: 25–30 plants a year could be achieved by 2025, he says, and more after that date. But John Large, an independent, London-based nuclear consultant, says the IEA projections are "pie in the sky". The greatest logjam is likely to occur not in infrastructure capacity but in developing adequate nuclear-safety and environmental regulations, he says. A. HARRER/BLOOMBERG/GETTY IMAGES Oil is now gushing into the Gulf of Mexico from BP's crippled well at a rate of 35,000 to 60,000 barrels (5.5 million to 9.5 million litres) a day, according to US federal estimates. Facing a media scrum and criticism from US politicians, BP's chief executive, Tony Hayward (pictured), gave low-key answers at a tense congressional hearing in Washington DC on 17 June, revealing little about the causes of the disaster. On 21 June, BP said that it had spent US$2 billion in two months trying to stop the oil flow. The company, based in London, had earlier agreed to set money aside for a US$20-billion fund for compensation claims stemming from the disaster. See page 993 for more on oil-spill research spending. Stem-cell scientist Shinya Yamanaka was last week awarded the 2010 Kyoto prize in advanced technology, by the Inamori Foundation of Kyoto, Japan. Yamanaka, at Kyoto University, pioneered the creation of induced pluripotent stem cells (see Nature 458, 962–965; 2009). Mathematician László Lovász, at Eötvös Loránd University in Budapest, won the basic-sciences prize. Each winner will receive ¥50 million (US$555,000). A scientist who argues that HIV does not cause AIDS has escaped censure from his university after an investigation found "insufficient evidence" that he broke faculty rules when he published a paper in the journal Medical Hypotheses last year expounding his views. The University of California, Berkeley, was investigating whether Peter Duesberg made false claims and failed to declare a relevant conflict of interest, but it concluded that there was no clear evidence against him and that academic freedom protected his right to publish. See go.nature.com/UnDzyN for more. Jean-Jacques Dordain will continue as director-general of the European Space Agency, Paris, until June 2015. The French former aerospace engineer has held the post since 2003; the agency's council announced on 17 June that it had elected him to a third four-year term in office. A controversial US Department of Defense project, which embedded social scientists into military units in Iraq and Afghanistan, has lost its director. Steve Fondacaro left the US Army's Human Terrain System programme on 11 June, but no reason was given for his departure. See page 993 for more. NASA's Kepler mission has discovered more than 700 potential extrasolar planets. On 15 June, NASA released the data associated with 306 parent stars that are likely to harbour planets. But the mission has been given until February 2011 to hold onto data for 400 other stars with the most Earth-like planet candidates as the team pursues confirmations with ground-based observations. The team cautions that as many as 50% may turn out to be false positives, but the set will vastly add to the 462 known exoplanets. Representatives of Russia's scientific diaspora meet in Saint Petersburg, to discuss how émigrés can help restore Russian science to its former glory. → go.nature.com/1Krh4i Canada hosts the G8 and G20 summits, in Muskoka and Toronto, respectively. Maternal and child health, climate change and nuclear proliferation will be discussed at the G8. → http://g8.gc.ca → http://g20.gc.ca Sixty-one Nobel Laureates meet more than 650 young researchers at this year's interdisciplinary meetings in Lindau, Germany. → www.lindau-nobel.org At the European Space Agency's Living Planet symposium in Bergen, Norway, expect results from the agency's latest three missions — satellites studying Earth's gravity (GOCE), soil moisture and ocean salinity (SMOS), and ice (CryoSat). → www.esa.int/LivingPlanet2010 JAXA Solar sail First images were released of the solar sail attached to Japan's IKAROS space capsule; now fully unfurled, it will be propelled by photons from the Sun. Europeans declaring themselves interested in scientific discoveries and technological developments. Europeans declaring themselves interested in sports news. Source: Eurobarometer survey, released 21 June There are currently no comments. This is a public forum. 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• Italy puts seismology in the dock
  - Nature (London) 465(7301):992 (2010)
  Scientists who assessed earthquake risk at L'Aquila could be indicted on manslaughter charges. The deadly earthquake that struck the central Italian city of L'Aquila on 6 April 2009, has had a bizarre aftershock: some of Italy's top seismologists could face charges of manslaughter for not alerting the population before the disaster. The indictment has outraged experts around the world, who note that earthquakes cannot be predicted and who say that the Italian government neglected to enforce building codes that could have reduced the toll. Citizens blame scientists for not warning of the L'Aquila earthquake.A. TARANTINO/AP PHOTO The indictments, issued on 3 June by the L'Aquila public prosecutor's office, name six scientists as being investigated for manslaughter in relation to the earthquake. In Italy, this step usually precedes a request for a court trial, and is meant to allow the accused time to prepare their defence. The list comprises Enzo Boschi, president of the National Institute for Geophysics and Vulcanology (INGV) in Rome, the main institute in charge of seismic monitoring; Giulio Selvaggi, director of the National Earthquake Center based at INGV; Franco Barberi, a volcanologist at the University of 'Roma Tre'; Claudio Eva, a professor of earth physics at the University of Genoa; Mauro Dolce, head of the seismic risk office in the Italian government's Civil Protection Agency; and Gian Michele Calvi, director of the European Centre for Training and Research in Earthquake Engineering in Pavia. A government official, Bernardo De Bernardinis, deputy technical head of the Civil Protection Age! ncy, is also under investigation. Assigning blame On 31 March 2009, all seven were in L'Aquila at a meeting of the Major Risks Committee, an expert group that advises the Civil Protection Agency on the risks of natural disasters. Frequent tremors had been recorded in the surrounding Abruzzo region, culminating in a magnitude-4.0 earthquake on 30 March. The meeting was convened by the service to ask the scientists whether a major earthquake was on its way. Immediately after that meeting, De Bernardinis and Barberi, acting president of the committee, held a press conference in L'Aquila, where De Bernardinis told reporters that "the scientific community tells us there is no danger, because there is an ongoing discharge of energy. The situation looks favorable". No other members of the committee were at the press conference. But on 6 April a magnitude-6.3 earthquake struck L'Aquila, killing 308 people, leaving about 1,600 injured and more than 65,000 homeless. A group of local citizens later said that many of the earthquake's victims had been planning to leave their homes — but had changed their minds after the committee's statements. In August 2009 they filed a formal request asking a prosecutor to investigate. L'Aquila's chief prosecutor, Alfredo Rossini, told the Italian press on 3 June that this had left him no choice but to proceed with an investigation and that his office had now gathered enough information to indict the individuals named. The minutes of the 31 March meeting, though, reveal that at no point did any of the scientists say that there was "no danger" of a big quake. "A major earthquake in the area is unlikely but cannot be ruled out," Boschi said. Selvaggi is quoted as saying that "in recent times some recent earthquakes have been preceded by minor shocks days or weeks beforehand, but on the other hand many seismic swarms did not result in a major event". Eva added that "because L'Aquila is in a high-risk zone it is impossible to say with certainty that there will be no large earthquake". Summing up the meeting, Barberi said, "there is no reason to believe that a swarm of minor events is a sure predictor of a major shock". All the participants agreed that buildings in the area should be monitored urgently, to assess their capacity to sustain a major shock. "These are the only sensible statements any scientist could make at that point," says Susan Hough, a geophysicist at the US Geological Survey in Pasadena, California. But Hough does disagree with some of the things said at the press conference. "The idea that minor earthquakes release energy and thus make things better is a common misperception. But seismologists know it's not true," she says. "I doubt any scientist could have said that." De Bernardinis, Boschi and Selvaggi said that they were unable to comment on the case because of the ongoing investigation. Before the indictment, Boschi had criticized the Civil Protection Agency's handling of the 31 March meeting. "Such a meeting", he stated in a letter on 16 September 2009 to Guido Bertolaso, the head of the Civil Protection Agency, "should have lasted hours if the Civil Protection Agency really wanted to consider all the data. Instead it only lasted one hour, and it was not followed by a joint statement but by a press conference about which we were not informed." The Civil Protection Agency responded by asking Boschi why he waited six months before objecting to the nature of the meeting, and stated that Boschi "never explained what specific actions" the department should have taken to reduce the risks from a potential earthquake. Solidarity Staff at INGV have signed a letter of solidarity with Boschi and Selvaggi. Seismologists worldwide have also rallied to the defence of the scientists, with almost 4,000 researchers from 100 different countries signing a letter to Giorgio Napolitano, Italy's president, urging decision-makers to concentrate on "earthquake preparedness and risk mitigation rather than on prosecuting scientists for failing to do something they cannot do yet — predict earthquakes". ADVERTISEMENT Barry Parsons, at the department of earth sciences at the University of Oxford, who signed the letter, says that Italy's maps of seismic risk are of the highest possible standard, and clearly show that Abruzzo is a very high-risk area. "The proven and effective way of protecting populations is by enforcing strict building codes," he says. "Scientists are often asked the wrong question, which is 'when will the next earthquake hit?' The right question is 'how do we make sure it won't kill so many people when it hits?'" This is a public forum. Please keep to our Community Guidelines. 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• 'Human Terrain' hits rocky ground
  - Nature (London) 465(7301):993 (2010)
  US Army social-science programme loses director. The US Army's controversial project for social scientists to serve alongside soldiers on the battlefield has suffered another setback with the loss of its director, retired US Army colonel Steve Fondacaro, who left on 11 June. Although no reason was given for his sudden departure, those familiar with the programme say that it is yet another sign of trouble for a project that has faced criticism since its inception four years ago. The US Army's beleaguered social-science programme faces an uncertain future.C. IDLEBERG Greg Mueller, a spokesman for US Army Training and Doctrine Command, based in Fort Monroe, Virginia, confirmed that Fondacaro is no longer manager of the Human Terrain System (HTS), but declined to provide details. He says that the army is now looking for a new civilian director. Colonel Sharon Hamilton will run the programme until a new director is found. Fondacaro said in a phone interview that, although not technically fired, he had been pushed out of the position. He said that there had been "a lot of tension" between himself and senior army leaders, exacerbated by congressional pressure. "This is just a culmination of that," he said. The HTS aims to help commanders to understand local culture and reduce violence. But critics, including the American Anthropological Association in Arlington, Virginia, see a contradiction between the goal of anthropology, to help local populations, and the goals of the army, which often wants to control them. The programme has also suffered more concrete setbacks. It has struggled to recruit and retain social scientists. Several deployed social scientists have been killed, a translator was kidnapped in January (and later released) and one civilian team member pleaded guilty to voluntary manslaughter after executing an Afghan man who attacked social scientist Paula Loyd last year. Loyd later died of her wounds. Roberto Gonzalez, an anthropologist and the author of American Counterinsurgency, a book on the HTS, says he is surprised that the leadership shake-up has been so long in coming. "Some argue that the HTS is suffering from poor management and lack of oversight, and that if these problems could be corrected it would be successful," he says. "I disagree. The entire programme is flawed because Human Terrain team members are thrust into an impossible situation in which they are torn between conflicting interests." Funding for the HTS has increased from US$10 million to US$100 million a year since it began in 2006. But in May, a congressional panel said that it would limit funding until the project had been assessed by the army. More changes lie ahead. The army has confirmed that it is seeking a new contractor to train Human Terrain teams. Georgia Tech Research Institute in Atlanta, which currently provides training, has decided to end its involvement — but did not give details. ADVERTISEMENT Fondacaro denied that problems with the programme were caused by his leadership, arguing that aspects such as contracting were beyond his control. "The record will show, if anybody cares to look, that the things I was able to manage worked quite well," he said. Asked about the programme in a meeting with reporters in March, US secretary of the army John McHugh said that he was "neither happy nor unhappy" with the HTS. "Whether it's a long-term solution or one in which we can glean short-term lessons and then move forward is still something we're not able to judge," McHugh said. 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.
• White House stalls oil-slick research
  - Nature (London) 465(7301):993 (2010)
  Half-billion-dollar BP fund put on hold. Plans to distribute monies from BP's ten-year Gulf of Mexico Research Initiative (GRI) have been thrown into turmoil by a last-minute edict from the White House. On 15 June, BP announced that it would distribute US$25 million in fast-track funding across three research institutions in its first step towards fulfilling a $500-million pledge for high-priority studies to assess environmental damage from the oil spill. BP had planned to put out a request for proposals for the remaining $475 million within days of the announcement and said that large-scale research centres would be established as part of its mission. "The bureaucratic hurdles are formidable." But on 16 June, the White House issued a vaguely worded statement that could slow the effort. The press release said that BP would consult with "governors, and state and local environmental and health authorities" to design its long-term monitoring programme within the research initiative. This has left the future of the initiative uncertain, even to members of an independent advisory panel of six scientists that the company had set up to evaluate research proposals and decide how the remaining funds would be divided up. The panel includes Rita Colwell, a former director of the US National Science Foundation, and the agency's former assistant director for geosciences Margaret Leinen. On the details of what the programme will entail, Leinen says, "I really am not in a position to talk about it — and I don't think any of us are". Researchers say that the government mandate could stall the process considerably. "It makes sense to coordinate the Gulf of Mexico research initiative with efforts that are already under way," says Jeffrey Short, an environmental chemist with Oceana, a marine conservation organization based in Washington DC. "But it will be difficult to achieve that coordination in a timely manner. The bureaucratic hurdles are formidable." ADVERTISEMENT BP spokeswoman Elizabeth Ashford says that the company will follow through with its initial $25-million commitment. This will be used to establish the interactions between oil, dispersants and the environment, and the ecological conditions on the Gulf Coast before the accident. "The idea was always that this would be independent from BP," says Ashford. "All of that intention is still there. But we do need and intend to be responsive to the White House." 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.
• African nations vow to support science
  - Nature (London) 465(7301):994 (2010)
  Policy-makers say that dependence on financial aid is hampering research, reports Linda Nordling. PhD students investigate malaria proteins at Kenya's Centre for Geographic Medicine Research.J. OKANGA/WELLCOME IMAGES Visitors expecting broken test tubes and threadbare carpets are often surprised by Kenya's Centre for Geographic Medicine Research in Kilifi. The gleaming white building, laden with top-notch equipment and perched atop a hill overlooking the azure Indian Ocean, is part of the Kenya Medical Research Institute (KEMRI), based in Nairobi, but would look at home in California or Singapore. World-class laboratories are not common in Africa, but they are becoming less of an exception. There is a whiff of a scientific renaissance in the air, with new labs mushrooming in the capitals of Kenya and Uganda and local researchers taking the helm of formerly Western-run institutions. Tom Egwang (above) and Ahmadou Lamine Ndiaye (below) say that foreign investment is hurting African research.K. LENARD/BURNESS COMMUNICATIONS The improved conditions carry a cost: continued dependence on foreigners, who foot most of the bills. "If you look at any of the researchers who carry out any significant research in Africa, 99.9% of their funding comes from outside," says Tom Egwang, a Ugandan immunologist and founding director of Uganda's Med Biotech Laboratories, headquartered in Kampala. "I really think that all these programmes are killing African science." Others agree that the millions flowing from philanthropists, non-governmental organizations (NGOs), aid agencies and traditional research funders into African science are undermining efforts to convince African governments to spend money on research. "Governments don't assume their responsibilities in this area, simply because the NGOs spend money in their place," says Ahmadou Lamine Ndiaye, vice-president of the National Academy of Science and Technology of Senegal. Dependence on international aid causes big problems for African scientists. Projects can be interrupted when grants run out, and the research agendas are set by donors rather than by African researchers and policy-makers. "Donors have their own priorities, and I don't think they would be able to provide all the resources that Africa needs," says Aida Opoku-Mensah, director of the information technology, science and technology division of the United Nations Economic Commission for Africa. "There needs to be a mind shift in African countries." Several new efforts are under way to tackle the problem. This March, African science ministers resolved that 2011 would be the start of an African decade for science, promising increased research budgets and attempts to use science and technology to drive development. A small, continent-wide research-grant programme, modelled on the European Union's framework programmes, is in the works, as is a pan-African training network for researchers undertaking PhDs. And donors and governments alike are talking up the need for more home-grown funding for research and development. Going local This week, the African Science, Technology and Innovation Endowment Fund will be launched at a Science with Africa conference in Addis Ababa, Ethiopia. Businesses — a rare source of investment in research and development in Africa — will be invited to add to the fund, which will provide innovation guidance and financial support for researchers and entrepreneurs. Several companies have already promised to contribute to the fund, including Nigeria's Zenith Bank and Bank of Industry, Zemen Bank in Ethiopia, and Ethiopian Airlines. In most African countries, private-sector research funding is small compared with government budgets, and only US$500,000 has been committed to this fund so far. This amount must double before the fund can issue the first round of research support, envisaged to be $100,000. "We feel that it is time to engage with the private sector," says Opoku-Mensah. Yet the problem does not rest simply in a lack of resources. Global Research Report Africa, published by Thomson Reuters in April, shows that the continent's wealthy nations, including oil producers such as Nigeria and Angola, generate fewer internationally recognized papers than many of their poorer neighbours when the sizes of their economies are taken into account. Although these countries could afford to put more funding into their universities, the money often goes into overseas accounts or is spent on imported goods rather than being invested domestically. Moreover, most African governments have more pressing priorities than funding science, says Malcolm Molyneux, a professor of tropical medicine at the University of Liverpool, UK, who headed the Malawi-Liverpool-Wellcome Trust Clinical Research Programme, based in Blantyre, for 13 years. "When a country is manifestly inadequate in every compartment of its responsibilities in education, health and agriculture, it's difficult to pontificate that more should be spent on research when there is a possibility of this being acquired from outside," he says. Hard habit to break African countries produce plenty of research papers, although many appear in local journals. Those published in internationally visible journals are often produced in collaboration with researchers in other countries — and focus on areas such as public health and agriculture. But African contributions can be substantial, as Global Research Report Africa reveals. Between 2004 and 2008, Nigerian scientists were co-authors on nearly 1% of agricultural science papers published in international journals, and Kenyans co-authored nearly 0.5% of the world's immunology papers and more than 0.3% of environment/ecology papers. Overall, scientists across the whole of Africa publish about 27,000 papers in international journals per year, which is only about the same volume as the Netherlands, although the African number has doubled since 1998 (see 'A modest research base'). The reliance on funding from foreign donors can, however, make it difficult to coordinate research activities within a country and to ensure that research priorities match development priorities. "In defined segments there is visible progress," says Mark Rweyemamu, executive director of the Southern African Centre for Infectious Disease Surveillance in Morogoro, Tanzania. Yet Africa also needs engineers, meteorologists and chemists. Undoing the dependency that has become ingrained in many of the continent's research institutions over decades will not be easy. Centres that started their life as field offices for researchers from developed countries might have 'gone local', but they continue to depend on their old patrons for money. The continent's most influential institutions, with scientists who have contributed to top-cited papers, are overwhelmingly reliant on donors. For example, KEMRI depended on international partners for two-thirds of its income in 2006–07, the last year for which an annual report is available. The Ifakara Health Institute in Tanzania expects to receive 3.72 billion shillings ($2.53 million) from international development partners in 2010–11, compared with just over 150 million shillings from the country's government (see 'Donor dependency'). Similarly, the University of Malawi's College of Medicine in Blantyre and the University of Ghana, based in Accra, both produce internationally recognized research — and depend on foreign donors for equipment, training and research funding. Click for a larger version.SOURCE: IFAKARA HEALTH INSTITUTE African science ministers have tried to remedy the situation before. In 2005, when the G8 countries pledged to double aid to Africa by 2010, they urged that some of it be used to build up African research, with African governments taking the lead. The governments, for their part, agreed in 2007 to increase funding for science and technology and urged one another to direct 1% of their gross domestic product (GDP) to these areas by 2010. The statistics will not be ready for another two to three years, but Africa's failure to achieve this ambition is beyond doubt. Few believe that there have been significant improvements to the 2007 figures released by the United Nations Educational Scientific and Cultural Organization last year. These figures estimated sub-Saharan Africa's spending (excluding South Africa) to be 0.3% of GDP — the same figure as the continent clocked up in 2002. "Funding has grown a little, but the amount is not enough," says Ndiaye. There are exceptions. Rwanda says that it has ramped up its science spending, although independent figures have yet to support this, and Tanzania's president, Jakaya Kikwete, has promised that the country will move towards the 1% of GDP goal. Meanwhile, the government of Uganda, flush from recent oil finds in the country's western parts, has also said that it wants to take more responsibility for funding science. It is not expected to renew the five-year, low-interest loan for $33 million that it secured from the World Bank's Millennium Science Initiative in 2006. "The government has pledged to provide money that it would otherwise borrow from the bank," says Maxwell Otim, deputy executive secretary of the Uganda National Council for Science and Technology. ADVERTISEMENT This time around, improved political stability on the continent augurs well for new investments in science. The Global Peace Index, published on 7 June by the Institute for Economics and Peace in Sydney, Australia, shows that the number of African conflicts and the availability of weapons decreased over the past three years, while cross-border relations improved. And although aid for Africa is being slashed as a result of the ongoing financial turmoil in rich countries, Africa's economies are expected to grow by 4.5% this year and by 5.2% in 2011, according to the Organisation for Economic Co-operation and Development's African Economic Outlook 2010, published last month. The continent is the world's poorest, and its science performance trails that of other developing regions. But viewed in the light of a progressively safer and more prosperous Africa, the current donor dominance could be a short-lived phase, says Molyneux. "It does not have to be like this forever," he says. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• German states wield the axe
  - Nature (London) 465(7301):996 (2010)
  University cuts are out of step with federal government's bid to spare research. Despite the federal government's strong support for science and higher education, the crisis in Germany's public finances is starting to take its toll, as cash-poor states prepare to cut university budgets. Slashed university budgets bring protestors out on the streets in Kiel, Germany.A. WARMUTH/PICTURE ALLIANCE/DPA/PHOTOSHOT In the state of Schleswig-Holstein last week, thousands rallied in the capital, Kiel, to protest against the imminent closure of the medical school at the University of Lübeck. "We will have to stop the enrolment of medical students as from the winter term 2011," says Rolf Hilgenfeld, a structural virologist at the university. "This is outrageous." And researchers in Lübeck and elsewhere fear worse is to come. The federal government has spared national agencies, such as the German Research Funding Council (DFG), from the multi-billion-euro cuts in public spending announced last month. But many of the states, which fund the universities, are struggling to keep financing at current levels. The Hesse government, for example, last month announced university budget cuts of €30 million (US$37 million) a year over the next five years. Universities in Saxony are facing similar cuts. In Schleswig-Holstein, the government announced in May that it will cut public expenditure by €125 million a year to close a looming budget deficit. Science and higher education will be hit hard. From 2015, the University of Lübeck will lose €24 million a year — 30% of its total budget — which scientists there say will not only close the medical school but threaten the university's very existence. The University of Lübeck also hosts a graduate school for computing in medicine and life sciences, and is part of a €35-million 'excellence cluster' in medical research on inflammation, both funded by the federal government. Both programmes are likely to be discontinued, says university president Peter Dominiak. The proposed cuts have to be approved by the state parliament, which is expected to vote in December. But some scientists are already preparing to leave. "The university will be damaged to such an extent that for me it makes no sense to stay," says Jan Born, a neuroscientist who earlier this year received a €2.5-million Leibniz prize, Germany's most prestigious scientific award, for his research on sleep and memory. ADVERTISEMENT The heads of the DFG and of the German Rectors' Conference (HRK), the state universities association, are concerned over the Lübeck cuts. "This … is a misstep with far-reaching negative consequences," Margret Wintermantel, president of the HRK, wrote to Peter Harry Carstensen, the Christian Democrat prime minister of Schleswig-Holstein, "not only for the University of Lübeck but for Schleswig-Holstein and Germany at large." 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.
• UK research centre born amid cuts
  - Nature (London) 465(7301):996 (2010)
  £600-million science complex planned for centre of London. The centre will be among the largest in the world.J. PIPERGER/WADSWORTH3D/UKCMRI As the United Kingdom grinds through its worst recession in decades, British researchers have revealed ambitious plans for a massive biomedical science complex in central London. The UK Centre for Medical Research and Innovation (UKCMRI) is the most significant scientific development in Britain "for a generation", says Paul Nurse, Nobel-prizewinning cell biologist and chair of the project's scientific planning committee. "If we get this right, it will send a message to the rest of the world that the UK is serious about science," says Nurse. Detailed plans for the building, which will be located near London's St Pancras International station and house 1,500 staff, were unveiled last week. The open-plan design reflects what Nurse calls his "somewhat unusual" ambitions for how research will be carried out. To encourage collaboration, Nurse says that the centre will forgo traditional academic departments for multidisciplinary 'interest groups' that are set up by the researchers themselves. Nurse hopes that the different teams will essentially drive their own research programmes. The grandiose plan will not come cheap. On top of construction costs of £600 million (US$890 million), the centre will cost £100 million per year to operate. The stiff price tag comes at a difficult time for several of the project's backers. The UK Medical Research Council (MRC), which will pay roughly half the construction costs, is expected to have its funding squeezed in the coming government budget, and University College London (UCL), which will contribute £46 million to the building, has recently made voluntary redundancies in preparation for tight times ahead. ADVERTISEMENT The new UK coalition government recently announced that it will pay its portion of the project on a year-by-year basis instead of as a single lump sum, but both the MRC and UCL say that they remain fully committed to the project. Plans for the new facility will be submitted to local authorities in August and, if approved, construction could begin early next year. 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.
• Strange lesions after stem-cell therapy
  - Nature (London) 465(7301):997 (2010)
  Unproven treatment results in mysterious masses. In a stark reminder that stem-cell therapy is uncharted territory, a stem-cell transplant given to a patient in Thailand who had kidney disease resulted in the development of cellular masses not previously reported. The lesions, described in a paper published online on 17 June in the Journal of the American Society of Nephrology, were not directly linked to the patient's subsequent death (D. Thirabanjasak et al. J. Am. Soc. Nephrol. doi:10.1681/ASN.2009111156; 2010). With hundreds of poorly regulated clinics that offer unproven stem-cell therapies now running, notably in China and Thailand, the episode is a warning to patients who may be considering such treatment. The patient had lupus nephritis, in which the immune system attacks the kidneys. In 2006, she underwent a procedure at a private clinic in which her own haematopoietic stem cells — which can develop into any type of blood cell — were injected into her kidneys. Details of the clinic and the rationale behind the treatment have not been released. "She didn't get any better from stem cells, we can say that." Haematopoietic stem cells have been used to treat lupus nephritis with some reports of success. But they are usually injected into the bloodstream, not the kidney,­ in an attempt to 'reset' the immune system. Six months later, the patient complained of pain and blood in the urine. Imaging studies revealed a four-centimetre mass on her left kidney and smaller masses in the kidney, liver and adrenal gland. Doctors at Chulalongkorn University in Bangkok removed the kidney, believing a malignant tumour to be present. But further analysis showed that it was something else. "I had never seen anything like it," says Paul Thorner, a pathologist at the Hospital for Sick Children in Toronto, Canada, who has a joint position at Chulalongkorn University and was a co-author on the paper. Thorner coined a term — angiomyeloproliferative — to describe the proliferation of blood-vessel and bone-marrow cells the team found. ADVERTISEMENT Patients are undergoing other experimental stem-cell therapies, but there is usually little follow-up to establish safety or efficacy. In one case reported last year, a boy treated with fetal stem cells at a Russian clinic developed tumours in his brain and spinal cord. In the Thai case, no post-mortem was carried out, as far as Thorner is aware, so his team could work only on the removed kidney. It is not known whether the smaller masses were linked to the main mass, or what would have happened had the patient not died from other complications. "She didn't get any better from stem cells, we can say that," says Thorner, who may try to reproduce the masses in animal experiments. 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.
• Genetics tells tall tales
  - Nature (London) 465(7301):998 (2010)
  The genetic basis of common traits may be buried deeper than researchers had thought. Human height has posed an emblematic challenge to geneticists searching for the link between genes and complex traits and diseases. It's strongly heritable — how tall one's parents are is 80–90% predictive of one's own stature. But studies scanning the genomes of tens of thousands of individuals for gene variants associated with height have come up short: around 50 variants have been identified, but together they account for only 5% or so of height's heritability. How tall will he grow?IMAGESTATE/ALAMY Many geneticists have begun to refer to this gap — seen in almost all complex traits and diseases investigated — as the 'missing heritability' of the genome1. But a study on the genetics of height published online in Nature Genetics this week2 suggests that this heritability may not be missing — it may simply be buried deeper than previously thought, in a multitude of genetic variants that have tiny effects individually. Genome-wide association studies (GWAS) scan the genomes of thousands of people at a time, looking for common single-letter mutations called SNPs (single nucleotide polymorphisms) associated with a trait or disease. To ensure that the associations between each SNP and a trait are real, scientists normally set an extremely high bar for their statistical significance — using a cut-off about a million times higher than is used in, say, epidemiological studies that link environmental factors and disease. But the new work, rather than considering SNPs one by one, uses a statistical analysis that considers what effect all the SNPs together have on height. "We explained more than half of the genetic variation in height," says Peter Visscher, a quantitative geneticist at the Queensland Institute of Medical Research in Brisbane, Australia, who led the study. A further analysis suggests that another batch of SNPs, less common than those picked up by GWAS, might explain the rest of the heritability of height. That assessment, though, doesn't reveal whether those variants are still relatively common, perhaps at the level of 2% of the population, or extremely rare — arising only in specific families. The results suggest two things, says Visscher. First, the effects of many common variants associated with a trait or disease are, on their own, likely to be quite small. Second, in order to spot them researchers will have to study groups of many hundreds of thousands of individuals. The problem of the missing heritability has led some researchers to question the very idea that the common genetic variants GWAS are designed to pick up will explain complex traits and diseases. Instead, they have shifted their focus to search for rare variants — by re-sequencing genes they suspect are involved, or whole genomes or exomes (the protein-coding sequences) in people with the trait. A study published online in Nature last week3,4, for example, identified a handful of rare variants of a specific gene that could raise a person's susceptibility to certain autoimmune diseases. Rare or common? Although rare variants are known to be at play in some complex traits, abandoning GWAS is premature, not to say illogical, says David Altshuler, director of medical and population genetics at the Broad Institute in Cambridge, Massachusetts. "I don't think you could say this new paper resolves the issue," he says. "Studies like this simply remind us that we shouldn't leap to conclusions about what we haven't yet explained." Increasingly, most researchers agree that there's no either/or answer. "I think the most likely scenario is there's a spectrum of variance," says Visscher. His group's study, though — and a similar analysis published last year on schizophrenia5 — suggests that there may be many more meaningful common variants to uncover, although that won't be easy. "If the true state of nature is that there are really very many causal variants, each with a small effect on disease risk or trait," says Visscher, "then that's not the fault of GWAS, that's just the way it is." * References * Maher, B. Nature456, 18-21 (2008). | Article | PubMed | ChemPort | * Yang, J. et al. Nature Genet. advance online publication doi:10.1038/ng.608 (2010). * Surolia, I. et al. Nature advance online publication doi:10.1038/nature09115 (2010). * Katsnelson, A. Naturedoi:10.1038/news.2010.300 (2010). * International Schizophrenia Consortium Nature460, 748-752 (2009). | Article | PubMed 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.
• Human genome at ten: Science after the sequence
  - Nature (London) 465(7301):1000 (2010)
  The completion of the draft human genome sequence was announced ten years ago. Nature 's survey of life scientists reveals that biology will never be the same again. Declan Butler reports. Download a PDF of this story. "With this profound new knowledge, humankind is on the verge of gaining immense, new power to heal. It will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases." So declared then US President Bill Clinton in the East Room of the White House on 26 June 2000, at an event held to hail the completion of the first draft assemblies of the human genome sequence by two fierce rivals, the publicly funded international Human Genome Project and its private-sector competitor Celera Genomics of Rockville, Maryland (see Nature 405, 983–984; 2000). Ten years on, the hoped-for revolution against human disease has not arrived — and Nature 's poll of more than 1,000 life scientists shows that most don't anticipate that it will for decades to come (go.nature.com/3Ayuwn). What the sequence has brought about, however, is a revolution in biology. It has transformed the professional lives of scientists, inspiring them to tackle new biological problems and throwing up some acute new challenges along the way. Almost all biologists surveyed have been influenced in some way by the availability of the human genome sequence. A whopping 69% of those who responded to Nature 's poll say that the human genome projects inspired them either to become a scientist or to change the direction of their research. Some 90% say that their own research has benefited from the sequencing of human genomes — with 46% saying that it has done so "significantly". And almost one-third use the sequence "almost daily" in their research. "For young researchers like me it's hard to imagine how biologists managed without it," wrote one scientist. "69% were inspired by the genome to become a scientist or change their research direction." The survey, which drew most participants through Nature 's print edition and website and was intended as a rough measure of opinion, also revealed how researchers are confronting the increasing availability of information about their own genomes. Some 15% of respondents say that they have taken a genetic test in a medical setting, and almost one in ten has used a direct-to-consumer genetic testing service. When asked what they would sequence if they could sequence anything, many respondents listed their own genomes, their children's or those of other members of their family (the list also included a few pet dogs and cats). Some are clearly impatient for this opportunity: about 13% say that they have already sequenced and analysed part of their own DNA. One in five said they would have their entire genome sequenced if it cost US$1,000, and about 60% would do it for $100 or if the service were offered free. Others are far more circumspect about sequencing their genome — about 17% ticked the box saying "I wouldn't do it even if someone paid me". Click for a larger version. Nature 's poll also gauged where the sequence has had the greatest effect on the science itself. Although nearly 60% of those polled said they thought that basic biological science had benefited significantly from human genome sequences, only about 20% felt the same was true for clinical medicine. And our respondents acknowledged that interpreting the sequence is proving to be a far greater challenge than deciphering it. About one-third of respondents listed the field's lack of basic understanding of genome biology as one of the main obstacles to making use of sequence data today. Sequence is just the start Studies over the past decade have revealed that the complexity of the genome, and indeed almost every aspect of human biology, is far greater than was previously thought (see Nature 464, 664–667; 2010). It has been relatively straightforward, for example, to identify the 20,000 or so protein-coding genes, which make up around 1.5% of the genome. But knowing this, researchers note, does not necessarily explain what those genes do, given that many genes code for multiple forms of a protein, each of which could have a different role in a variety of biological processes. "The total sequence was needed, I think, to allow us to see that our one gene–one protein model of genetics was much too simplistic," wrote one respondent. A decade of post-genomic biology has also focused new attention on the regions outside protein-coding genes, many of which are likely to have key functions, through regulating the expression of protein-coding genes and by making a slew of non-coding RNA molecules. "Now we understand," wrote another survey respondent, "that, without looking at the dynamics of a genome, determining its sequence is of limited use." Some big projects are under way to fill in the gaps, including the Encyclopedia of DNA Elements (ENCODE) and the Human Epigenome Project, an effort to understand the chemical modifications of the genome that are now thought to be a major means of controlling gene expression. The biggest effects of the genome sequence, according to the poll, have been advances in the tools of the trade: sequencing technologies and computational biology. Technological innovation has sent the cost of sequencing tumbling, and the daily output of sequence has soared (see Nature 464, 670–671; 2010). "Deep sequencing technology is now becoming a staple of scientific research. Would this have occurred if it wasn't for the technological push required to finish the human genome?" read one response. Data dreams, analysis nightmares Cheaper and faster sequencing has brought its own problems, however, and our survey revealed how ill-equipped many researchers feel to handle the exponentially increasing amounts of sequence data. The top concern — named by almost half of respondents — was the lack of adequate software or algorithms to analyse genomic data, followed closely by a shortage of qualified bioinformaticians and to a lesser extent raw computing power. Other concerns include data storage, the quality of sequencing data and the accuracy of genome assembly. Commenting on the survey results, David Lipman, director of the US National Center for Biotechnology Information in Bethesda, Maryland, says that the worries about data handling and analysis were an issue even in the earliest discussions of the genome project. Perhaps, he suggests, "there's a sort of disappointment that despite having so much data, there is still so much we don't understand". Click for a larger version. Eric Green, director of the National Human Genome Research Institute (NHGRI) in Bethesda, says that the institute is well aware of the need for more bioinformatics experts, better software and a clearer understanding of how the differences between genomes influence human health. He says the institute is planning to publish in late 2010 its next strategic five-year plan for the genomics field. One possible solution to the computing challenge, which was discussed at an NHGRI workshop in late March, is cloud computing, in which laboratories buy computing power and storage in remote computing farms from companies such as Google, Amazon and Microsoft. The European Nucleotide Archive, launched on 10 May at the European Molecular Biology Laboratory's European Bioinformatics Institute in Cambridge, UK, will also offer labs free remote storage of their genome data and use of bioinformatics tools. "13% have sequenced part of their own DNA." Given ten years' of hindsight and the current set of obstacles, it's no surprise that researchers now state somewhat modest expectations for what human genomics can deliver and by when. The rationale for sequencing and exploring the human genome — to revolutionize the finding of new drugs, diagnostics and vaccines, and to tailor treatments to the genetic make-up of individuals — is the same today. But almost half of respondents now say that the benefits of the human genome were oversold in the lead up to 2000. "While I do feel that the gains made by the human genome project are extraordinary and affect my research significantly, I still feel that it was overhyped to the general population," read one typical response. More than one-third of respondents now predict that it will take 10–20 years for personalized medicine, based on genetic information, to become commonplace, and more than 25% even longer than that. Some 5% don't expect it will happen in their lifetime. "Ou! r understanding of the genome will not come in a single flash of insight. It will be an organized hierarchy of billions of smaller insights," says David Haussler, head of the Genome Bioinformatics Group at the University of California, Santa Cruz. ADVERTISEMENT Green says that when the Human Genome Project was envisioned, scientific leaders of the day predicted that it would take 15 years to generate the first sequence, and a century for biologists to understand it. "I think they got that about right," he says. "While we still don't have all the answers — being a mere 10% of the way into the century with a human genome sequence in hand — we have learned extraordinary things about how the human genome works and how alterations in it confer risk for disease." Haussler agrees. "All that happened in the first ten years is still just early rumblings of much more dramatic changes to come when we begin to truly understand the genome," he says. There are currently no comments. This is a public forum. Please keep to our Community Guidelines. You can be controversial, but please don't get personal or offensive and do keep it brief. Remember our threads are for feedback and discussion - not for publishing papers, press releases or advertisements.
• Scientific Academies: In the best company
  - Nature (London) 465(7301):1002 (2010)
  The grandfather of scientific national academies is staging major celebrations this week for its 350th birthday. But, like similar elite groups around the world, Britain's Royal Society has had to work hard to stay relevant and influential, reports Colin Macilwain. Download a PDF of this story. One thing that scientists have learned since the seventeenth century is how to throw a party. This week, the Queen is set to celebrate with hundreds of Britain's most brilliant minds, kicking off a summer of festivities to mark the 350th anniversary of the Royal Society of London for the Improvement of Natural Knowledge. The public will be invited to partake in a carnival of celebrity lectures, debates, live TV shows and exhibits to showcase science and the Royal Society's role in it. The choice of the South Bank — London's main arts centre and a major tourist bazaar — for the ten-day extravaganza signals the society's hunger to be seen as up to date, inclusive and important, not exclusive and aloof. National academies of science in more than 100 nations are aiming for the same goal, with varying success. Many were born in an era when a few select individuals practiced science, and those groups evolved to offer behind-the-scenes advice to governments. Now, the academies represent much more diverse communities, and they must take their messages not only to governments but also directly to the public. The Royal Society and its kindred academies have had to evolve in their own unique ways to meet the challenges of the twenty-first century. They try to offer sober advice on some of the most divisive issues — such as climate change, reproductive biology and genetically modified food — without offending their patrons or members. They must be seen to be independent of government, despite considerable reliance on public funding. And they need to reflect the growing ethnic and gender diversity of the scientific community, while still selecting members on the basis of their scientific reputations. Ever more nations are establishing academies of their own. They range from the Ethiopian Academy of Sciences in Addis Ababa, which opened for business two months ago, to the US National Academy of Sciences (NAS) in Washington DC, which employs 1,100 full-time staff members to turn out 200 reports each year for the government. "The academy's function is to provide the consensus view of the scientific community," says Bruce Alberts, former president of the NAS. Given the range of topics that it handles and the diversity of views within that community, he says, "it is very difficult to do". The Royal Society and the NAS are two of the largest independent scientific academies in the world (see 'Two elites'), and illustrate two principal models of operation. The Royal Society is a self-constituted club with no formal, official role in government; the NAS is chartered to provide advice at the behest of the US Congress. (A different type of academy, of which the Chinese Academy of Sciences is an example, is effectively part of the state and runs many of the government science programmes in several communist and formerly communist countries.) click for a larger version. Some of the differences between the Royal Society and NAS models can be traced back to their respective histories. The NAS, like many other national academies, was set up by a patron — President Abraham Lincoln, at the height of the American Civil War, in 1863. The Royal Society, in contrast, was started by scientists themselves, expressly to promote science (see 'The Royal Society through the ages'). But these founders were strong supporters of a monarchy recently restored after the English revolution — and their society soon sought, and got, the patronage of King Charles II. Early on, the Royal Society made clear that it owed allegiance not to king and country but to scientific truth. The society maddened King George III, for example, by siding with its fellow Benjamin Franklin in a debate about the shape of lightning conductors, even as Franklin fomented rebellion in the colonies. The society has continued to chart its own course. Like other national academies, it establishes its rules and elects its own members — an arrangement that draws charges of elitism. "There's a sense of pride here in being elitist: the proportion of scientists who are fellows is very small," says Martin Rees, who became the society's president in 2005. "But we're elite only in the sense that we ought to be elite." High standards The society maintains its standards through a complex annual election process, which has evolved since it first started elections to select members in 1847. Recommendations for new fellows go to a network of sectional committees, which examine the nominations. They pick the top candidates and put them before the full society to endorse, rather than having a general election of all the nominations. The committees have tried to pull down the average age at which fellows are elected. "There's more likelihood now of electing fellows in mid-career, in their mid-40s rather than their late 50s," says John Krebs, a zoologist at the University of Oxford, UK, and chairman of the Royal Society's science policy advisory group, who was only 39 when elected in 1984. Members are also asked to submit letters nominating individuals for positions in office. Some 200 of them did so before April's announcement that Paul Nurse, a cell biologist and president of Rockefeller University in New York, would succeed Rees at the end of this year. The empire that Nurse will inherit has two principal arms. Most of the Royal Society's work, paid for by a £52-million (US$77-million) block grant from the government, supports early-career researchers through various types of awards, as well as 305 highly prestigious university research fellowships. The society's endowment financed £13 million of policy work and other activities this year, generating statements and reports that provide the Royal Society's public face. Peter Hennessy, a historian at Queen Mary, University of London and a leading authority on British governance, says that the Royal Society's stock in the corridors of power is high. "It has always had an influence in Whitehall, where it is seen as a gold-standard institution," he says. "When the Royal Society has an input, people listen to it." William Waldegrave, science minister in the Conservative UK government from 1992 to 1994, agrees. He relied on it, in particular, to help him pick scientific advisers. "I think the Royal Society does have very high prestige; it is one of these brands that always carries weight," he says. He is dismissive of the idea that the block grant could enable the government to influence the society. "It would be a very rash minister who would try to pull that lever," he says. "The Royal Society is one of these brands that always carries weight." Since Waldegrave's time in office, the Royal Society has assumed a more aggressive and professional approach to public affairs. The change was driven partly by high-profile scientific crises a decade ago, concerning genetically modified food and bovine spongiform encephalopathy (BSE). These shook public confidence in science, and, to an extent, science's confidence in itself. The Royal Society responded in 2000 by electing Robert May, an Australian physicist-turned-ecologist, as its 58th president. May had previously served as the UK government's chief scientific adviser, and he helped transform the Royal Society from an inward-looking body into a public force, says Krebs. With his government experience, May "could see how an independent voice like the Royal Society's could get real traction", Krebs says. Although less voluble than May, Rees is a media-savvy scientist who has helped to keep the society in the public eye. Under his presidency, the society set up a Science Policy Centre, advised by Krebs' group, to consider policy issues and decide which the Royal Society should report on. One of the centre's first publications was a report on geoengineering, released in September 2009. James Wilsdon, the centre's director, says that the report has "helped to change the terms of the debate", prompting British research councils to officially consider some geoengineering approaches, such as cloud seeding, for the first time, as well as triggering their serious discussion in the media. Rees has used the society's anniversary celebrations to encourage a large number of TV documentaries on the BBC and other channels, most of them celebrating the achievements of Royal Society fellows past and present. (As part of the festivities next week, the Royal Society and Nature will co-host a conference that looks ahead 50 years on topics such as data storage and scientific careers.) Rees has also raised about £100 million from individuals and businesses for the society's own endowment, almost doubling its size. Rees's reign is not without its detractors. Some say that the Royal Society has retreated from politically contentious issues, to place greater emphasis on advocating science funding. In April, Richard Pike, chief executive of the Royal Society of Chemistry in London, Britain's largest learned society, criticized a government plan to confer with the Royal Society on budget matters, questioning its independence from government. "They seem not to be challenging government policy as forthrightly as they could be," says Pike. Rees says that Pike is the only individual to make this criticism, and that others accept that the Royal Society's policy arm is independent of government. Speaking out on policy Across the Atlantic, the NAS has even closer ties with its government, and so has evolved in different ways from the Royal Society. Most of the academy's studies are requested by Congress and are paid for through contracts with federal agencies. These contracts enable the academy and its sister organizations in Washington DC, the National Academy of Engineering and the Institute of Medicine, to support a large staff of specialists. The quasi-governmental status of the academy places its operations under more scrutiny than those of the Royal Society. A decade ago, for example, environmental groups went to court to argue that the academy should not be allowed to bar the public from panel discussions. "At the time it was a very serious threat," says William Colglazier, the academy's executive officer. The NAS adopted reforms, such as public consultation on panel membership and some open meetings, that have strengthened the academy's processes, he says. The academy has also come under fire for the lack of diversity in its membership. Its president, atmospheric scientist Ralph Cicerone, concedes that the number of female members — about 12% — is "not good enough", and is also concerned about its under-representation of Asian-Americans, the causes of which, he says, the academy is now looking into. The academy is cautious about taking a stand on policy issues, although it has, for example, issued statements on the teaching of evolution and creationism, most recently in 2008. The NAS has also joined with other academies around the world in several consensus statements on what is known about global warming. "We make policy statements of our own pretty rarely," says Cicerone. "We have to choose topics where what we say is going to matter." May, who is also a member of the NAS, observes that the US academy is "more constrained" than the Royal Society "by the fact that it has 1,100 staff producing reports, and depending on government money", so that it "has to think twice" about issuing critical reports that might make enemies in Congress. Colglazier says that the NAS has honed its procedures over the past century to ensure the independence of its reports. "The academy is perceived as a place to go for impartial study," he says, "and that reputation could be lost very easily." Some would like the academy to speak out more. Robert Park, a physicist at the University of Maryland in College Park who comments on science policy issues in his online newsletter What's New, says that he'd like to see the academy take a more strident line on hot issues such as creationism. "They would be better off in the long run if they ignored Congress and said the things that need to be said, without any hesitation," he says. Others contend that the US academy is wiser to hold its fire and maintain its influence. That remains strong, particularly among the 'barons' who run congressional committees, says David Goldston, former chief of staff on the House science committee. "They are among the only honest brokers in an increasingly polarized political environment," he says. In 2001, for example, the academy issued a report on climate change that helped to constrain the Bush administration, and its allies in Congress, from openly questioning the evidence linking human activity to global warming. And last month, the academy published a trio of massive reports called 'America's Climate Choices', which explains the science of climate change and makes the case for reducing emissions and for adapting to anticipated conditions. Although many of its conclusions could be found in the 2007 assessments issued by the Intergovernmental Panel on Climate Change (IPCC) in Geneva, Switzerland, the academy reports could influence US lawmakers as they debate climate legislation this summer. Global movement Around the globe, national academies are seeking to expand their public role to achieve the kind of influence enjoyed by the Royal Society and the NAS. "There's a whole move now to make academies a voice for science in every nation of the world," says Bruce Alberts. "Around the globe, national academies are trying to expand their public roles." In Europe, only a few countries have established national academies as influential in their own capitals as the Royal Society. Two of the strongest are the Royal Swedish Academy of Sciences in Stockholm, founded by Carl Linnaeus and other scientists in 1739, and the Royal Netherlands Academy of Arts and Sciences in Amsterdam, founded in 1808. Germany took a major step in 2007, when the federal government officially recognized the Leopoldina, in Halle, as the country's scientific academy for the first time. Jörg Hacker, the biologist who assumed its presidency in March, says that it is increasing its staff to about 70, and that it will be fully independent, despite its reliance on federal and state government funds. In Africa, numerous academies have been established or reconstituted, including the Ethiopian Academy of Sciences. The track record of African academies has been mixed so far, with several struggling to attract young scientists and effective leaders. But Alberts credits the Academy of Science of South Africa with helping to finally reverse the government's denial that HIV causes AIDS. Increasingly, national academies have sought to unite on global issues such as climate change. The InterAcademy Panel based in Trieste, Italy, was created in 1993 and has issued numerous joint policy statements on behalf of its 104 member academies. An InterAcademy Council, meanwhile, was set up in 2000 with a secretariat in Amsterdam, to undertake major studies. Its current review of the IPCC for the United Nations is due in late August. ADVERTISEMENT Critics may contend that the public is indifferent to the academies' grand pronouncements, and that their reports are valued by politicians more for the cover they provide than for the carefully nuanced information they contain. But supporters remain assured that a wider purpose is being served. "We only address scientific issues," says Stephen Cox, executive secretary of the Royal Society, "and we have become more important because there are so many more issues today that have a scientific component." Colin Macilwain is a freelance writer based in Edinburgh, UK. 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.
• Coordinated action needed for Europe's research programmes
  - Nature (London) 465(7301):1005 (2010)
  Nature | Correspondence | Opinion Coordinated action needed for Europe's research programmes * Iain W. Mattaj1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:1005Date published:(24 June 2010)DOI:doi:10.1038/4651005aPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Plans are under way for integrated European research infrastructures that will foster synergy and collaboration among Europe's scientists (see http://go.nature.com/fsnB7a). The European Strategy Forum on Research Infrastructures (ESFRI) has put forward more than 40 priority projects, but these will be hard to implement without extensive European cooperation, even on a realistic timescale of 10–15 years. Construction and running costs must be financed by national mechanisms, which will be difficult if every project applies to all 37 ESFRI member states and requires a separate national decision, as is now planned. Without coordinated action between the ESFRI member states and the European Commission, this process will be chaotic, inconsistent, costly and time-consuming. A European decision-taking body of member-state representatives could be set up that would implement agreed member-state policy on prioritization, funding, site selection and construction of the projects, while ensuring that legitimate national interests are taken into account. European countries could, for example, act together to equip the ESFRI with the extra responsibilities necessary to realize its plans. Integration of existing expertise into the planning of the ESFRI projects could be improved. As well as developing appropriate legal and governance systems, the new research infrastructures will have to mobilize, recruit and train specialist staff to operate them. Several European institutions have already solved these problems. The intergovernmental EIROforum organizations that operate some of Europe's existing international research infrastructures have governance designed for international membership and operation, and sustainable, performance-based funding systems. These should serve as models for the new research infrastructures and as sources of expert advice (see Establishing New Research Infrastructures in Europe — The EIROforum Experience; available at http://go.nature.com/4JfVEj). Author information * Author information * Comments Affiliations * European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany mattaj@embl.org * Iain W. Mattaj Additional data
• More patent protection for medicines with a new purpose
  - Nature (London) 465(7301):1005 (2010)
  Nature | Correspondence | Opinion More patent protection for medicines with a new purpose * Gareth Morgan1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:1005Date published:(24 June 2010)DOI:doi:10.1038/4651005bPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg You are right to urge the US government and others to encourage the re-use of old medicines by granting exclusivity rights (Editorial, Nature465, 267; 2010). But it is not correct to say that the European Union (EU) already rewards innovators in this area with a further year of patent protection. The EU awards an extra year's exclusivity for the technical data that are used to obtain the marketing authorization for the product, as long as the indications constitute a "significant clinical benefit". Because data exclusivity usually expires before patent protection, this provision is of limited value. One solution would be for regulators to extend patent life when existing medicines have been repurposed for new uses — but this would only assist projects undertaken by the original patentee. Another would be to exclude generic products from the market for a limited period should a third party, or the patentee, repurpose a medicine. The repurposed use could be assessed according to similar criteria and judged against new indications of significant clinical benefit (where these do not amount to repurposing). However, this would still not protect companies in situations in which generic products are already on the market. Also, holders of repurpose patents could be allowed to enforce the patent when generic off-label use is damaging their monopoly. Author information * Author information * Comments Affiliations * DLA Piper LLP, 3 Noble Street, London EC2V 7EE, UK gareth.morgan@dlapiper.com * Gareth Morgan Additional data
• Closure threat to key museum research facility
  - Nature (London) 465(7301):1005 (2010)
  Nature | Correspondence | Opinion Closure threat to key museum research facility * Harry Elderfield1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulf Riebesell2 Search for this author in: * NPG journals * PubMed * Google Scholar * John Raven3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jean-Pierre Gattuso4 Search for this author in: * NPG journals * PubMed * Google Scholar * Jere Lipps5 Search for this author in: * NPG journals * PubMed * Google Scholar * AffiliationsJournal name:NatureVolume:465,Page:1005Date published:(24 June 2010)DOI:doi:10.1038/4651005cPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg As leading representatives of the environmental and Earth science communities, we are gravely concerned about the proposed closure of the micropalaeontology research group at London's Natural History Museum (see http://go.nature.com/KCppCe). Micropalaeontology is of considerable strategic and international importance. It underpins biological and geochemical proxy reconstructions of past climates. It is critical for industrial oil and gas exploration. It allows the evolutionary and palaeobiological study of organisms that have the most complete fossil record. The museum's micropalaeontology research group has made acclaimed contributions in all of these areas. Loss of this expertise will compromise research in these fields and the training of the next generation of industry and research micropalaeontologists. We accept that the Natural History Museum's researchers are not directly responsible for collections management. But micropalaeontologists are needed to interface with the many professional users of the museum's resources. The use and development of its micropalaeontology collection is likely to suffer in the long term as a result of the research group's closure. The museum's trustees and director are being forced to respond to funding constraints that will require savings to be made across all departments. Instead of closing a whole research group with such key expertise, we urge the museum's management to produce a more balanced set of proposals that will be less damaging to palaeoclimate research, industrial biostratigraphy and evolutionary palaeobiology (see also http://go.nature.com/Eo4Thh). Author information * Author information * Comments Affiliations * Department of Earth Sciences, Cambridge CB2 3EQ, UK he101@esc.cam.ac.uk * Harry Elderfield * Leibniz Institute of Marine Sciences, 24105 Kiel, Germany * Ulf Riebesell * Division of Plant Sciences, Invergowrie, Dundee DD2 5DA, UK * John Raven * Observatoire Océanologique, F-06234 Villefranche-sur-mer CEDEX, France * Jean-Pierre Gattuso * Department of Integrative Biology & Museum of Paleontology, California 94720, USA * Jere Lipps Additional data
• Gender agenda: let's track women's trial participation
  - Nature (London) 465(7301):1005 (2010)
  Nature | Correspondence | Opinion Gender agenda: let's track women's trial participation * Angela Ballantyne1 Search for this author in: * NPG journals * PubMed * Google Scholar * Wendy Rogers2 Search for this author in: * NPG journals * PubMed * Google Scholar * AffiliationsJournal name:NatureVolume:465,Page:1005Date published:(24 June 2010)DOI:doi:10.1038/4651005dPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Your discussion of sex bias in biomedical research (Nature465, 665; 2010 and Nature465688–690; 2010) doesn't mention the poor basic monitoring of female participation in clinical trials. Only the Office of Research on Women's Health in the United States systematically collects and publishes such data, and its statistics relate solely to publicly funded research. The research community needs to be able to access participation data easily so that nuanced analysis of inclusion patterns can be conducted — for example, to take account of the proportion of women in non-sex-specific research. A simple solution would be for clinical-trials registries to collect data on the sex of participants. Author information * Author information * Comments Affiliations * Department of Primary Health Care & General Practice, University of Otago, Wellington 6242, New Zealand angela.ballantyne@otago.ac.nz * Angela Ballantyne * Department of Philosophy; and Australian School of Advanced Medicine, Macquarie University, NSW 2109, Australia * Wendy Rogers Additional data
• Academies must engage with society
  - Nature (London) 465(7301):1009 (2010)
  Nature | Opinion Academies must engage with society * Yves Quéré1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:1009Date published:(24 June 2010)DOI:doi:10.1038/4651009aPublished online23 June 2010 As the UK Royal Society prepares for a festival celebrating its 350th year, Yves Quéré urges all scientific academies to welcome women and young scientists and to take part in public and political discourse. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Recently I asked a group of French teenagers what they thought an academy was. After a long silence, one boy ventured: "I think ... it is a club of old gentlemen." He put his finger on three of the most common failings of scientific academies. They have few female members, few young members and they act too much like private clubs instead of speaking up on crucial matters of science and technology. Before looking at how to make academies more relevant and effective, it is worth reflecting on why they exist. Since the establishment in 1603 of the Lincean Academy in Rome (pictured) — the first national academy of sciences of modern times — the idea behind such organizations has been to promote the role of science in society and politics, and support scientists and science education. The best ones have come to embody three attributes. One is scientific expertise, because membership tends to be restricted to a nation's top scientists. Another is independence from external political, economic, religious or social pressures, enabling academies to speak openly on any matter. The last is stability in the face of constantly shifting social and political landscapes, because members are generally elected for life. M. LISTRI/CORBIS Many national academies are seen as private clubs. There are several crucial ways in which academies can champion science and technology in their countries. The first is to promote excellence in scientific research and stimulate the public understanding of science, for example by awarding grants, publishing high-level proceedings or organizing public debates. They can also release reports on issues of public interest, such as the US National Academies' On Being a Scientist: A Guide to Responsible Conduct in Research, published in 2009. Second, academies can mediate between scientists and politicians. This role has been pioneered particularly successfully by the UK Royal Society, which celebrates its 350th anniversary this year. In 2001, the Royal Society established a scheme that pairs scientists with a Member of Parliament (MP) to help scientists understand the parliamentary process and the pressures that politicians work under and to help MPs to improve their knowledge of how science works. More than 170 of these pairings, which involve reciprocal visits to the Houses of Parliament and to research facilities, have been established. Inspired by this, the French Academy of Sciences launched a similar project in 2005 in which an academy member teams up with a member of the French parliament and a promising young scientist. So far about 50 of these three-way partnerships are up and running. Third, academies can bolster science education. For example, those of Australia, France and the United States have pioneered a worldwide effort to promote a hands-on approach to teaching science in schools, known as 'enquiry-based learning'. This has led to specially tailored education initiatives in many countries. Fourth, academies can help boost science in less developed countries by giving financial support to scientists, such as the many grants and fellowships offered each year by TWAS, the Academy of Sciences for the Developing World, in Trieste, Italy. Last, academies can help increase prestige for scientific disciplines by organizing prizes, such as the Nobel prizes awarded by the Royal Swedish Academy of Sciences. International responsibility Science academies can also have an international role in issues such as the technology divide between developed and developing countries and the international response to natural disasters. One example is the Independent Review of the IPCC Assessment Process being done by the InterAcademy Council (IAC) — a group of 15 national academies, hosted by the Royal Netherlands Academy of Arts and Sciences in Amsterdam — at the behest of UN secretary-general Ban Ki-moon. The IAC will deliver its report at the end of August. Crucial to the coordination of such work is the IAP (formerly the InterAcademy Panel). This global network of more than 100 of the world's science academies is the parent body of the IAC. IAP activities include: helping nascent academies to strengthen their roles as independent advisers to governments; exploring how science and technology can improve the forecasting and management of natural disasters such as the earthquake in Haiti in January; and expanding electronic access to scientific information, such as to online journals and in developing countries. The IAP also delivers short statements aimed at the United Nations, governments or the general public on behalf of its members on controversial global science-related issues, such as bioweapons and the teaching of evolution. Despite all these positive actions, many academies of science are too passive and too reticent to speak out on important issues. Often, their members are content to accept the distinction of membership without meeting the obligations that come with it. The suggestion in March by Alhassan Zaku, the former Nigerian minister of science and technology, that African science and technology academies are not doing enough to accelerate the continent's development, could apply to academies in a number of countries globally. All academies have a responsibility to contribute to public debates on science and technology, particularly in cases where there is scientific misconduct, where scientists are the victims of human-rights abuses or where science or education is under- or misrepresented or poorly funded. A continued failure to meet these obligations calls an organization's credibility into question. Encouragingly, many academies have started to change, for example by increasing their public profile and their networking, such as through the IAP and IAC and by increasing their numbers of young and female members — only in the academies of Latvia, Cuba, South Africa and Mexico do women make up more than 20% of the members. Above all, to remain relevant and useful, academies should keep sight of their fundamental responsibility: to promote the idea that science is both a magnificent adventure for mankind and a necessary force for development and therefore a source of hope for the most deprived people on the planet. Author information * Author information * Comments Affiliations * Yves Quéré is former co-chair of the InterAcademy Panel (2000–06), Académie des Sciences, Délégation à l'Enseignement et à la Formation, 23 quai de Conti, 75006 Paris, France. yves.quere@academie-sciences.fr Additional data
• The father of parallel universes
  - Nature (London) 465(7301):1010 (2010)
  Nature | Books and Arts | Opinion The father of parallel universes * Robert P. Crease1Journal name:NatureVolume:465,Pages:1010–1011Date published:(24 June 2010)DOI:doi:10.1038/4651010aPublished online23 June 2010 Robert P. Crease is fascinated by a biography of quantum physicist Hugh Everett III, the difficult man behind one of the most logical and bizarre ideas in the history of human thought. The Many Worlds of Hugh Everett III: Multiple Universes, Mutual Assured Destruction, and the Meltdown of a Nuclear Family by Peter Byrne Oxford University Press: 2010. 348 pp.$45, £25 Buy this book: USUKJapan Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The 'many worlds' theory of quantum mechanics is one of the most logical, bizarre and ridiculed ideas in the history of human thought. In The Many Worlds of Hugh Everett III, investigative journalist Peter Byrne details the short, fragmented life of the physicist who created the theory. A compulsive model-builder, Hugh Everett III "burned to reduce the complexity of the universe to rational formulae". Yet while he tried to grasp everything through physics, he kept losing track of his own life. Everett entered Princeton University in 1953 to study mathematics, attracted to the new field of game theory. A year later he switched to physics, intrigued by quantum mechanics and its measurement problem. Quantum mechanics uses a wave equation to encapsulate the protean qualities of the microscopic world, which it represents as a superposition of many possible states. Whenever such a quantum system is measured, or interacts in any way with the classical world, it abruptly adopts one of these states, corresponding to a particular observation. In the prevailing explanation for this strange quantum behaviour — the Copenhagen interpretation, promulgated in the 1920s by Niels Bohr and Werner Heisenberg — the wave is not a physical entity but describes the probabilities for each possible measurement. The superposed states collapse when a reading is taken and an outcome is realized. The Universe is cast in this interpretation as a cosmic apartheid, split into a determinate real domain and an indeterminate quantum domain. The measurement switch between them is abrupt, magically eliminating all possibilities bar one. COURTESY OF M. EVERETT Hugh Everett III: his 'many worlds' theory was ignored for years after it was published. In his 1957 doctoral dissertation, written under the supervision of John Wheeler, Everett found a simple yet outlandish way to avoid this bizarre collapse of the wave function. When a quantum system is measured, he proposed, the alternative possibilities don't vanish — the system splits into a series of parallel, almost-identical worlds. Each of these worlds itself keeps branching as more measurements unfold, the junctures being at every place where the quantum domain contacts the classical world. "Schizophrenia with a vengeance," wrote one of Everett's sympathizers. Everett's idea wasn't taken seriously, even though it worked. Fellow graduate student Charles Misner recalls that "no one could fault his logic, even if they couldn't stomach his conclusions", adding that: "The most common reaction to this dilemma was just to ignore Hugh's work." Everett left the field and never published on quantum mechanics again. Fortunately, the cold war created a market for game-theorists and modellers, who worked in military research to chart the possible outcomes of nuclear war. Here Everett found respect, having invented an 'Everett algorithm' to improve on the traditional Lagrange multiplier method for calculating consequences in logistics problems. Starting in 1956, he worked for the Pentagon's top-secret Weapons Systems Evaluation Group, devising nuclear strategies and estimating the lethal effects of fallout, and from 1964 worked for the Lambda Corporation, another military think tank. Years after its publication, Everett's take on quantum mechanics was the subject of a 1970 article in Physics Today by theoretical physicist Bryce DeWitt, who named it the 'many worlds' interpretation. The catchy phrase helped attract attention to the idea and made it acceptable to discuss. Science-fiction authors also took note. Before Everett's dissertation, alternative worlds had featured in the fiction of H. G. Wells and Jorge Luis Borges, among others. Renewed scientific interest boosted the theory's popularity in science fiction, where it features still. Neal Stephenson's novel Anathem (William Morrow, 2008) is a recent example that uses it as a plot device. Invariably, however, these portrayals cheat the physics by intersecting the branched worlds. Everett's personal life was as erratic as his career. Byrne describes him as a stubborn, overweight, chain-smoking alcoholic who ignored his children and mistreated his wife. "His objective function didn't include emotional values," says one friend. According to another, "He looked at life as a game, and his object was to maximize fun. He thought physics was fun. He thought nuclear war was fun." Or modelling it, anyway. At the end of his life, the near-bankrupt Everett was writing code for a software program to calculate mortgage payments in various scenarios. He died of a heart attack while drunk. As paramedics carried the corpse away, his son realized that he did not remember ever having touched his father in life. Following Everett's wishes, his widow threw out his cremated remains in the rubbish. His daughter, who had schizophrenia and married an addict, became addicted to alcohol and drugs herself and later committed suicide. The Many Worlds of Hugh Everett III is short on critical analysis and slightly long on sordid details. There is much championing of Everett and his theories. Byrne's opinions can be heavy-handed, and he casts Bohr and Wheeler as villains. He strains hard to find meaning, proposing that the story of Everett's flamboyant mother Katherine, a pulp-fiction writer with manic depression, "captures the difficulty of being a self-reliant woman in mid 20th century America", and that Everett's life "reflects America's collective personality during the Cold War and beyond". Byrne does not clearly explain why most scientists find Everett's interpretation to be over the top. "It's an extravagant violation of Occam's Razor," as one of my physicist colleagues puts it. Why postulate uncountable infinities of unknowable, branching universes to address a problem for which there are solutions that prune the branches? Everett's idea is merely an interpretation; it fails to make predictions and cannot be falsified. The many worlds theory is still garish after all these years. Nevertheless, it is fascinating to read the story of its creator, himself too obsessed with models to intersect effectively with the real world. Author information * Author information * Comments Affiliations * Robert P. Crease is professor of philosophy at Stony Brook University, 213 Harriman Hall, Stony Brook, New York 11794-3750, USA. He is author of The Great Equations and J. Robert Oppenheimer: A Life. rcrease@notes.cc.sunysb.edu Additional data
• Soft-matter miracles
  - Nature (London) 465(7301):1011 (2010)
  Nature | Books and Arts | Opinion Soft-matter miracles * David Quéré1Journal name:NatureVolume:465,Page:1011Date published:(24 June 2010)DOI:doi:10.1038/4651011aPublished online23 June 2010 Matière sensible: Mousses, gels, cristaux liquides et autres miracles (Sensitive Matter: Foams, Gels, Liquid Crystals and Other Miracles) by Michel Mitov Seuil: 2010. 179 pp.18 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Soft-matter research investigates ambiguous states of matter, the paradoxical properties of which rely on the art of mixture. An emulsion formed simply of oil and water plus a few molecules of detergent gains the stability of a cream. Similarly, foam produced from air bubbles in soapy water transforms those two fluids into an almost-solid state. In Matière sensible, liquid-crystal researcher Michel Mitov marvels at the surprising behaviour of these materials. Rather than naming the book after his discipline, Mitov uses the title 'sensitive matter'. The expression 'soft matter' was coined as a joke in the 1970s by physicist Madeleine Veyssié — indeed, the French term matière molle sounds sleazy. However, it acquired a majesty when physicist Pierre-Gilles de Gennes chose it as the title of his Nobel lecture in 1991. From then on, the scientific community was converted. Mitov's book, in French, begins with a description of emulsions, foams, polymer solutions, gels and colloids. He introduces their first sensitive quality — that tiny quantities of additives can dramatically alter the properties of a liquid. Bubbles and foams are created by adding less than one-tenth of a gram of soap to a litre of water. This blocks the gravitational drainage that would otherwise make these constructions collapse in a fraction of a second. Firemen know that a similar concentration of long polymer chains in water makes jets of the fluid twice as powerful by reducing turbulence in the hose. Remarkably, both of these examples remain partly unexplained: in this field, art often precedes understanding by decades. S. LAPORTA/AP San Gennaro's 'blood' may owe its liquefaction to the quirks of soft matter. The book reveals another form of sensitivity — that many of these critical architectures are easily disrupted. Small causes can generate big effects. Mitov explains how foam can be destroyed by hydrophobic particles; shampooing hair for a second time, for example, gives more lather than the first because the dirt particles have been removed. He also explains how tiny changes in pH or temperature can destroy the lipid capsules that surround many drugs. It is this controlled disintegration that allows drug delivery to specific places in the body. The control of soft matter is even more fascinating than its architecture. Mitov describes the miracle of San Gennaro, a ritual that has taken place three times a year since 1389 in Naples cathedral, Italy. In the ceremony, a sealed glass ampoule is displayed to the faithful. It contains a brown solid that is said to be the blood of San Gennaro. At the end of the ceremony, the substance often liquefies into a soft gel that looks like wet blood. Mitov describes witnessing the ritual and puzzles at how the miracle works. The phenomenon is seasonal, the blood being more fluid in warmer weather, implying that the brown material might be temperature-sensitive. Alternatively, the gel's fluidity may be driven by manipulation of the ampoule, as is the case for some Bingham fluids that flow above a given stress, or for thixotropic liquids whose viscosity can decrease as stress increases. Mitov suggests centuries-old recipes for materials that give such behaviour, including spermaceti — a waxy lipid extracted from whales' heads — or clay solutions. But he ultimately allows uncertainty to persist, suggesting only that the sacred 'blood' might contain a blend of both elements. This emblematic example shows how subtle and smart a complex fluid can be, and illustrates the challenge of understanding these diverse materials. Mitov doesn't say much about the future of soft-matter research. But his book ably reflects a goal of the field — to extract beautiful intellectual challenges from 'dirty' industrial or everyday questions. Matière sensible is an excellent guide to the labyrinthine world of soft matter. Author information * Author information * Comments Affiliations * David Quéré is professor of physics at the École Polytechnique, 91128 Palaiseau, France, and a senior scientist at CNRS/ESPCI, 10 Rue Vauquelin, Paris, France. He is co-author of the book Capillarity and Wetting Phenomena: Drops, Bubbles, Pearls, Waves. david.quere@espci.fr Additional data
• Stem-cell theatrics
  - Nature (London) 465(7301):1012 (2010)
  Nature | Books and Arts | Opinion Stem-cell theatrics * Giuseppe Testa1Journal name:NatureVolume:465,Page:1012Date published:(24 June 2010)DOI:doi:10.1038/4651012aPublished online23 June 2010 Staminalia: A Dream and a Trial Written and directed by Valeria Patera Commissioned by the consortia ESTOOLS and NeuroStemcell, among others. 27 May, Gulbenkian Foundation, Lisbon Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Good theatre needs good conflicts — and stem-cell science provides plenty. Written and directed by Valeria Patera, the play Staminalia premiered at the Gulbenkian Foundation in Lisbon on 27 May during the final meeting of the ESTOOLS consortium. Funded by the European Union, the consortium has pioneered tools for human embryonic stem-cell research over the past four years (http://www.estools.eu). The production is based on philosopher Armando Massarenti's Italian-language book Staminalia (Guanda, 2008; see Nature456, 444–445; 2008), which describes the fierce political disputes that have erupted over stem-cell research in Italy. The play was also inspired by Elena Cattaneo, a leading stem-cell scientist at the University of Milan who is a prominent voice in the Italian public debate. The play is in two parts: a trial and a dream. The trial unfolds as a dialogue between a stem-cell scientist and her religious fundamentalist daughter. The walls of the scientist's university have been tarnished with graffiti equating stem-cell labs with Auschwitz, and the harsh confrontation between mother and daughter exposes two incompatible views of the world and of our place within it. The dream is the most convincing section of the play; drama thrives when clashes are whispered rather than shouted, when tension is evoked rather than declared. A tense piece of modern ballet conveys the unease unleashed in the sleeping mother by her daughter's accusations. Two dancers — playing supportive angels and doubt-mongering demons — sculpt the space, while images of stem cells and Catholic clerics flash onto the screen behind them. The contrast between the near-naked dancers and the shrouded cardinals with faces distorted as if in a Francis Bacon painting powerfully conveys the clash between two views of the flesh — joyful and liberated versus sinful and oppressed. A further contrast is in scale, between the macroscopic bodies on stage and their molecular equivalents on the screen, the latter a dance of cells lit up with the markers that have become the epistemic and aesthetic canon of stem-cell science. http://WWW.DAVIDEDORTONA. COM Dance, drama, ethics — and biotechnology. These juxtapositions highlight how, in modern biology — from genome sequencing to synthetic biology — we understand life through the same tools that allow us to redesign it. Science has developed beyond mere observation, beyond the paltry task of discerning "the seed from the oak tree", as the mother describes it in the trial. The dream reminds us that we understand bodies by breaking them apart into components and that this microscopic gaze brings with it the power of molecular intervention. The more we learn about cells, the more we are able to manipulate them — and the more options society has to use them. Which options should we choose? In the age of simple observation, nature was considered a source of moral norms. With the advent of molecular intervention, nature has become a source of tools with which to transgress its own limits. Staminalia captures this tension well. The dancers' bodies are natural both in their near-nakedness and in the perfection of their movements, achieved through years of training. The play prompts us to ask whether our response to them would be different if artificial enhancement of our bodies could replace countless hours in the gym. In the age of synthetic genomes and cell-fate reassignment, will we be able to tell natural from unnatural? And does that matter? We will need the best of our collective creativity to align the scientific and social innovations of the molecular age. Staminalia is thus a fitting celebration of ESTOOLS, a consortium that has put bioethical analysis and creative public engagement at the forefront of its activities. Author information * Author information * Comments Affiliations * Giuseppe Testa is a stem-cell biologist and bioethicist at the European Institute of Oncology, Milan, Italy. His forthcoming book with Helga Nowotny is Naked Genes: Reinventing the Human in the Molecular Age. giuseppe.testa@ifom-ieo-campus.it Additional data
• Books in brief
  - Nature (London) 465(7301):1012 (2010)
  Nature | Books and Arts | Opinion Books in brief * Joanne Baker Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:1012Date published:(24 June 2010)DOI:doi:10.1038/4651012bPublished online23 June 2010 Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Humans took a wrong evolutionary turn when they invented agriculture, argues geneticist and geographer Spencer Wells in Pandora's Seed (Allen Lane, 2010). Our hunter-gatherer bodies are ill-equipped for the overly structured life ushered in by managed food production: grain crops have made us sedentary overbreeders, and animal husbandry has entrenched disease. The societal hierarchies that formed to control food resources and maintain inequality have led to the stress-related illnesses of today. Wells suggests that we should instead match our lifestyle to our genetic inheritance. Death writ large is the subject of How it Ends (W. W. Norton, 2010) by astronomer Chris Impey. From individuals to species, our planet and the Universe, the book uses the thread of extinction to poke at issues such as the extension of human life, evolutionary competition and cosmology. Impey cautions that we cannot escape the Sun's eventual dimming and the disintegration of space-time, but takes a holistic rather than a mournful view, seeing existence as a fleeting joy. Vanished Ocean (Oxford Univ. Press, 2010) pieces together the story of Tethys, a vast equatorial waterway that disappeared some 6 million years ago when the continents shifted. Only small pools such as the Caspian Sea remain. Geologist Dorrik Stow explains the detective work that has unearthed Tethys's shadow in rocks from Morocco to China. He relates this ocean's significance for the fossil record, from dinosaurs to the organisms that formed oil, and how its disappearance holds lessons for understanding environmental change today. Stow also recalls the drying up and refilling of the Mediterranean, highlighting the impact of shifting oceans on climate. Additional data
• Q&A: Prime-time dissection with Joy Reidenberg
  - Nature (London) 465(7301):1013 (2010)
  Nature | Books and Arts | Opinion Q&A: Prime-time dissection with Joy Reidenberg * John Gilbey Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:1013Date published:(24 June 2010)DOI:doi:10.1038/4651013aPublished online23 June 2010 Joy Reidenberg is a professor of anatomy at Mount Sinai School of Medicine in New York. She is also the scalpel-wielding comparative anatomist in the award-winning documentary series Inside Nature's Giants (titled Raw Anatomy in the United States), the second series of which is currently being screened. Reidenberg explains why the spectacle of slicing up animals is good for the public understanding of science and why the discipline of anatomy is still very much alive. Inside Nature's Giants/Raw Anatomy Now showing on UK Channel 4 and on the US National Geographic Channel. Produced by Windfall Films Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg WINDFALL FILMS Each programme centres on the dissection of a large animal — in this series, we look at a great white shark, big cats and a giant squid. I cut open the animal and interpret its structures and features, and co-presenter Richard Dawkins adds the evolutionary background. It is amazing to see how different each animal has become through adaptations to varying environments. We also see a lot of commonalities, indicating that many animals arose from a shared ancestor. No animals were killed specifically for the programmes. A wish list of target animals was identified, and the crew scouted out corpses of candidates from that list. In the case of the whale that we dissected in the first series, its stranding was very sad, but it was serendipitous for us. The fact that some people get nauseous when exposed to the sight of a dissection is a comment on our cultural brainwashing. In a less-developed society, in which meat doesn't come from a supermarket, we would have to go out and kill animals for food. When we see dead meat, we should get hungry, not nauseous. Perhaps many of us have moved away from this cultural viewpoint to fit into society. But there is also a deep attraction to anatomy that could be considered a retreat to wilder, uncivilized days. Anatomy is a visual science. I was attracted to it because it was the perfect way to combine art and science — two disciplines that I love, because I am also an artist. My lab looks at animals that have unusual anatomy, especially those adapted to environmental extremes. We hope to find inspiration in nature so that we can model those adaptations to create new medical cures, treatments or protective technologies for humans. Doing this series is the perfect way to combine my research and teaching. I fly all over the world to dissect the most unusual animals. I also reach a much wider audience than I would if I was restricted to the academic lecture hall. I hope that viewers will appreciate the diversity of scientific research, including field and bench work. They will see basic scientists as people who are trying to improve our understanding of nature, and applied scientists as those who are trying to mimic nature. It will help people to be less frightened of their own insides, and more fascinated by why and how their body has evolved and how it functions. I would like to see a follow-up series that delves deeper into the scientific proof of evolution: it is embarrassing to me that so many Americans reject evolution. Fans have said that they have been inspired to become veterinarians or research scientists after seeing the series. Some women congratulate me for being a pioneer and role model for young women aspiring to enter the mostly male-dominated field of science. Some folks just admire my bravery in delving into the slime to literally dissect the animal from the inside out. Unfortunately, many people think that it is an old and outdated science, and that everything has already been found. In fact, huge discoveries are still happening. Some of the most exciting ones have come from advances in visualizing living anatomy by using modern imaging technologies. For example, in my own research area, fossils are being reconstructed on the basis of anatomical relationships derived from images of live animals — these show how soft tissues and bone interact under varying controlled conditions. I would like to dissect a penguin. It is an aquatic bird with an external body form that has evolved and converged with that of marine mammals. I think it would be fascinating to trace how it differs internally from other birds — aquatic, terrestrial and tree-dwelling — and explore the similarities with other aquatic animals. Additional data
• Astronomy: Exoplanet caught speeding
  - Nature (London) 465(7301):1017 (2010)
  Nature | News and Views Astronomy: Exoplanet caught speeding * Mercedes López-Morales1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Pages:1017–1018Date published:(24 June 2010)DOI:doi:10.1038/4651017aPublished online23 June 2010 The masses of exoplanets have so far been inferred from the tiny gravitational pull they exert on the host stars. It is now possible to measure them from shifts in spectral lines arising from the planets' atmospheres. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Binary stars are gravitationally bound pairs of stars that orbit a common centre of mass. They are valuable systems. For more than a century, they have enabled astronomers to measure the masses of stars directly. All that was needed was to interlace Newton's law of gravitation with measurements of the stars' Doppler shift — the change in the wavelength of their light spectrum that is caused by their motion towards or away from Earth. A star–planet system is also a binary system but is a special case: one of the objects (the planet) is much smaller and fainter than the other (the host star), so that only the star's light, and therefore its Doppler shift (the so-called wobble), can be detected easily. For this reason, the masses of exoplanets have never been measured directly but only inferred — until now. On page 1049 of this issue, Snellen et al.1 provide the first evidence of an exoplanet's Doppler signal, which enabled them to measure the planet's mass directly. Snellen and his team have developed an ingenious strategy to detect an exoplanet's Doppler signal (Fig. 1, overleaf). While the known exoplanet HD 209458b (refs 2, 3) moved across the face of (transited) its host star, the authors monitored it by using high-resolution spectroscopy, which is sensitive to small changes in a planet's orbital velocity. They focused their analysis on a small region in the near-infrared part of the spectrum, between 2.29 and 2.35 micrometres, in which they predicted that the atmosphere of the planet would produce many spectral lines. For this planet, they expected spectral lines to be produced by carbon monoxide, water vapour or methane. During a planetary transit, the light from the star passes through the thin atmosphere of the planet. The chemicals in that atmosphere produce small spectral absorption lines on the stellar spectrum. Because of the fast orbital motion of the planet with respect to the star, the planet's atmospheric spectral lines ! appear shifted by an amount that can be detected by carefully analysing the data. Figure 1: An exoplanet's Doppler signal. When a planet passes in front of its host star, light from the star crosses the atmosphere of the planet. During the crossing, the stellar light is partially absorbed by molecules in the planet's atmosphere. Depending on whether the planet moves towards or away from an observer on Earth, when the stellar light reaches the observer, absorption lines arising from the planet's atmosphere will be shifted towards the blue part of the light spectrum (shorter wavelength) or the red part (longer wavelength), respectively. By measuring these Doppler shifts in atmospheric absorption lines, Snellen et al.1 have been able to detect the orbital motion of the planet directly and in this way derive its mass. * Full size image (95 KB) With their technique, Snellen and colleagues1 were able not only to detect both the orbital motion of the planet, which moves at a speed of about 140 kilometres per second around the star, and its mass (0.64 times the mass of Jupiter), but also to estimate the abundance of molecules in the planet's atmosphere. The authors clearly detected absorption lines attributable to CO but did not detect either H2O or CH4. What's more, the team's data reveal what seems to be the first direct indication of longitudinal winds in an exoplanetary atmosphere. Analogously to the Earth–Moon system, HD 209458b is tidally locked to its host star, meaning that the same side of the planet always faces the star. As a result, the planet has a hot dayside, heavily irradiated by stellar light, and a cooler nightside, which is never directly lit by the star. As in any fluid with a temperature gradient, heat moves from the hot side of the planet to the cold one, resulting in longitudinal atmospheric winds. From the perspective of an observer on Earth, when the planet crosses in front of the star, the heat flow in the atmosphere is observed as material, in this case CO gas, moving towards the observer; that is, the CO spectral lines are shifted towards the blue part of the spectrum. Snellen et al.1 detect longitudinal winds of about 2 km per second, which is more than 7,000 km per hour — roughly six times t! he speed of sound at Earth's sea level. Measuring spectral lines from molecules in the atmosphere of an exoplanet and using them to derive the planet's mass directly is a remarkable achievement. Equally striking is the fact that the observations have been made using ground-based telescope facilities. Until just a few months ago, such challenging precision measurements were thought to be possible only from space-based platforms. The high variability of Earth's atmosphere seemed to present an insuperable obstacle to attaining the precision necessary for detecting the faint signal of exoplanets. Space-borne instruments such as the Spitzer Space Telescope and the Hubble Space Telescope were the only option and, with the cryogenic lifetime of Spitzer coming to an end, the new field of exoplanet atmosphere studies might have come to a grinding halt until the launch of the James Webb Space Telescope, scheduled for 2014. Snellen and colleagues' results1 were obtained with one of the European Southern Observatory's Very Large Telescopes, which have a main mirror of 8.2 metres in diameter, and their findings are just the tip of the iceberg in understanding the physics of exoplanet atmospheres. A new fleet of telescopes with primary mirrors of 20 m or more is in sight — including the planned Giant Magellan Telescope (24.5 m), the Thirty Meter Telescope (30 m) and the European Extremely Large Telescope (42 m) — ensuring further progress in this field. Small rocky planets like Earth will soon be discovered. When this happens, and if current developments in instrumentation and observational techniques continue, researchers will be ready to characterize the atmosphere of these planets. References * References * Author information * Comments * Snellen, I. A. G., de Kok, R. J., de Mooij, E. J. W. & Albrecht, S.Nature465, 1049–1051 (2010). * Article * Charbonneau, D., Brown, T. M., Latham, D. W. & Mayor, M.Astrophys. J.529, L45–L48 (2000). * ISI * PubMed * Article * Henry, G. W., Marcy, G. W., Butler, R. P. & Vogt, S. S.Astrophys. J.529, L41–L44 (2000). * ISI * PubMed * Article Download references Author information * References * Author information * Comments Affiliations * Mercedes López-Morales is in the Department of Terrestrial Magnetism, Carnegie Institution of Washington, Washington DC 20015, USA. mercedes@dtm.ciw.edu Additional data
• Ecology: Fish in Lévy-flight foraging
  - Nature (London) 465(7301):1018 (2010)
  Nature | News and Views Ecology: Fish in Lévy-flight foraging * Gandhimohan M. Viswanathan1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Pages:1018–1019Date published:(24 June 2010)DOI:doi:10.1038/4651018aPublished online23 June 2010 Lévy flights are a theoretical construct that has attracted wide interdisciplinary interest. Empirical evidence shows that the principle applies to the foraging of marine predators. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Ecologists have long drawn inspiration from mathematics. Theory applied to population dynamics is one example. Another is the Lévy-flight foraging hypothesis1, which has been invoked to explain the strategies of organisms searching for food. Lévy flights, or walks, are characterized by rare but extremely long 'step' lengths, and the same sites are revisited much less frequently than in a normal diffusion process. The existence of Lévy flights as a foraging strategy has been the subject of controversy, but Humphries et al.2 (page 1066 of this issue) now report a notable advance. They have carried out a direct empirical test of the Lévy-flight foraging hypothesis, using the largest animal-movement data set assembled for this purpose. How organisms move and disperse is of central importance in several fields. The classic paradigm of simple diffusion is used to describe a wide variety of phenomena, ranging from how humans dispersed out of Africa to how pollen spreads. Until the twentieth century, Fick's laws were thought to be universally valid for describing diffusion. The physiologist Adolf Fick introduced the idea that diffusion is proportional to the gradient of concentration; this idea describes Brownian motion and is analogous to Fourier's law of heat conduction. A prediction of the theory of Fickian diffusion is that the mean squared displacement of a 'random walker' increases linearly with time, not superlinearly (for example, quadratically) or sublinearly (for example, as the square root). Any process that is inconsistent with Fick's laws is known as anomalous diffusion: superdiffusion leads to superlinear growth of the mean squared displacement with time, whereas subdiffusion leads to sublinear g! rowth. Much of the interest in Lévy flights is due to their superdiffusive properties. The rare but long steps of Lévy flights follow the simple rule that a step of length l is chosen from a probability density function P(l) ~ l−μ, with 1 < μ ≤ 3. Such an asymptotic power-law function is sometimes termed a 'fat-tailed distribution' because the tail falls off much more gently than for a Gaussian (or normal) distribution — hence it is 'fat'. This property lies at the heart of the interesting and unusual behaviour of Lévy flights. Why would animals adopt a Lévy-flight foraging strategy? In a Brownian random walk, the walker frequently returns to the same place (Fig. 1). By contrast, Lévy walkers can outperform Brownian walkers by revisiting sites far less often1, 3. Biological Lévy flights were first conjectured to be a useful search strategy in 1985, during a NATO Advanced Study Institute conference4. A decade later, an analysis of data obtained from recording devices attached to the legs of wandering albatrosses generated broad interest in biological Lévy flights and prompted many further investigations5. Figure 1: Comparison of a Lévy flight with a Brownian random walk. , Walks of identical total length of 1,000 unit steps are shown drawn to scale. Lévy flights (or walks) have ultra-long steps, which are absent from Brownian walks. , A close-up of the Brownian walk, in which the walker returns many times to previously visited locations (a phenomenon known as 'oversampling'). By contrast, the Lévy walker occasionally takes long jumps to new territory. This reduction in oversampling is part of the theoretical basis for interest in the Lévy-flight foraging hypothesis, which predicts that Lévy flights offer higher search efficiencies in environments where prey is scarce. Humphries et al.2 show that marine predators often move in patterns that are consistent with this hypothesis. (Plots modified from ref. 10.) * Full size image (98 KB) Formulation of the Lévy-flight foraging hypothesis arose from a study1 that showed mathematically that Lévy flights, characterized by an inverse square distribution of step lengths, optimize random searches under specific conditions, when targets (such as prey) are scarce. Scarcity of resources is common, and observations of Lévy flights have been extended to species ranging from dinoflagellates6 to fish7, and even to human movement8. Such findings have been the subject of a News Feature in these pages9. Moreover, random search has blossomed into an interdisciplinary subfield of physics3, as discussed in a new book on the physics of foraging10. The results reported by Humphries et al.2 give a convincing answer to whether the Lévy-flight foraging hypothesis stands up to empirical scrutiny — one of the more controversial problems in theoretical movement ecology. The authors' data set of more than 107 measurements, compiled from electronic tags on 55 individual fish — sharks, tuna, billfish and a sunfish— is an order of magnitude larger than the last reported data set7. They find strong evidence of Lévy flights, but, as predicted theoretically, these flights are not universal. Lévy flights are expected in places where prey is scarce (such as the open ocean), whereas a Brownian strategy is more likely to occur where prey is abundant (as in marine regions where the mixing of water bodies produces high densities of phytoplankton, zooplankton and organisms higher in the food chain). The observed2 pattern of switching between search modes is not entirely consistent with these expectations. But it is nonetheless pl! ausible, as seen for instance in the data on a blue shark that moved from the prey-rich waters of the western English Channel to the oceanic environment of the Bay of Biscay. The fact that some organisms perform Lévy flights has deep implications that transcend those for marine ecosystems, and it raises many questions. Did humans disperse from Africa superdiffusively rather than diffusively? Does pollen from genetically modified crops spread superdiffusively? What are the consequences if influenza epidemics spread superdiffusively? In a reaction-diffusion context, superdiffusion leads to significantly increased overall reaction rates, because the reacting species — which may be chemical or biological — meet each other more often. What more can be learned about such interactions? These questions and many more await investigation. References * References * Author information * Comments * Viswanathan, G. M.et al. Nature401, 911–914 (1999). * ChemPort * ISI * PubMed * Article * Humphries, N. E.et al. Nature465, 1066–1069 (2010). * Article * Raposo, E. P., Buldyrev, S. V., da Luz, M. G. E., Viswanathan, G. M. & Stanley, H. E.J. Phys. A42, 434003 (2009). * Article * Shlesinger, M. F. & Klafter, J. in On Growth and Form (eds Stanley, H. E. & Ostrowsky, N.) 279–283 (Kluwer, 1985). * Viswanathan, G. M.et al. Nature381, 413–415 (1996). * ChemPort * ISI * Article * Bartumeus, F., Peters, F., Pueyo, S., Marrasé, C. & Catalan, J.Proc. Natl Acad. Sci. USA100, 12771–12775 (2003). * ChemPort * PubMed * Article * Sims, D. W.et al. Nature451, 1098–1102 (2008). * ChemPort * PubMed * Article * González, M. C., Hidalgo, C. A. & Barabási, A.-L.Nature453, 779–782 (2008). * ChemPort * PubMed * Article * Buchanan, M.Nature453, 714–716 (2008). * ChemPort * PubMed * Article * Viswanathan, G. M., da Luz, M. G. E., Raposo, E. P. & Stanley, H. E.The Physics of Foraging (Cambridge Univ. Press, in the press). Download references Author information * References * Author information * Comments Affiliations * Gandhimohan M. Viswanathan is at the Instituto de Física, Universidade Federal de Alagoas, Maceió, Alagoas 57072-970, Brazil. gandhi.viswanathan@pq.cnpq.br Additional data
• Evolutionary biology: Expanding islands of speciation
  - Nature (London) 465(7301):1019 (2010)
  Nature | News and Views Evolutionary biology: Expanding islands of speciation * Erin S. Kelleher1 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel A. Barbash1 Search for this author in: * NPG journals * PubMed * Google Scholar * AffiliationsJournal name:NatureVolume:465,Pages:1019–1020Date published:(24 June 2010)DOI:doi:10.1038/4651019aPublished online23 June 2010 Speciation can occur even when the incipient species coexist and can interbreed. An extensive analysis of two fruitfly strains suggests that many genomic regions contribute to speciation in such cases. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Speciation is a process of branching, whereby one species splits into two. How do the genomes of two nascent species become differentiated from each other in sympatry, the situation in which they share a geographical range and can exchange genetic information through interbreeding? In a paper published in Proceedings of the National Academy of Sciences, Michel et al.1 address this question. They reveal that the degree of genomic differentiation in the early stages of sympatric speciation may be vastly under-appreciated. Michel and colleagues studied two strains of the fruitfly Rhagoletis pomonella (Fig. 1, overleaf), which feed and breed on hawthorn and apple fruits, respectively, and demonstrate that their genomes are highly differentiated. This finding stands in contrast to 'genomic island' models2, according to which interbreeding homogenizes the vast majority of the genome between incipient species, except for a few regions that are crucial for the reproductive isolation that is ultimately necessary for species to diverge. It is particularly unexpected because the colonization of apple fruits by hawthorn R. pomonella occurred only about 150 years ago, suggesting that this exceptional genomic divergence has occurred in the evolutionary blink of an eye. Figure 1: Rhagoletis pomonella — genomic test case for sympatric speciation. J. BERGER, BUGWOOD.ORG * Full size image (81 KB) Sympatric speciation has long been a contentious topic. Darwin himself was a proponent of speciation in sympatry, arguing that competition is an engine of speciation and biodiversity3. Evolutionary biologists, however, have struggled to understand how two distinct gene pools emerge from a single population of organisms in the face of interbreeding and genetic exchange. Benjamin Walsh, an early investigator of R. pomonella, proposed4 that their specialized ecology, in which they favour a particular host plant, allows for sympatric speciation when members of the population are able to colonize a new host such as apple fruit. Adaptation to a new host requires differences in traits such as breeding time, which will isolate colonizing individuals from those that remain on the ancestral host. Recent hypotheses about sympatric speciation have focused on the genomic architecture of divergence, such as how much genetic variation is shared between incipient species, and how this variation is distributed throughout the genome. One hypothesis5, 6 is that chromosomal rearrangements such as inversions, in which part of a chromosome becomes reversed, can provide a 'safe haven' that maintains clusters of genes that influence reproductive isolation. The process of recombination between different arrangements of parental chromosomes is often suppressed or can produce inviable progeny, effectively eliminating genetic exchange and allowing divergent gene clusters to be maintained in the face of interbreeding and gene flow between incipient species. An alternative view7 is that genes subject to strong divergent selection between incipient species, such as those relevant for habitat choice, can create differentiated regions in the genome even in the absence of chromosomal rearrangements. Selection on such genes will also lead to differentiation of adjacent genes owing to their physical association. If the adjacent genes themselves acquire genetic variation that is disparately adaptive between incipient species, the differentiated region will expand in size between forms. Genomic models of speciation with gene flow make a simple prediction — during the early stages of speciation, some genomic islands will be clearly distinguishable between incipient species, but the vast majority of the genome will remain undifferentiated because of considerable genetic exchange. Several studies have used population-genetic approaches to reveal exactly this pattern. For example, two forms of the mosquito Anopheles gambiae are distinguishable in only three chromosomal regions containing unique genetic variation, whereas the rest of the genome contains shared variation2, 8, 9. In the pea aphid Acyrthosiphon pisum pisum, highly differentiated regions between forms that breed on red clover and alfalfa are clustered near genomic regions that affect habitat choice, linking exceptionally divergent regions with those that might influence reproductive isolation7. At first glance, Michel and colleagues' study1 seems to recapitulate previous conclusions about the genomic signatures of sympatric speciation. Their application of standard population-genetic methods reveals that genetic variation between the apple and hawthorn strains of R. pomonella is exceptional in only two independent regions of the genome. Both of these regions are encompassed by chromosomal rearrangements, which is consistent with the hypothesized role of reduced recombination. However, the authors probed more deeply into the ecologically based differences between the two strains. They took into account their geographical range (according to latitude), their timing of eclosion (emergence of an adult from a pupa) and the extent of diapause (environmentally induced developmental arrest). That is, they examined how genetic variation changed across latitude, associated genetic variation with differences in eclosion time, and performed laboratory selection experiments on diapause versus direct development to observe the response of linked genetic markers. Differences in the fruiting times of apple and hawthorn trees, the new and ancestral hosts of R. pomonella, make diapause and eclosion traits ecologically crucial for host adaptation and reproductive isolation. Strikingly, Michel et al.1 found that more than 50% (of 39) sampled genomic loci show evidence of adaptive differences, and many seem not to be within chromosomal rearrangements. Their results suggest that much more of the genome may be differentiated between sympatric incipient species than previously thought. Useful extensions of this work would be to obtain a better understanding of the positions and frequencies of chromosomal inversions in the apple and hawthorn strains, and to increase the density of genetic markers to provide a more detailed picture of genomic divergence. One implication of the results of Michel et al. is that studies of sympatric speciation that are confined to identifying genomic regions of exceptional differentiation between strains are potentially misleading in overlooking regions that affect reproductive isolation. This conclusion is echoed in several reports and reviews on the topic6, 9, 10. Further investigation of candidate genomic regions involved in reproductive isolation remains a promising direction for research, both in R. pomonella and in other examples of incipient speciation with gene flow, such as in pea aphids, A. gambiae mosquitoes and cichlid fish. References * References * Author information * Comments * Michel, A. P.et al. Proc. Natl Acad. Sci. USA107, 9724–9729 (2010). * PubMed * Article * Turner, T. L., Hahn, M. W. & Nuzhdin, S. V.PLoS Biol.3, e285 (2005). * ChemPort * PubMed * Article * Darwin, C.On the Origin of Species (Murray, 1859). * Walsh, B. D.Proc. Entomol. Soc. Phil.3, 403–430 (1864). * Navarro, A. & Barton, N. H.Evolution57, 447–459 (2003). * ISI * PubMed * Noor, M. A. F. & Bennett, S. M.Heredity103, 439–444 (2009). * ChemPort * PubMed * Article * Via, S. & West, J.Mol. Ecol.17, 4334–4345 (2008). * PubMed * Article * della Torre, A.et al. Insect Mol. Biol.10, 9–18 (2001). * ChemPort * PubMed * Article * White, B. J., Cheng, C., Simard, F., Costantini, C. & Besansky, N. J.Mol. Ecol.19, 925–939 (2010). * ChemPort * PubMed * Article * Turner, T. L. & Hahn, M. W.Mol. Ecol.19, 848–850 (2010). * PubMed * Article Download references Author information * References * Author information * Comments Affiliations * Erin S. Kelleher and Daniel A. Barbash are in the Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA. esk72@cornell.edu; dab87@cornell.edu Additional data
• Organic chemistry: Amide bonds made in reverse
  - Nature (London) 465(7301):1020 (2010)
  Nature | News and Views Organic chemistry: Amide bonds made in reverse * Karl Scheidt1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Pages:1020–1022Date published:(24 June 2010)DOI:doi:10.1038/4651020aPublished online23 June 2010 Amide bonds connect the amino acids in proteins and occur in many other useful molecules. An amide-forming reaction that turns the conventional approach on its head offers a practical way of making these bonds. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg As the main chemical linkage found in proteins, the amide bond is incredibly important. What's more, amides are found in many synthetic polymers, biologically active naturally occurring compounds and pharmaceutically active small molecules. The usual way in which chemists make amides is by reacting a carboxylic acid group (COOH), which is electron deficient, with an amine group (NHR, where R can be a hydrogen atom or a hydrocarbon group), which is electron rich. On page 1027 of this issue, Johnston and colleagues1 describe a fresh approach to forming amide bonds. In their process, the polarity of the reacting groups is reversed, thus overcoming some of the problems with existing methods. At first glance, the reaction of a carboxylic acid with an amine to make an amide — known as a condensation reaction because it produces water as a side product — looks simple (Fig. 1a). One might expect the electron-rich amine to attack and add to the electron-deficient acid when the two compounds are combined. In fact, each reactant must be chemically activated for condensation to occur, and this involves several challenges. Figure 1: Polarity reversal in amide synthesis. , Conventional protocols for amide synthesis involve the reaction of a carboxylic acid (an electron-deficient group) with an amine (an electron-rich group). The equilibrium of the process favours the starting materials, but the use of a dehydrating reagent to remove water that is formed during the reaction pushes the equilibrium towards the desired products. R1 and R2 represent hydrocarbon groups. , Johnston and colleagues1 report an umpolung strategy for amide synthesis, in which the electron polarity of the reagents is opposite to that in the conventional approach. Instead of carboxylic acids, they use α-bromo nitroalkanes, which are sources of electron-rich anions, and instead of amines, they use N-iodo amines, which are electron deficient. The nitro (NO2) group and the bromine and iodine atoms in the starting materials end up in side products of the reaction (not shown). The reaction is a practical alternative to conventional methods and overcomes some of the problems a! ssociated with those methods. * Full size image (40 KB) First, in the absence of an activating agent, the overall equilibrium of the process favours the starting materials rather than the products. Second, congestion caused by the presence of bulky groups around the amine and the acid can greatly slow the condensation. And last, but not least, the stereochemistry of the carboxylic acid — the orientation of the groups around the carbon atom to which the acid group is attached, often referred to as handedness — must be maintained. The last issue is particularly important when constructing peptides from chiral amino acids (those that have handedness). In many cases, the stereochemistry of these amino acids is sensitive — it can be scrambled under the conditions used to form amide bonds. Such scrambling would cause the resultant peptide to be formed as a complex mixture of isomers, each of which has different physical properties. In a spectacular demonstration of evolutionary power, nature has created the ribosome to produce amides with high efficiency and with complete control of the stereochemistry of each amino acid2, 3. A central challenge for chemists and biologists for more than 50 years has been to find similarly effective ways of making amides, but using simple reagents rather than complex biomolecular machinery. Many of the strategies that have been developed to form amide bonds involve removing the water that is formed as a side product, to push the equilibrium of the process towards the desired product4 (Fig. 1a). An early advance of this type was the discovery that carbodiimide compounds could function as dehydrating agents in the synthesis of β-lactam antibiotics5. Since the inception of using these reagents, many others have been devised to overcome the issues of reactivity and stereoselectivity. These have been tremendously successful, as demonstrated by the fact that Robert Bruce Merrifield's technology for peptide synthesis, for which he won the 1984 Nobel Prize in Chemistry, can be automated6. In addition to the conventional dehydration strategies, approaches based on other chemical reactions have emerged, greatly expanding the repertoire of amide syntheses. Among these, both Staudinger ligation7 and native chemical ligation8 have become useful techniques for making amide bonds between non-peptide substrates or between large peptide molecules. Powerful reactions in which transition-metal catalysts are used to form amides from amines and alcohols (which contain OH groups) have also been reported9. Yet, even after five decades of advances, there are still challenges in amide synthesis10. Johnston and colleagues1 now describe a new concept in the formation of amide bonds. They have essentially turned the problem upside down by reversing the electronic characteristics of the reactants used in dehydration reactions. In chemists' parlance, the general strategy of reversing the polarity of a functional group (from electron rich to electron poor, or vice versa) to facilitate a reaction that would not otherwise be possible is termed umpolung11. In their innovative approach, Johnston and colleagues used halo nitroalkanes, which are sources of electron-rich anions, as surrogates for carboxylic acids — more specifically, for the electron-poor carbonyl group (C=O) within the carboxylic acid (Fig. 1b). Similarly, they replaced electron-rich amines with electron-deficient amines, using N-iodo amines (in which one of the hydrogen atoms of an amine group has been replaced by an iodine atom). In fact, the authors made their N-iodo amines in situ, by simply adding a source of iodine to amines in their reaction mixtures. The addition of a base to the reactants triggers a process, presumably involving multiple steps, in which the halo nitroalkanes attack and react with the N-iodo amines, ultimately generating the desired amide. The authors propose a reaction mechanism (see Fig. 3 on page 1029) that, although not conclusively proven, is strongly supported by their experimental evidence1. The mechanism involves the formation of an unusual intermediate under mild conditions, which will certainly pique the interest of chemists, offering research opportunities for some time to come. The development of an umpolung amide-forming reaction is not just a satisfying intellectual achievement — there are far-reaching practical aspects to this work. When carried out with simple amines (many of which are cheaply available) and halo nitroalkanes (which are easily prepared), the reaction provides the expected amide products with reliable efficiency. But the process shines when used to make dipeptides, which are conventionally made by coupling two amino acids. Johnston and co-workers had previously found a catalyst that allowed them to make complex bromo nitroalkane compounds with a high level of control over the stereochemistry12. The authors have now1 used these compounds as surrogates for certain unusual amino acids (known as aryl glycines) in their umpolung reaction. Amide-forming reactions with aryl glycines are usually challenging, because the stereochemistry of the amino acids is easily scrambled. But the authors find that their new process delivers dipepti! des containing aryl glycines with no erosion of stereochemistry. What's more, they have demonstrated that the umpolung reaction works for all standard amino acids, with no erosion of stereochemistry. Johnston and colleagues' approach1 to amide synthesis is operationally straightforward, versatile and exciting. Given access to any basic collection of standard organic compounds, chemists will certainly be able to implement this method quickly. The mechanistically unusual process also opens up possibilities. For example, it is valuable to be able to take safe, readily available sources of nitrogen and incorporate nitrogen atoms into organic compounds, and the authors' work highlights a useful strategy for doing this that has not been fully appreciated. Finally, this umpolung reaction will undoubtedly aid medicinal chemists in making biologically active amide-containing compounds, some of which might one day help to treat disease. References * References * Author information * Comments * Shen, B., Makley, D. M. & Johnston, J. N.Nature465, 1027–1032 (2010). * Article * Williamson, J. R.Cell139, 1041–1043 (2009). * PubMed * Article * Yonath, A.Angew. Chem. Int. Edn49, 4340–4354 (2010). * Article * Montalbetti, C. A. G. N. & Falque, V.Tetrahedron61, 10827–10852 (2005). * Article * Sheehan, J. C. & Hess, G. P.J. Am. Chem. Soc.77, 1067–1068 (1955). * ChemPort * Article * Merrifield, R. B.Angew. Chem. Int. Edn Engl.24, 799–810 (1985). * Article * Köhn, M. & Breinbauer, R.Angew. Chem. Int. Edn43, 3106–3116 (2004). * Article * Kent, S. B. H.Chem. Soc. Rev.38, 338–351 (2009). * PubMed * Article * Gunanathan, C., Ben-David, Y. & Milstein, D.Science317, 790–792 (2007). * ChemPort * PubMed * Article * Valeur, E. & Bradley, M.Chem. Soc. Rev.38, 606–631 (2009). * ChemPort * PubMed * Article * Seebach, D.Angew. Chem. Int. Edn Engl.18, 239–258 (1979). * Article * Singh, A., Yoder, R. A., Shen, B. & Johnston, J. N.J. Am. Chem. Soc.129, 3466–3467 (2007). * ChemPort * PubMed * Article Download references Author information * References * Author information * Comments Affiliations * Karl Scheidt is in the Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Silverman Hall, Northwestern University, Evanston, Illinois 60208, USA. scheidt@northwestern.edu Additional data
• Neuroscience: A plastic axonal hotspot
  - Nature (London) 465(7301):1022 (2010)
  Nature | News and Views Neuroscience: A plastic axonal hotspot * Jan Gründemann1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Häusser1 Search for this author in: * NPG journals * PubMed * Google Scholar * AffiliationsJournal name:NatureVolume:465,Pages:1022–1023Date published:(24 June 2010)DOI:doi:10.1038/4651022aPublished online23 June 2010 Neurons generate their output signal — the action potential — in a distinct region of the axon called the initial segment. The location and extent of this trigger zone can be modified by neural activity to control excitability. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The brain changes with experience. But where are these changes, which ultimately result in altered patterns of activity, stored in neural circuits? Although the plasticity of the synaptic connections between neurons has received much attention, the intrinsic excitability of a neuron — its responsiveness to synaptic input — can also be markedly altered by experience. In this issue, two groups (Grubb and Burrone1 and Kuba et al.2) identify a new target of intrinsic plasticity in the axon, the output structure of the neuron. They show that the proximal region of the axon known as the axon initial segment, the initiation site of the action potential (the neuron's output signal), can be modified to make the cell more or less responsive to inputs. Activity-dependent changes in neural circuits are crucial for brain development and memory formation. Deprivation of a sensory modality such as visual input causes long-term changes in sensory circuits3. The conventional view is that such activity-dependent plasticity involves changes in the strength of synapses. This idea has tremendous appeal, given that synaptic changes can be highly specific and show a wide dynamic range, and that, given their vast numbers, synapses offer enormous capacity for information storage. Changing the overall intrinsic excitability of a neuron is an alternative, complementary mechanism for information storage. This widespread strategy, which is not specific to individual synapses, is of immense value in neural circuits. It allows multi-purpose circuits to switch between activity modes4, enables adjustments to be made in the firing rate of neurons during sensorimotor learning5, and provides a powerful mechanism for the homeostatic regulation of activity6. Intrinsic plasticity can come about through the altered composition, density and distribution of ion channels in the neuronal membrane that are activated by changes in voltage (voltage-gated ion channels). Which channels are altered, and where, is crucial for determining the selectivity and impact of the excitability change. Over the past decade, activity-dependent changes in the density and function of many voltage-gated channels have been reported7, 8, 9, 10. By being restricted to subneuronal compartments, such as individual segments of dendrites11, 12 — short, branching neuronal processes that receive synaptic input — such changes can provide some degree of specificity. But typically they are widespread, being found mainly in the neuron's cell body and dendrites. Grubb and Burrone1 (page 1070) and Kuba et al.2 (page 1075) implicate a specific axonal structure in intrinsic plasticity — the axon initial segment (AIS), a highly organized, ion-channel-enriched matrix of proteins that is situated close to the cell body. Significantly, the fact that the action potential is initiated in the AIS13 would allow this form of plasticity to regulate the final site of integration of the synaptic input directly. To investigate how the location of the AIS might depend on activity, Grubb and Burrone use cultures of neurons from the hippocampus. They find that when extracellular potassium levels are chronically elevated, mimicking increased neuronal activity, the AIS shifts away from the cell body. This movement involves wholesale translocation of several types of AIS-specific protein, thereby creating a non-excitable 'spacer' region — 21 micrometres long — between the AIS and the cell body. This shift further isolates the action-potential trigger site from the synaptic input to the dendrites and thereby reduces the ability of the input to trigger action potentials. Consequently, neurons with a more distal AIS are less excitable and require stronger stimulation to fire. To achieve more precise control over neuronal activity, Grubb and Burrone manipulated their cultures so that the neurons expressed a membrane protein called channelrhodopsin-2 (ChR2), which is a light-activated ion channel14 (Fig. 1a). They could then use light stimuli to directly trigger spiking with precise temporal control. Long-term, regular, low-frequency light stimulation at 1 hertz had little effect on AIS location. But when the neurons were activated by high-frequency bursts of light, the AIS shifted significantly. Figure 1: Intrinsic plasticity, courtesy of the axon initial segment (AIS). , Grubb and Burrone1 show that, in cultured hippocampal neurons expressing the light-activated channel ChR2, bursts of activity triggered by light lead to a calcium-dependent movement of the AIS away from the cell body. Consequently, neuronal excitability is reduced. , Kuba et al.2 find that, in neurons from the nucleus magnocellularis of chicks, deafness — and thus loss of sensory input — caused by removal of the cochlea increases the length of the AIS, leading to a corresponding compensatory increase in neuronal excitability. , Activity-dependent structural reorganization of the AIS can therefore shift the strength of the synaptic input required to produce a particular neuronal output — a homeostatic mechanism. * Full size image (54 KB) What mechanisms underlie these activity-dependent changes? Many forms of neuronal plasticity are triggered by increases in intracellular calcium-ion concentration. Indeed, Grubb and Burrone1 show that blocking T- and L-type calcium channels prevents the AIS from moving. This suggests that activity-dependent calcium signals provide a read-out of the pattern of neuronal activity, which triggers structural plasticity at the AIS. But these experiments were carried out on neurons in cell culture, raising the question of whether this form of homeostatic axonal plasticity occurs in the intact brain. Kuba et al.2 neatly answer this question. They had previously found that, in brainstem neurons responsible for encoding sound, the precise location and length of the AIS depend on the characteristic sound frequency that each neuron processes15. Now they have tested the effects of hearing loss on the AIS location (Fig. 1b). Removing the cochlea, the auditory part of the inner ear, from one-day-old chicks causes loss of synaptic input to neurons in the nucleus magnocellularis — an essential relay station in the auditory pathway. Kuba and co-workers find that such input deprivation has a dramatic effect on the AIS of these neurons: following hearing loss, the AIS is elongated by roughly 70%. These nucleus magnocellularis neurons lack dendrites, confirming that the excitability changes are indeed restricted to the axon. Intriguingly, although Kuba et al. did not detect changes in the density and subtype composition of sodium channels in the AIS, hearing deprivation increased total sodium currents in the axons, and this could be attributed to the expansion of the AIS. Consequently, smaller current injections were sufficient to trigger action potentials after hearing deprivation, indicating that neuronal excitability had increased to compensate for the reduced synaptic drive. Together, these papers1, 2 show that the AIS is a powerful target for homeostatic plasticity mechanisms. Notably, the changes in the AIS are bidirectional and reversible — properties crucial for the proposed homeostatic role of such mechanisms. The two studies also open the door to exploring how AIS plasticity occurs in different types of neuron under various conditions that affect neural circuits. For instance, both teams used relatively crude methods to alter neuronal activity: long-term increases in neuronal activity or sensory deprivation. More subtle and controlled manipulations, over shorter timescales, could reveal whether AIS plasticity is restricted to developmental and pathological conditions, or whether it is a normal physiological mechanism that could dynamically regulate excitability. The studies identify distinct mechanisms for modulating neuronal excitability — either displacement or extension of the AIS (Fig. 1a,b). It will therefore be necessary to determine which prevails in different neuronal network states and brain areas. Neither group directly addressed how the changes in the AIS alter the integration of synaptic input by the neurons. This is particularly relevant for inputs mediated by the neurotransmitter γ-aminobutyric acid (GABAergic inputs), which cluster at the AIS16. Do these GABAergic synapses move with the AIS, and, if not, how does this affect their ability to influence the generation of action potentials? Finally, if the molecular mechanisms underlying this form of plasticity are identified, they could provide targets for manipulating neuronal excitability in various disease states that involve altered excitability, particularly epilepsy. References * References * Author information * Comments * Grubb, M. S. & Burrone, J.Nature465, 1070–1074 (2010). * ChemPort * Article * Kuba, H., Oichi, Y. & Ohmori, H.Nature465, 1075–1078 (2010). * Article * Wiesel, T. N. & Hubel, D. H.J. Neurophysiol.26, 1003–1017 (1963). * ChemPort * ISI * PubMed * Weimann, J. M. & Marder, E.Curr. Biol.4, 896–902 (1994). * ChemPort * ISI * PubMed * Article * Nelson, A. B., Krispel, C. M., Sekirnjak, C. & du Lac, S.Neuron40, 609–620 (2003). * ChemPort * PubMed * Article * Zhang, W. & Linden, D. J.Nature Rev. Neurosci.4, 885–900 (2003). * Article * Desai, N. S., Rutherford, L. C. & Turrigiano, G. G.Nature Neurosci.2, 515–520 (1999). * Shah, M. M., Hammond, R. S. & Hoffman, D. A.Trends Neurosci. doi:10.1016/j.tins.2010.03.002 (2010). * Lin, M. T., Luján, R., Watanabe, M., Adelman, J. P. & Maylie, J.Nature Neurosci.11, 170–177 (2008). * Article * Fan, Y.et al. Nature Neurosci.8, 1542–1551 (2005). * Article * Makara, J. K., Losonczy, A., Wen, Q. & Magee, J. C.Nature Neurosci.12, 1485–1487 (2009). * Article * Frick, A., Magee, J. & Johnston, D.Nature Neurosci.7, 126–135 (2004). * Article * Clark, B. D., Goldberg, E. M. & Rudy, B.Neuroscientist15, 651–668 (2009). * PubMed * Article * Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K.Nature Neurosci.8, 1263–1268 (2005). * Article * Kuba, H., Ishii, T. M. & Ohmori, H.Nature444, 1069–1072 (2006). * ChemPort * PubMed * Article * Somogyi, P., Nunzi, M. G., Gorio, A. & Smith, A. D.Brain Res.259, 137–142 (1983). * ChemPort * PubMed * Article Download references Author information * References * Author information * Comments Affiliations * Jan Gründemann and Michael Häusser are at the Wolfson Institute for Biomedical Research, and the Department of Physiology, Pharmacology and Neuroscience, University College London, Gower Street, London WC1E 6BT, UK. m.hausser@ucl.ac.uk Additional data
• DNA repair: How to accurately bypass damage
  - Nature (London) 465(7301):1023 (2010)
  Nature | News and Views DNA repair: How to accurately bypass damage * Suse Broyde1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dinshaw J. Patel2 Search for this author in: * NPG journals * PubMed * Google Scholar * AffiliationsJournal name:NatureVolume:465,Pages:1023–1024Date published:(24 June 2010)DOI:doi:10.1038/4651023aPublished online23 June 2010 Ultraviolet radiation can cause cancer through DNA damage — specifically, by linking adjacent thymine bases. Crystal structures show how the enzyme DNA polymerase η accurately bypasses such lesions, offering protection. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg In this issue, two papers — by Silverstein et al.1 (page 1039) and Biertümpfel et al.2 (page 1044) — describe the crystal structure of the enzyme DNA polymerase η (Polη), which can efficiently and accurately overcome DNA damage caused by ultraviolet radiation. These data are of particular interest because they elucidate how the inactivation of Polη leads to XPV, a variant form of xeroderma pigmentosum — a type of severe skin cancer in humans. DNA polymerase enzymes mediate DNA replication and repair. In eukaryotes (organisms such as animals, plants and yeast), at least 14 such polymerases, with diverse functions, have been identified3. For instance, DNA polymerases of the Y family specialize in DNA-lesion bypass. According to the polymerase-switch model4, when a high-fidelity replicative polymerase encounters a DNA-distorting lesion, it stalls and is replaced by one or more lesion-bypass polymerases. The bypass polymerases transit the lesion and extend the DNA until the perturbation has been passed. The replicative polymerase then resumes its task of rapidly synthesizing the growing DNA chain. Humans have four Y-family DNA polymerases: Polι, Polκ, REV1 and Polη. The crystal structures of ternary complexes — containing one of these polymerases, together with template and primer DNA, and the deoxyribonucleoside 5′-triphosphate (dNTP) positioned ready for addition to the growing primer chain — have been solved for Polι (ref. 5), Polκ (ref. 6) and REV1 (ref. 7). Together with the structures of the non-human Y-family polymerases Dpo4 (ref. 8) and Dbh (ref. 9), these structures have revealed that some features are unique to a particular Y-family member, whereas others are universal to all members. For example, like other polymerases, all Y-family polymerases have a hand-like shape, with palm, fingers and thumb domains10, as well as an active site with evolutionarily conserved carboxylate-containing amino-acid residues (aspartic acid and glutamic acid) and two divalent metal ions, usually magnesium ions (Mg2+). In addition, being generally of low fidelity, Y-family polymerases have a spacious and solvent-accessible active site to facilitate lesion bypass11. This feature is in contrast to that of high-fidelity polymerases, the fingers of which close tightly on the nascent base pair to promote accurate replication10, 12. What's more, Y-family polymerases have a domain termed the little finger, or PAD, which aids in gripping the DNA11, 13. None of the human Y-family polymerases was found to be highly specialized for the error-free bypass of specific types of DNA damage, although the structures and biochemical evidence provided clues to the nature of the lesions that the e! nzymes are designed to process5, 6, 7, 11, 13, 14. The most elusive and intriguing of the human bypass polymerases is Polη. On a functional level, it is essential for error-free bypass of a highly prevalent lesion that results from exposure to ultraviolet radiation, including sunlight11, 13. The lesion is called a cis–syn thymine dimer (Fig. 1a, overleaf): two adjacent thymine bases on the same strand form two covalent bonds to produce an open-book-like structure, causing a distortion when incorporated in B-DNA — the most common conformation of DNA. Polη bypasses this lesion in an error-free manner, correctly incorporating an adenine base opposite each of the thymines in the covalently linked dimer15, 16. How it can do this has remained a structural mystery. Figure 1: Accurate lesion bypass by Polη. , Ultraviolet (UV) radiation catalyses covalent linkages between two adjacent thymine (T) bases in a DNA strand so that they form a distorting mutagenic lesion, the T–T dimer. Backbone phosphorus, yellow; oxygen, red; nitrogen, dark blue. , Biertümpfel et al.2 report the structure of human Polη in a ternary complex containing dATP correctly positioned opposite the 3′ base of the thymine dimer in the template strand. This structure reveals an active site (the area within the dashed lines) that is enlarged compared with other Y-family polymerases and that accommodates the two covalently linked thymine bases to permit 'Watson–Crick' hydrogen bonding with the dATP, which is oriented for catalysis mediated by two metal ions (purple spheres). Silverstein and colleagues1 present a related ternary complex of yeast Polη, uncovering a remarkably similar strategy for thymine-dimer bypass (not shown). Thymine dimer, orange; template bases, blue; primer bases, green; incoming nu! cleotide, white. , The crystal structure of human Polη is shown in a ternary complex2 in which the DNA has been replicated past the thymine-dimer lesion by the addition of two nucleotides (A). Unlike other lesion-bypass polymerases, Polη contains a molecular splint — a continuous protein interface between the core (palm and finger) and little finger domains, which cannot be seen in this view — that holds the growing duplex in its normal B-DNA conformation, allowing efficient and accurate extension past the thymine dimer. * Full size image (266 KB) Silverstein et al.1 report two crystal structures of a yeast Polη in ternary complexes: one with incoming dATP and a DNA template strand that contains two normal thymines, and another with dATP and a template strand that contains a cis–syn thymine dimer. Biertümpfel et al.2 present a similar structural pair for human Polη (Fig. 1b), together with additional structures showing the thymine dimer after replication has progressed so that two extra nucleotides have been incorporated (Fig. 1c). Together, the structures1, 2 show that key structural elements are conserved across the evolutionary span from yeast to humans. To solve these structures, clever mutational strategies were required to break crystal-packing forces that came into play in an earlier study17. The structures provide an elegant explanation for how the dimer is replicated in an error-free manner and for the curious fact that the dimer is as accurately replicated as unmodified thymines. Together with kinetic studies2, they reveal how extension past the lesion can be efficiently carried out. What is the trick? Compared with other Y-family human polymerases, Polη has a more spacious active site because the polymerase core (palm and fingers) is rotated away from the little finger, allowing two nucleotides to be housed in the active site instead of just one. This is necessary because the two thymines that are linked as a result of ultraviolet-radiation-induced damage cannot be uncoupled. Moreover, van der Waals forces and hydrogen-bonding interactions specifically hold the coupled thymines so that they can be partnered with adenine, hence the higher fidelity for the lesion than for the undamaged thymine. Another feature that is unique to Polη, accounting for the ready extension past the dimer, is the presence of a stiff spine, or 'molecular splint', that holds the growing duplex chain rigidly in its normal B-DNA conformation, without allowing slippage or other structural anomalies. In this respect, Polη differs from other Y-family polymerases, all of which have a gap between the core and the little finger instead of the continuous protein surface that creates the molecular splint. The open space, the volume of which differs among polymerases, allows greater flexibility and opportunity for error in the growing duplex. Gratifyingly, mutations that are observed in patients with XPV are explained by the structure of the human enzyme. For example, the arginine residue present at position 111 of Polη is part of the molecular splint, and mutation of the bases encoding this amino acid to produce histidine has been observed in patients with XPV and is likely to disrupt the splint. Every open door leads to another door, and the same holds true for these fascinating Polη structures. Resolving the structures of binary complexes — without the dNTP — is essential to gain insight into conformational changes that may be induced by the binding of the dNTP. So far, all evidence suggests that the large conformational movement, that is, the closing of the fingers on dNTP binding, seen in high-fidelity polymerases does not occur in members of the Y family. But there are indications of more subtle conformational reorganizations, the details of which may depend on the specific bypass polymerase. These early movements need to be understood in order to delineate the mechanistic details of the ensuing chemical reaction of nucleotide addition. The suggestions that Y-family polymerases in general are engaged in other forms of DNA repair besides lesion bypass are intriguing. For example, Polκ has recently been implicated in nucleotide-excision-repair synthesis18. Polη has also been implicated in the repair of DNA strand breaks, specifically in filling in gaps that are created by the displaced loops produced in homologous recombination19, 20. And Biertümpfel and colleagues' structure suggests that another DNA-binding site on the other side of the enzyme may be used in this process2. It will certainly be exciting to determine how Polη is involved in these repair processes and in other cellular processes such as the generation of antibody diversity. Polymerase structure and function remains a research frontier despite the amazing progress that has been achieved in the past decade. References * References * Author information * Comments * Silverstein, T. D.et al. Nature465, 1039–1043 (2010). * Article * Biertümpfel, C.et al. Nature465, 1044–1048 (2010). * Article * Pavlov, Y. I., Shcherbakova, P. V. & Rogozin, I. B.Int. Rev. Cytol.255, 41–132 (2006). * PubMed * Article * Friedberg, E. C., Lehmann, A. R. & Fuchs, R. P.Mol. Cell18, 499–505 (2005). * ChemPort * ISI * PubMed * Article * Nair, D. T., Johnson, R. E., Prakash, S., Prakash, L. & Aggarwal, A. 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• Obituary: Cecil Terence Ingold (1905–2010)
  - Nature (London) 465(7301):1025 (2010)
  Nature | News and Views Obituary: Cecil Terence Ingold (1905–2010) * Nicholas P. Money1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:1025Date published:(24 June 2010)DOI:doi:10.1038/4651025aPublished online23 June 2010 A leading light in the twentieth-century study of fungi. Article tools * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg T. INGOLD Terence Ingold, one of the most influential mycologists of the twentieth century, died in Northumberland, UK, on 31 May at the inspiring age of 104. His researches spanned more than 70 years, and there have been few, if any, individuals who have made a more significant impact on the appreciation of fungi by the wider scientific community. In the 1930s he discovered a ubiquitous but previously overlooked group of aquatic fungi, later called the Ingoldian hyphomycetes. But he is probably better known for his lifelong interest in mechanisms of spore dispersal. Ingold began his laboratory investigations on fungi in 1926, as an undergraduate at Queen's University in Belfast. Doctoral work at London's Royal College of Science, now part of Imperial College London, was followed by lectureships at the universities of Reading and Leicester, and (in 1944) by a chair at Birkbeck College, University of London. Ingold's study of aquatic fungi began in 1938 with his analysis of water samples taken from a brook that ran close to his home north of Leicester. The spores of some of these fungi assume beautiful shapes, many with the form of stars or crescents, which collide with drowning leaf fragments that serve as their food. They become rafted on the surface of air bubbles, and may escape into the air. When Ingold presented his discovery at a meeting in Cambridge, UK, one smart alec countered that he had simply misidentified some leaf hairs. The folly of this pronouncement is proven by continuing international research on the diversity and ecology of these microorganisms. Beyond their abundance in streams, Ingoldians have been found in rainwater run-off from buildings, in melting snow and ice, and in plant tissues, in which they may be active symbionts rather than agents of decay. But Ingold's first mycological love was for the biophysical, in the form of the parade of graceful propulsion mechanisms that have evolved among the fungi. Examples include the hydrostatic guns that squirt spore-containing sporangia skyward above streams of pressurized fluid, and the remarkable process used by spores to jump from mushroom gills. He revelled in these phenomena, drawing on a keen knowledge of physics to advance a discipline more often associated with the non-experimental cataloguing of new species. The mushroom mechanism was the trickiest he tackled. It had perplexed mycologists since its description in the nineteenth century and had fascinated another great experimentalist, A. H. Reginald Buller (1874–1944). Ingold studied the process for decades and designed some of the crucial experiments that demonstrated that it operates as a kind of catapult energized by surface tension. The artillery fungus, Sphaerobolus stellatus, was another of his favourites, with its spectacular snap-buckling mechanism that shoots a pinhead-sized sporangium over a distance of 6 metres. Many of his experiments on spore movements seemed inspired by Heath Robinson (or Rube Goldberg, for US readers), and included the study of cultures in a hyperbaric chamber and readings from a 'spore clock' whose face became spattered with discharged spores. But these contraptions were highly effective in providing insights into the way that fungi work. By deciphering the physics of spore discharge processes,! Ingold helped other researchers to elucidate the complex relationships between weather conditions and the spread of epidemic plant diseases and mould-based allergies. Ingold's first book, Spore Discharge in Land Plants (1939), which was more mycological than botanical, was followed by a half-dozen exclusively fungal titles written, primarily, for students. His Fungal Spores: Their Liberation and Dispersal (1971) was a masterly guide to the field, and is one of the classic books most likely to be found on the bookshelves of mycologists and plant pathologists throughout the world. In recent days, I have been ruminating on the fact that this book was published as a sort of mid-career offering when he was 66 years old. He continued to study the fungi for another 30 years. Ingold's sense of humour was apparent through his published cartoons of fungi. But he did not come from the stand-up-comedian school of scientific educators, and was a deeply thoughtful man. Following his retirement in 1972, he loved to walk the country lanes around his home in Oxfordshire and ponder questions about fungi, and life in general. During these years, he studied fungi in a home laboratory and published numerous papers concerning fungal development and spore discharge. As a student, I joined him on some of his strolls, imbibing fragments of knowledge from a gentleman who knew the name of every plant and fungus, and could add an anecdote about each organism's biology. I would be reduced to nodding in silent acquiescence, hoping he would be kind enough to defer testing my knowledge. Yet for a man who lived so long and knew so much, his advice to the neophyte was limited. When I asked him for tips for matching his vigorous longevity, he uttered one unhelpful word: �! �Genes." Terence Ingold was characteristically humble about the significance of his scientific contributions. He confessed regret that he had not spent more time in the laboratory, having instead invested much of his energy on administrative tasks. But colleagues in Britain and abroad benefited greatly from his distraction from the fungi. He kept his department in London running during the final months of the Second World War. And he travelled widely in the 1950s and 1960s as a representative of the University of London, assisting in the development of higher education in countries that had obtained independence from Britain. He was particularly influential in the foundation, in 1966, of the University of Botswana, Lesotho and Swaziland, which offered a regional alternative to education in South Africa during the apartheid era. He made time for mycological investigations during many of these journeys, and claimed that, if he were "transported to a part of the world without knowledge of its locality", he could "make a very rough guess as to its latitude by examining the spora of a suitable stream". In small ways in the lab, and in a larger manner in Africa, he made the world a more interesting place. Author information * Author information * Comments Affiliations * Nicholas P. Money is in the Department of Botany, Miami University, Oxford, Ohio 45056, USA. moneynp@muohio.edu Additional data
• Human adult germline stem cells in question
  - Nature (London) 465(7301):E1 (2010)
  Nature | Brief Communication Arising Human adult germline stem cells in question * Kinarm Ko1 Search for this author in: * NPG journals * PubMed * Google Scholar * Marcos J. Araúzo-Bravo1 Search for this author in: * NPG journals * PubMed * Google Scholar * Natalia Tapia1 Search for this author in: * NPG journals * PubMed * Google Scholar * Julee Kim1 Search for this author in: * NPG journals * PubMed * Google Scholar * Qiong Lin2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Christof Bernemann1 Search for this author in: * NPG journals * PubMed * Google Scholar * Dong Wook Han1 Search for this author in: * NPG journals * PubMed * Google Scholar * Luca Gentile1 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Reinhardt1 Search for this author in: * NPG journals * PubMed * Google Scholar * Boris Greber1 Search for this author in: * NPG journals * PubMed * Google Scholar * Rebekka K. Schneider2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Sabine Kliesch4 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Zenke2, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Hans R. Schöler1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Corresponding authorJournal name:NatureVolume:465,Page:E1Date published:(24 June 2010)DOI:doi:10.1038/nature09089Received11 September 2009Accepted23 March 2010 * Article (November, 2008) * Brief Communication Arising (June, 2010) Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Arising from: S. Conrad et al.Nature456, 344–349 (2008); Conrad et al.reply Conrad et al. have generated human adult germline stem cells (haGSCs) from human testicular tissue, which they claim have similar pluripotent properties to human embryonic stem cells (hESCs)1. Here we investigate the pluripotency of haGSCs by using global gene-expression analysis based on their gene array data1 and comparing the expression of pluripotency marker genes in haGSCs and hESCs, and in haGSCs and human fibroblast samples derived from different laboratories, including our own. We find that haGSCs and fibroblasts have a similar gene-expression profile, but that haGSCs and hESCs do not. The pluripotency of Conrad and colleagues' haGSCs is therefore called into question. View full text Subject terms: * Stem cells * Cell biology Accession codes * Accession codes * Author information * Comments Primary accessions Gene Expression Omnibus * GSE11350 * GSE12583 * GSE15322 * GSE15148 * GSE10831 Author information * Accession codes * Author information * Comments Affiliations * Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster 48149, Germany * Kinarm Ko, * Marcos J. Araúzo-Bravo, * Natalia Tapia, * Julee Kim, * Christof Bernemann, * Dong Wook Han, * Luca Gentile, * Peter Reinhardt, * Boris Greber & * Hans R. Schöler * Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen 52074, Germany * Qiong Lin, * Rebekka K. Schneider & * Martin Zenke * Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen 52074, Germany * Qiong Lin, * Rebekka K. Schneider & * Martin Zenke * Department of Clinical Andrology, Centre for Reproductive Medicine and Andrology, University of Münster, Münster 48149, Germany * Sabine Kliesch * Faculty of Medicine, University of Münster, Münster 48149, Germany. * Hans R. Schöler Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Hans R. Schöler (office@mpi-muenster.mpg.de) Additional data
• Conrad et al. reply
  - Nature (London) 465(7301):E3 (2010)
  Nature | Brief Communication Arising Conrad et al. reply * Sabine Conrad1 Search for this author in: * NPG journals * PubMed * Google Scholar * Markus Renninger3 Search for this author in: * NPG journals * PubMed * Google Scholar * Jörg Hennenlotter3 Search for this author in: * NPG journals * PubMed * Google Scholar * Tina Wiesner1 Search for this author in: * NPG journals * PubMed * Google Scholar * Lothar Just1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Bonin4 Search for this author in: * NPG journals * PubMed * Google Scholar * Wilhelm Aicher5, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Hans-Jörg Bühring7 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulrich Mattheus2 Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas Mack2 Search for this author in: * NPG journals * PubMed * Google Scholar * Hans-Joachim Wagner2 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen Minger8 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthias Matzkies9 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Reppel9 Search for this author in: * NPG journals * PubMed * Google Scholar * Jürgen Hescheler9 Search for this author in: * NPG journals * PubMed * Google Scholar * Karl-Dietrich Sievert3 Search for this author in: * NPG journals * PubMed * Google Scholar * Arnulf Stenzl3 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas Skutella1, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Corresponding authorJournal name:NatureVolume:465,Page:E3Date published:(24 June 2010)DOI:doi:10.1038/nature09090 * Brief Communication Arising (June, 2010) Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Replying to: K. Ko et al.Nature465, 10.1038/nature09089 (2010) Ko et al.1 challenge our description of human adult germline stem cells (haGSCs)2, indicating that we have instead cultured testis fibroblasts. However, they do not follow the experimental procedures we describe2 and so fail to reproduce our findings. View full text Author information * Author information * Comments Affiliations * Institute of Anatomy, Department of Experimental Embryology, Österbergstraße 3, 72074 Tübingen, Germany * Sabine Conrad, * Tina Wiesner, * Lothar Just & * Thomas Skutella * Institute of Anatomy, Department of Cellular Neurobiology, Österbergstraße 3, 72074 Tübingen, Germany * Ulrich Mattheus, * Andreas Mack & * Hans-Joachim Wagner * Department of Urology, University Clinic Tübingen, Hoppe-Seyler-Straße 3, Tübingen 72076, Germany * Markus Renninger, * Jörg Hennenlotter, * Karl-Dietrich Sievert & * Arnulf Stenzl * Institute of Anthropology and Human Genetics, Microarray Facility, University Clinic, Calwerstraße 7, 72076 Tübingen, Germany * Michael Bonin * ZMF Research Laboratories, University Clinic Tübingen, Waldhörnlestraße 22, 72072 Tübingen, Germany * Wilhelm Aicher * Center for Regenerative Biology and Medicine (ZRM), Paul-Ehrlich-Straße 15, 72076 Tübingen, Germany * Wilhelm Aicher & * Thomas Skutella * Department of Internal Medicine II, University Clinic Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany * Hans-Jörg Bühring * Stem Cell Biology Laboratory, Wolfson Centre for Age-Related Diseases, King's College London, King's College, London SE1 1UL, UK * Stephen Minger * Institute of Neurophysiology, University of Cologne, Robert-Koch-Straße 39, 50931 Cologne, Germany. * Matthias Matzkies, * Michael Reppel & * Jürgen Hescheler Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Thomas Skutella (Thomas.Skutella@regmed.uni-tuebingen.de) Additional data
• Umpolung reactivity in amide and peptide synthesis
  - Nature (London) 465(7301):1027 (2010)
  Nature | Article Umpolung reactivity in amide and peptide synthesis * Bo Shen1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Dawn M. Makley1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey N. Johnston1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1027–1032Date published:(24 June 2010)DOI:doi:10.1038/nature09125Received22 December 2009Accepted22 April 2010 Abstract * Abstract * Author information * Supplementary information * Comments Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The amide bond is one of nature's most common functional and structural elements, as the backbones of all natural peptides and proteins are composed of amide bonds. Amides are also present in many therapeutic small molecules. The construction of amide bonds using available methods relies principally on dehydrative approaches, although oxidative and radical-based methods are representative alternatives. In nearly every example, carbon and nitrogen bear electrophilic and nucleophilic character, respectively, during the carbon–nitrogen bond-forming step. Here we show that activation of amines and nitroalkanes with an electrophilic iodine source can lead directly to amide products. Preliminary observations support a mechanism in which the polarities of the two reactants are reversed (German, umpolung) during carbon–nitrogen bond formation relative to traditional approaches. The use of nitroalkanes as acyl anion equivalents provides a conceptually innovative approach to ami! de and peptide synthesis, and one that might ultimately provide for efficient peptide synthesis that is fully reliant on enantioselective methods. View full text Subject terms: * Chemical biology * Biochemistry Figures at a glance * Figure 1: Comparison of component polarization in conventional condensative amide synthesis and α-bromo nitroalkane–amine coupling. * Figure 2: Amide and peptide synthesis. Ph, phenyl; NIS, N-iodo succinimide; THF, tetrahydrofuran. * Figure 3: Mechanistic hypothesis for amide synthesis from an α-bromo nitroalkane and amine. * Figure 4: Experiments designed to probe intermediacy of possible carbonyl electrophiles. * Figure 5: Stereoselective peptide synthesis. Boc, t-butoxy carbonyl; e.e., enantiomeric excess; d.r., diastereomeric ratio. , H,Quin(6(9Anth)2Pyr)-BAM·H+−OTf. * Figure 6: Enantioselective peptide synthesis. Shown is a carbonyl dianion synthon approach. Ar, aromatic ring substituent; LG, leaving group; R, alkyl substituent. Author information * Abstract * Author information * Supplementary information * Comments Affiliations * Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235-1822, USA * Bo Shen, * Dawn M. Makley & * Jeffrey N. Johnston * Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235-1822, USA * Bo Shen, * Dawn M. Makley & * Jeffrey N. Johnston Contributions The reaction was conceptualized and reduced to practice by B.S. and J.N.J. Experiments were performed by B.S. (mechanism and scope) and D.M.M. (scope). The manuscript was prepared by J.N.J. with input from all coauthors. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Jeffrey N. Johnston (jeffrey.n.johnston@vanderbilt.edu) Supplementary information * Abstract * Author information * Supplementary information * Comments PDF files * Supplementary Information (759K) This file contains Supplementary Experiments and Methods. * Supplementary Figures (1.7M) This file contains Supplementary Figures 1-97 with legends. Additional data
• A coding-independent function of gene and pseudogene mRNAs regulates tumour biology
  - Nature (London) 465(7301):1033 (2010)
  Nature | Article A coding-independent function of gene and pseudogene mRNAs regulates tumour biology * Laura Poliseno1, 4, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Leonardo Salmena1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Jiangwen Zhang2 Search for this author in: * NPG journals * PubMed * Google Scholar * Brett Carver3 Search for this author in: * NPG journals * PubMed * Google Scholar * William J. Haveman1 Search for this author in: * NPG journals * PubMed * Google Scholar * Pier Paolo Pandolfi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1033–1038Date published:(24 June 2010)DOI:doi:10.1038/nature09144Received21 September 2009Accepted22 April 2010 Abstract * Abstract * Author information * Supplementary information * Comments Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attri! bute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs. View full text Subject terms: * Cancer * Molecular biology * Cell biology * Genetics * Genomics Figures at a glance * Figure 1: PTENP1 is targeted by PTEN-targeting miRNAs. , Working hypothesis: PTEN is protected from miRNA binding by PTENP1. miRNAs are indicated by red, blue and green structures. 5′ and 3′ UTRs, open rectangles; open reading frames, filled rectangles. , PTEN (top) and PTENP1 (bottom) 3′ UTRs contain a highly conserved (dark grey) followed by a poorly conserved (light grey) region. PTEN-targeting miRNA seed matches within the high homology region are conserved between PTEN and PTENP1. , Binding of PTEN-targeting miRNAs to PTENP1. Seeds and seed matches, bold; canonical pairings, solid lines; non-canonical pairings (G·U), dotted lines. , PTEN-targeting miR-19b and miR-20a decrease PTEN and PTENP1 mRNA abundance. , miR-17 and miR-19 family inhibitors (Imix) derepress PTENP1 abundance (left). PTEN is used as positive control (right). IC, miRNA inhibitor negative control. , , mean ± s.d., n ≥ 3. *P < 0.05; **P < 0.01; ***P < 0.001. * Figure 2: PTENP1 3′ UTR exerts a tumour suppressive function by acting as a decoy for PTEN-targeting miRNAs. –, PIG/ψ3′ UTR-infected DU145 cells show increased PTEN mRNA and protein levels () reduced phosho-AKT levels upon EGF stimulation () and decreased proliferation rate (). , Growth in semisolid medium of DU145 cells infected with PIG, PIG/ψ3′ UTR or PIG/PTEN. , PTEN mRNA levels 24 h after the transfection of pCMV/ψ3′ UTR in parental HCT116 or HCT116 DICER−/− cells. Data are normalized using pCMV empty-transfected cells. , Growth curve of DU145 cells transfected with control siLuc, si-PTEN/PTENP1, si-PTEN or si-PTENP1. , mRNA levels of PTEN (left) and PTENP1 (right) 24 h after the transfection of siLuc (white), si-PTEN/PTENP1 (blue), si-PTEN (black) and si-PTENP1 (red). , Western blot of PTEN 48 h after the transfection of the indicated siRNAs. Quantification of PTEN protein is reported. Data in , – indicate mean ± s.d., n ≥ 3. *P < 0.05; **P < 0.01. * Figure 3: Loss of PTENP1 in cancer. , , Expression level of PTEN (black) and PTENP1 (red) in a panel of normal human tissues () and prostate tumour samples (). Prostate sample expression values derived from both commercial and clinical sources were independently normalized and combined for correlation analysis. Linear regression of PTEN versus PTENP1 expression is shown in the upper left corner. , Cluster analysis of 48 sporadic colon cancer samples interrogated by Affymetrix Human SNP Array. , Heat map and cluster analysis of Affymetrix Human Exon 1.0 ST Array for normalized PTEN intensity values. , Plot of log ratio of PTENP1 copy number (CN) against log10PTEN expression intensity. Lines of best fit represent regression analyses of two populations. The correlation coefficient (r) measures the reliability and the P-value measures the statistical significance of the correlation between the x and y variables. * Figure 4: PTEN 3′ UTR and KRAS1P 3′ UTR function as decoys and a general model for endogenous miRNA decoy mechanism. , PTENP1 mRNA level 24 h after the transfection of the empty pCMV or pCMV/PTEN3′ UTR plasmid in DU145 cells (left) and growth curve (right). , KRAS mRNA level 24 h after the transfection of the empty pCMV or pCMV/K1P3′ UTR plasmid in DU145 cells (left) and growth curve (right). , Model: X and Y are different transcripts targeted by the same miRNA(s). In the steady state (middle), equilibrium exists between the miRNA molecules and their targets X and Y. Downregulation of X (left) leads to increased availability of miRNA molecules to bind to Y, thus decreasing its abundance. By contrast, overexpression of X (right) leads to fewer miRNA molecules free to bind to Y, and thus Y abundance increases. Red rectangles, miRNA molecules. X and Y can be a pseudogene and its cognate protein-coding gene. Data in and indicate mean ± s.d., n ≥ 3. *P < 0.05; ***P < 0.001. Author information * Abstract * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Laura Poliseno & * Leonardo Salmena Affiliations * Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA * Laura Poliseno, * Leonardo Salmena, * William J. Haveman & * Pier Paolo Pandolfi * FAS Research Computing & FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA * Jiangwen Zhang * Human Oncology and Pathogenesis Program, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA * Brett Carver * Present address: Department of Dermatology, New York University Medical Center, New York, New York 10016, USA. * Laura Poliseno Contributions P.P.P. spearheaded and supervised the project; L.P., L.S. and P.P.P. designed experiments; L.P., L.S. and W.J.H. performed experiments; B.C. provided prostate cancer patient sample cDNAs. J.Z. performed all bioinformatic analyses. L.P., L.S. and P.P.P. analysed the data and wrote the paper. All authors critically discussed the results and the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Pier Paolo Pandolfi (ppandolf@bidmc.harvard.edu) Supplementary information * Abstract * Author information * Supplementary information * Comments PDF files * Supplementary information (7.4M) This file contains Supplementary Data, Supplementary Figures 1- 19 with legends, Supplementary Tables 1-3 and References. Additional data
• Structural basis for the suppression of skin cancers by DNA polymerase η
  - Nature (London) 465(7301):1039 (2010)
  Nature | Article Structural basis for the suppression of skin cancers by DNA polymerase η * Timothy D. Silverstein1 Search for this author in: * NPG journals * PubMed * Google Scholar * Robert E. Johnson2 Search for this author in: * NPG journals * PubMed * Google Scholar * Rinku Jain1 Search for this author in: * NPG journals * PubMed * Google Scholar * Louise Prakash2 Search for this author in: * NPG journals * PubMed * Google Scholar * Satya Prakash2 Search for this author in: * NPG journals * PubMed * Google Scholar * Aneel K. Aggarwal1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:1039–1043Date published:(24 June 2010)DOI:doi:10.1038/nature09104Received17 December 2009Accepted19 April 2010 Abstract * Abstract * Accession codes * Author information * Supplementary information * Comments Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg DNA polymerase η (Polη) is unique among eukaryotic polymerases in its proficient ability for error-free replication through ultraviolet-induced cyclobutane pyrimidine dimers, and inactivation of Polη (also known as POLH) in humans causes the variant form of xeroderma pigmentosum (XPV). We present the crystal structures of Saccharomyces cerevisiae Polη (also known as RAD30) in ternary complex with a cis-syn thymine-thymine (T-T) dimer and with undamaged DNA. The structures reveal that the ability of Polη to replicate efficiently through the ultraviolet-induced lesion derives from a simple and yet elegant mechanism, wherein the two Ts of the T-T dimer are accommodated in an active site cleft that is much more open than in other polymerases. We also show by structural, biochemical and genetic analysis that the two Ts are maintained in a stable configuration in the active site via interactions with Gln 55, Arg 73 and Met 74. Together, these features define the basis f! or Polη's action on ultraviolet-damaged DNA that is crucial in suppressing the mutagenic and carcinogenic consequences of sun exposure, thereby reducing the incidence of skin cancers in humans. View full text Subject terms: * Cancer * Structural biology * Genetics * Genomics * Molecular biology Figures at a glance * Figure 1: Polη–DNA–dATP ternary complexes. , Structure of Polη with undamaged DNA. The palm, fingers, thumb domains and the PAD are shown in cyan, yellow, orange and green, respectively. The DNA is in grey, and the putative Mg2+ ions are in dark blue. The templating 3′T (and the 5′T) and incoming dATP are in red. , Structure of Polη with a cis-syn T-T dimer in DNA. The cis-syn T-T dimer and incoming dATP are shown in red. Yellow and orange dashed lines depict unstructured loops in the fingers and thumb domains, respectively. * Figure 2: Close-up views of the active site regions. , The active site regions with undamaged (left) and T-T dimer-containing (right) DNAs. The palm and fingers domains and the PAD are shown in cyan, yellow and green, respectively. The DNA is coloured grey, and the putative Mg2+ ions (A and B) are dark blue. The undamaged templating T (and the 5′T) (left), the cis-syn T-T dimer (3′T and 5′T) (right), and incoming dATP are in red. Highlighted and labelled are the catalytic residues (D30, D155 and E156), residues that interact with the triphosphate moiety of incoming dATP (Y64, R67 and K279), residues that interact with templating T and the 5′T (Q55, W56, M74 and R73), and F35, which stacks against the dATP sugar. R73 is shown in two orientations in the T-T dimer structure. Y452 is also shown (right), which stacks against the base of the nucleotide 5′ to the T-T dimer. The residues are coloured to match the domain they belong to. , Simulated annealing Fo − Fc omit maps (contoured at 3.0σ) of undamaged templating! T (and the 5′T) and incoming dATP (left), and cis-syn T-T dimer and incoming dATP (right). , Hydrogen bonding and van der Waals interactions between residues on the fingers domain (Q55, W56, I60, R73 and M74) and undamaged Ts (left) and cis-syn T-T dimer (right). * Figure 3: Conformational changes in Polη ternary complex. , Conformational change in Polη on complex formation. On DNA and dNTP binding, the PAD swings by as much as ~13.6 Å towards the major groove of the DNA. The thumb also rotates towards the DNA but to a much lesser extent than the PAD. , Comparison between our Polη ternary complex and that reported previously between Polη and a cisplatin adduct19. In the structure from ref. 19, Polη has an apo-like conformation (see Fig. 3a), wherein the PAD occupies a position similar to that in the apo Polη structure. * Figure 4: Comparison between Polη and Polκ. , Polκ (grey) superimposed on the Polη ternary complex via the palm domain. In Polκ, the fingers domain is in close proximity to the cis-syn T-T dimer (red) and it collides with the 5′T of the T-T dimer. , Left, molecular surface of Polη in the ultraviolet-damaged ternary complex. Both Ts of the T-T dimer fit unhindered within the active site cleft. Right, molecular surface of Polκ when superimposed on the Polη ternary complex via the palm domain. The 5′T of the T-T dimer collides with M135 and other residues of the Polκ fingers domain. Accession codes * Abstract * Accession codes * Author information * Supplementary information * Comments Primary accessions Protein Data Bank * 3MFH * 3MFI * 3MFH * 3MFI Author information * Abstract * Accession codes * Author information * Supplementary information * Comments Affiliations * Department of Structural and Chemical Biology, Mount Sinai School of Medicine, Box 1677, 1425 Madison Avenue, New York, New York 10029, USA * Timothy D. Silverstein, * Rinku Jain & * Aneel K. Aggarwal * Department of Biochemistry and Molecular Biology, 301 University Boulevard, University of Texas Medical Branch, Galveston, Texas 77755-1061, USA * Robert E. Johnson, * Louise Prakash & * Satya Prakash Contributions A.K.A. and T.D.S. designed the crystallographic studies; S.P., L.P. and R.E.J. designed the biochemical and genetic studies; T.D.S., R.E.J., R.J. and L.P. performed the experiments; all of the authors contributed to the writing of the paper. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Aneel K. Aggarwal (aneel.aggarwal@mssm.edu) or * Satya Prakash (saprakas@utmb.edu) Atomic coordinates and structure factors files have been deposited in the Protein Data Bank under accession codes 3MFH and 3MFI. Supplementary information * Abstract * Accession codes * Author information * Supplementary information * Comments PDF files * Supplementary Information (21.9M) This file contains Supplementary Tables 1-3 and Supplementary Figures 1-11 with legends. Additional data
• Structure and mechanism of human DNA polymerase η
  - Nature (London) 465(7301):1044 (2010)
  Nature | Article Structure and mechanism of human DNA polymerase η * Christian Biertümpfel1 Search for this author in: * NPG journals * PubMed * Google Scholar * Ye Zhao1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Yuji Kondo3 Search for this author in: * NPG journals * PubMed * Google Scholar * Santiago Ramón-Maiques1, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Mark Gregory1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jae Young Lee1, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Chikahide Masutani3 Search for this author in: * NPG journals * PubMed * Google Scholar * Alan R. Lehmann4 Search for this author in: * NPG journals * PubMed * Google Scholar * Fumio Hanaoka3, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Wei Yang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:1044–1048Date published:(24 June 2010)DOI:doi:10.1038/nature09196Received09 April 2010Accepted21 May 2010 Abstract * Abstract * Accession codes * Author information * Supplementary information * Comments Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase (Pol), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Pol at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol acts like a 'molecular splint' to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Pol orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Pol missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Pol in replicating through D loop and D! NA fragile sites. View full text Subject terms: * Biochemistry * Molecular biology * Cancer * Structural biology Figures at a glance * Figure 1: Structure of human Polη. , The ternary complex of human Polη with a normal DNA. Protein domains are shown in distinct colours and labelled. The DNA template is coloured orange and the primer yellow. Oxygen and nitrogen atoms are coloured red and blue, respectively. dAMPNPP is shown in ball-and-stick representation; Mg2+ is shown as purple spheres. All structural figures were made using PyMOL (http://www.pymol.org). , The active site. Mg2+ coordination is indicated by pale yellow dashed lines. The 3′-OH of the primer strand is 3.2 Å from the α-phosphate as indicated by the red dashed line. , Human Polη–DNA interactions around the active site. Protein side chains from the finger and palm domain are shown as light blue and pink sticks, respectively. , Interactions with the upstream DNA. The LF domain (shown as light purple ribbon diagram) contacts both template and primer, and the thumb domain (shown in green) only makes 3–4 hydrogen bonds with the primer strand. Side chains that make DNA c! ontacts are highlighted in stick representation and labelled. * Figure 2: Structures of lesion DNAs. , Overlay of TT1, TT2, TT3 and TT4 DNA with the DNA in Nrm (undamaged). CPDs are shown as red sticks. DNA and Mg2+ are coloured as in Fig. 1. –, The replicating base pairs in four ternary complexes (highly similar in TT3 and TT4) are each shown with human Polη residues that contact the bases and deoxyribose. Hydrogen bonds are shown as dashed lines. , The CPD in TT3 and TT4 forms Watson–Crick-like hydrogen bonds but cannot base stack with neighbouring nucleotides. * Figure 3: Functional analyses of Q38A and R61A mutant Polη. , Efficiencies (kcat/Km) of wild type (WT) and two mutants in correct and incorrect nucleotide incorporation on normal (ND) and CPD DNA. These values are derived from Supplementary Table 3. , CPD bypass by wild-type (left) and Q38A mutant Polη (right). The DNA sequence for primer extension assays is shown. Magenta-coloured TT represents the CPD. The same DNA template with a two-nucleotide-longer primer was used for the kinetic assay shown in Fig. 3a. Reactions were carried out at a substrate:enzyme molar ratio of 100:1 for the indicated incubation time. Termination probabilities ([In]/Σn−end[I], where In is band intensity at the nth position) on normal (ND) and CPD DNA are plotted below. * Figure 4: Human Polη is a molecular splint. , The DNA binding surfaces of various Y-family polymerases are shown with electrostatic surface potentials. Blue and red represent the positive and negative charge potential at the + and −10 kT e−1 scale, respectively. The thumb domain in all cases and the N-clasp of Polκ are removed for clarity. Five phosphorus atoms at position −1 to −5 in the human Polη Nrm (yellow) and TT4 (orange) structures are also shown. , The extensive interactions between human Polη and the template strand in TT4 (as an example) are shown. Hydrogen bonds are indicated by dashed lines. The finger and LF domains are coloured in light purple and light green. Two residues forming hydrophobic interactions with the CPD bases are shown in teal. , A view approximately 90° from . Detailed human Polη–DNA interactions are shown in Supplementary Fig. 9. * Figure 5: XPV mutations. , Arg 111 contacts DNA template and stacks with Pro 316 of the LF domain. , Mapping of eight missense XPV mutations. The protein is represented by the Cα trace, DNA by tube-and-ladder representation, and the altered residues are shown as cyan ball-and-stick representation. , Local interactions of Ala 117 and Thr 122 and their relation to the active site. Most side chains are removed for clarity. , Arg 361 supports Pro 316 and the β-strand that forms an extensive hydrogen-bond network with the DNA template. , Gly 263 and Ala 264 are adjacent to the thumb–DNA primer interface. G263V and A264P substitutions would clash with Leu 258 and Lys 261. Electron densities are shown as meshes in panels and . Accession codes * Abstract * Accession codes * Author information * Supplementary information * Comments Primary accessions Protein Data Bank * 3MR2 * 3MR3 * 3MR4 * 3MR5 * 3MR6 * 3MR2 * 3MR3 * 3MR4 * 3MR5 * 3MR6 Author information * Abstract * Accession codes * Author information * Supplementary information * Comments Affiliations * Laboratory of Molecular Biology, NIDDK, NIH, 9000 Rockville Pike, Building 5, Room B103, Bethesda, Maryland 20892, USA * Christian Biertümpfel, * Ye Zhao, * Santiago Ramón-Maiques, * Mark Gregory, * Jae Young Lee & * Wei Yang * Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou 310029, China * Ye Zhao * Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan * Yuji Kondo, * Chikahide Masutani & * Fumio Hanaoka * Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK * Alan R. Lehmann * Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan * Fumio Hanaoka * Present addresses: Spanish National Cancer Research Centre, Madrid 28029, Spain (S.R.-M.); Dongguk University-Seoul, Seoul 100-715, Korea (J.Y.L.). * Santiago Ramón-Maiques & * Jae Young Lee Contributions C.B. determined the five structures; Y.Z. prepared the samples and grew the crystals; Y.K. did the kinetic and bypass assays; S.R.-M. determined the type 1 structure; M.G. prepared the clone and type 1 crystals; J.Y.L. made mutants; C.M. designed the functional assays; A.R.L. identified the unpublished XPV mutations; F.H. conceived the project; and W.Y. supervised the structure determination. C.B., Y.Z., F.H. and W.Y. prepared the manuscript. C.B. and Y.Z. contributed equally to the study. All authors discussed the results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Wei Yang (wei.yang@nih.gov) or * Fumio Hanaoka (fumio.hanaoka@gakushuin.ac.jp) Atomic coordinates and structure factors for the reported crystal structures have been deposited with the Protein Data Bank under accession codes 3MR2 (Nrm), 3MR3 (TT1), 3MR4 (TT2), 3MR5 (TT3) and 3MR6 (TT4). Supplementary information * Abstract * Accession codes * Author information * Supplementary information * Comments PDF files * Supplementary Information (4.2M) This file contains Supplementary Figures 1-9 with legends and Supplementary Tables 1-3 Additional data
• The orbital motion, absolute mass and high-altitude winds of exoplanet HD 209458b
  - Nature (London) 465(7301):1049 (2010)
  Nature | Letter The orbital motion, absolute mass and high-altitude winds of exoplanet HD 209458b * Ignas A. G. Snellen1 Search for this author in: * NPG journals * PubMed * Google Scholar * Remco J. de Kok2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ernst J. W. de Mooij1 Search for this author in: * NPG journals * PubMed * Google Scholar * Simon Albrecht1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1049–1051Date published:(24 June 2010)DOI:doi:10.1038/nature09111Received04 February 2010Accepted15 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg For extrasolar planets discovered using the radial velocity method1, the spectral characterization of the host star leads to a mass estimate of the star and subsequently of the orbiting planet. If the orbital velocity of the planet could be determined, the masses of both star and planet could be calculated using Newton's law of gravity, just as in the case of stellar double-line eclipsing binaries. Here we report high-dispersion ground-based spectroscopy of a transit of the extrasolar planet HD 209458b. We see a significant wavelength shift in absorption lines from carbon monoxide in the planet's atmosphere, which we conclude arises from a change in the radial component of the planet's orbital velocity. The masses of the star and planet are 1.00 ± 0.22MSun and 0.64 ± 0.09MJup respectively. A blueshift of the carbon monoxide signal of approximately 2 km s−1 with respect to the systemic velocity of the host star suggests the presence of a strong wind fl! owing from the irradiated dayside to the non-irradiated nightside of the planet within the 0.01–0.1 mbar atmospheric pressure range probed by these observations. The strength of the carbon monoxide signal suggests a carbon monoxide mixing ratio of (1–3) × 10−3 in this planet's upper atmosphere. View full text Subject terms: * Astronomy * Astrophysics Figures at a glance * Figure 1: CO signal in the transmission spectrum of exoplanet HD 209458b. The cross-correlation is shown between a template spectrum of 56 CO lines and Very Large Telescope spectra of HD 209458 taken between a planet orbital phase of −0.025 < θ < 0.035. The beginning and end of the transit are at θ ± 0.018. The systemic velocity21 of the host star HD 209458a is −14.77 km s−1 (blueshifted), and the velocity of the Paranal observatory in the direction of the star is 11.0 km s−1 at the time of observation. This means that a planet's CO signal is expected to be blueshifted by ~26 km s−1 at mid-transit, exactly where a faint signal is present in the data. and show the same data, with the linear greyscales indicating the cross-correlation signal (dark means absorption). In the cross-correlation is plotted as a function of the geocentric radial velocity, and in the cross-correlation is plotted in the rest-frame of the host star, showing the CO signal in the centre. During the transit, the planet signal moves by! 30 km s−1 owing to the change in the radial component of the planet's orbital velocity. For the cross-correlation in , our initial model transmission spectrum of CO was added to the data at three times the nominal level, to demonstrate the resemblance to the observed signal. * Figure 2: The expected carbon monoxide signal as function of the planet orbital velocity. The observed CO signal is shown in greyscale as in Fig. 1. The dotted lines indicate the expected change in radial velocity of the planet over the transit for orbital velocities of 50, 100 and 150 km s−1. We determined the planet orbital velocity to be 140 ± 10 km s−1 (1σ) using chi-squared analysis. The orbital velocities of both the planet and the star around the planet–star centre-of-mass are known, allowing the masses of both objects to be determined using solely Newton's law of gravitation: M1 = 1.00 ± 0.22MSun and M2 = 0.64 ± 0.09MJup (1σ). * Figure 3: The carbon monoxide signal integrated over the transit. The cross-correlation signal from all spectra taken during the transit were combined assuming a planetary orbital velocity of 140 km s−1, individually weighted by the depth of the transit signal at the observed epoch. The integrated signal is statistically significant at the 5.6σ confidence level. We derive a CO volume mixing ratio of (1–3) × 10−3 for the upper atmosphere of HD 209458b, with the precision governed by the uncertainty in the pressure–temperature profile and in the level of masking of the CO signal by CH4. The CO signal is blueshifted by ~2 km s−1 with respect to the systemic velocity of the host star, which suggests a velocity flow from the dayside to the nightside driven by the large incident heat flux on the dayside. Author information * Author information * Supplementary information * Comments Affiliations * Leiden Observatory, Leiden University, Postbus 9513, 2300 RA Leiden, The Netherlands * Ignas A. G. Snellen, * Ernst J. W. de Mooij & * Simon Albrecht * SRON, Sorbonnelaan 2, 3584 CA Utrecht, The Netherlands * Remco J. de Kok * Department of Physics, and Kavli Institute for Astrophysics and Space Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA * Simon Albrecht Contributions I.A.G.S. participated in the development of the concept of this research and the analysis code, participated in the observations, the analysis and interpretation of the data and writing the manuscript. R.J.d.K. developed the planet atmosphere models and participated in the analysis and interpretation of the data and writing the manuscript. E.J.W.d.M. participated in the development of the concept of this research, and in the analysis and interpretation of the data and writing the manuscript. S.A. participated in the development of the concept of this research, and in the analysis and interpretation of the data and writing the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Ignas A. G. Snellen (snellen@strw.leidenuniv.nl) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (782K) This file contains Supplementary Information comprising: Observational set-up; Data reduction and analysis; The model transmission spectra; The cross-correlation analysis; Supplementary Figures S1-S2 with legends and References. Additional data
• Efficient quantum memory for light
  - Nature (London) 465(7301):1052 (2010)
  Nature | Letter Efficient quantum memory for light * Morgan P. Hedges1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jevon J. Longdell2 Search for this author in: * NPG journals * PubMed * Google Scholar * Yongmin Li3 Search for this author in: * NPG journals * PubMed * Google Scholar * Matthew J. Sellars1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1052–1056Date published:(24 June 2010)DOI:doi:10.1038/nature09081Received09 January 2010Accepted13 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Storing and retrieving a quantum state of light on demand, without corrupting the information it carries, is an important challenge in the field of quantum information processing. Classical measurement and reconstruction strategies for storing light must necessarily destroy quantum information as a consequence of the Heisenberg uncertainty principle. There has been significant effort directed towards the development of devices—so-called quantum memories—capable of avoiding this penalty. So far, successful demonstrations1, 2, 3, 4, 5, 6 of non-classical storage and on-demand recall have used atomic vapours and have been limited to low efficiencies, of less than 17 per cent, using weak quantum states with an average photon number of around one. Here we report a low-noise, highly efficient (up to 69 per cent) quantum memory for light that uses a solid-state medium. The device allows the storage and recall of light more faithfully than is possible using a classical memory, f! or weak coherent states at the single-photon level through to bright states of up to 500 photons. For input coherent states containing on average 30 photons or fewer, the performance exceeded the no-cloning limit. This guaranteed that more information about the inputs was retrieved from the memory than was left behind or destroyed, a feature that will provide security in communications applications. View full text Subject terms: * Applied physics * Engineering * Information technology Figures at a glance * Figure 1: Experimental set-up. Light from a highly stabilized dye laser, gated by acousto-optic modulators (AOMs), is directed at a 2-cm-long Pr:Y2SiO5 crystal mounted between Teflon plates, surrounded by four copper block electrodes with holes to allow the beams through. The crystal and holder are held in a liquid helium cryostat at 3 K. The memory is prepared by first burning a spectral trench over the full length of the crystal using the forward beam, then burning back a feature in the central 14 mm using a beam from the side. This side excitation avoided propagation effects and allowed the feature to be created only in the centre of the crystal, where the electric gradient field was monotonic. Inset, the component of the electric field along the propagation axis as determined by finite-element modelling of the holder, including the dielectric constant of the crystal and its Teflon mount. The shaded region represents the length over which the feature was created. The field gradient was created by g! rounding V3 and V4 and applying 20 V to V1 and V2. The gradient was switched by changing this to −20 V. V3 and V4 were used in the preparation sequence, as described in Supplementary Information. * Figure 2: Efficiency and spectral measurements. Measured and simulated data showing the obtained echoes and the corresponding absorption spectra. The simulations were based on Maxwell–Bloch equations. The input pulse was calibrated by measuring the transmission of a pulse through the transmissive spectral trench before every experiment. This trench was measured to be <2% absorbing using separate measurements with the laser far off resonance. The uncertainty in this measurement is taken into account in quoted efficiencies. , Input and retrieved pulses. The field begins switching at t = 1.4 μs for the first retrieved pulse and at t = 2.0 μs for the second. In the case of no field switch, 97% of the input pulse energy is absorbed. , Absorption spectrum of the prepared feature measured by transmission of a short pulse. The dynamic range of the measurement was insufficient to resolve the peak absorption of the feature, which was confirmed by independent measurements on shorter interaction lengths to be 100 dB cm−! 1. The black dotted trace represents a perfect measurement of the feature used in the simulations. , Absorption spectrum when the field was not switched to retrieve the pulse, that is, with 20 V applied to the end electrodes. The Stark shift of the ions is such that their resonant frequency is negatively correlated with their depth. This means that the higher-frequency side of this spectrum is due to ions towards the input end of the crystal and that the low-frequency side is due to those towards the output end. The simulation used the electric field determined in the inset of Fig. 1. * Figure 3: Noise due to the memory and comparison with benchmarks. –, Sets of 1,000 obtained quadrature values versus phase of the local oscillator for stored pulses (blue dots), in units of vacuum noise. The pulses had respective mean photon numbers of N = 4 (), 30 (), 500 () and 19,000 (). For the N = 500 and 19,000 data sets, the quadrature values of the input pulses are also shown (red dots). The green line and blue band respectively represent the mean amplitude and standard deviation of the Gaussian state fit to the corresponding set of retrieved data. The cyan line and pink band represent the same for the N = 500 and N = 19,000 input states. –, The blue line represents noise introduced by the memory, in units of the vacuum variance, for the four input states: N = 4 (), 30 (), 500 () and 19,000 (). Here the blue band indicates the 68 ± 1% (s.d.) confidence interval in our determination of the added variance as a function of phase. The dashed dark and light green lines indicate the performance of an ideal phase-insensitive clas! sical memory and a symmetrical 1 → 2 state-cloning device, respectively. For all the retrieved quadrature values, a 50-kHz frequency shift and 5π/6 phase shift relative to the input mode have been accounted for. Author information * Author information * Supplementary information * Comments Affiliations * Laser Physics Centre, Research School of Physics and Engineering, Australian National University, Canberra, Australian Capital Territory 0200, Australia * Morgan P. Hedges & * Matthew J. Sellars * Jack Dodd Centre, Physics Department, University of Otago, Dunedin 9016, New Zealand * Jevon J. Longdell * State Key Laboratory of Quantum Optics and Quantum Optics Devices, Institute of Opto-Electronics, Shanxi University, Taiyuan 030006, China * Yongmin Li Contributions The initial project was conceived by M.J.S. and J.J.L. Various preliminary experiments were conducted by M.P.H. with assistance and guidance from M.J.S., J.J.L. and Y.L. The final experiment was designed, built and conducted by M.P.H. under the guidance of M.J.S. Data was analysed by M.P.H. with assistance in interpretation by M.J.S. and J.J.L. Theoretical modelling was done by M.P.H., building on work of J.J.L. Supplementary noise theory was prepared by M.P.H. with assistance from J.J.L. and comments from Y.L. The manuscript was prepared by M.P.H., M.J.S. and J.J.L. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Morgan P. Hedges (mph111@physics.anu.edu.au) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (80K) This file contains Supplementary Methods and Data and References. Additional data
• Coherent control of Rydberg states in silicon
  - Nature (London) 465(7301):1057 (2010)
  Nature | Letter Coherent control of Rydberg states in silicon * P. T. Greenland1 Search for this author in: * NPG journals * PubMed * Google Scholar * S. A. Lynch1 Search for this author in: * NPG journals * PubMed * Google Scholar * A. F. G. van der Meer2 Search for this author in: * NPG journals * PubMed * Google Scholar * B. N. Murdin3 Search for this author in: * NPG journals * PubMed * Google Scholar * C. R. Pidgeon4 Search for this author in: * NPG journals * PubMed * Google Scholar * B. Redlich2 Search for this author in: * NPG journals * PubMed * Google Scholar * N. Q. Vinh2, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * G. Aeppli1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1057–1061Date published:(24 June 2010)DOI:doi:10.1038/nature09112Received09 November 2009Accepted20 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Laser cooling and electromagnetic traps have led to a revolution in atomic physics, yielding dramatic discoveries ranging from Bose–Einstein condensation to the quantum control of single atoms1. Of particular interest, because they can be used in the quantum control of one atom by another, are excited Rydberg states2, 3, 4, where wavefunctions are expanded from their ground-state extents of less than 0.1 nm to several nanometres and even beyond; this allows atoms far enough apart to be non-interacting in their ground states to strongly interact in their excited states. For eventual application of such states5, a solid-state implementation is very desirable. Here we demonstrate the coherent control of impurity wavefunctions in the most ubiquitous donor in a semiconductor, namely phosphorus-doped silicon. In our experiments, we use a free-electron laser to stimulate and observe photon echoes6, 7, the orbital analogue of the Hahn spin echo8, and Rabi oscillations familiar f! rom magnetic resonance spectroscopy. As well as extending atomic physicists' explorations1, 2, 3, 9 of quantum phenomena to the solid state, our work adds coherent terahertz radiation, as a particularly precise regulator of orbitals in solids, to the list of controls, such as pressure and chemical composition, already familiar to materials scientists10. View full text Subject terms: * Applied physics * Engineering * Materials science Figures at a glance * Figure 1: The principle of the experiment. , The spectrum of an isolated phosphorus donor in silicon. The primary excitation and two-photon ionization paths are shown in red; dephasing paths—photoelectron collisions and phonon decay—are shown in blue. , The Bloch sphere, with some sample wave packets. The ground state, 1s(A1) (|0), is at the south pole and the excited state, 2p0 (|1), is at the north pole. Around the equator, the wave packet varies as the relative phase of a 50:50 mixture evolves in time. This is the time-dependent combination we excite to produce the photon echo. , The classic Hahn sequence, and the corresponding behaviour of the Bloch vector. Ideally, the first pulse has an area of π/2 and the second pulse has an area of π. τ2E, interval between the rephasing beam and the echo. * Figure 2: Experimental orbital echo detection. , Schematic of the experimental geometry. The 1 beam (green) is the pump pulse referred to in Fig. 1c and the 2 beam (blue) is the rephasing pulse in Fig. 1c. They intersect in the sample (at ~5° in the experiment) and the echo pulse (E, red) is emitted in the direction 22 − 1. The total path lengths are not drawn to scale. We show the set-up for measuring the echo direction (ANGLE) and the arrival time (TIMING), which uses cross-correlation with a reference pulse (*, dotted line). A, attenuators; BS, beam splitter; D, detector; MM, moving mirror; P1, polarizer; P2, analyser; R, optical delay line. , Angle-resolved echo. The intensities of the angle-resolved signals were recorded by translating the detector across the far field (, ANGLE), which shows that E = 22 − 1 as predicted. a.u., arbitrary units. , Time-resolved echo. Result of cross-correlation of the reference beam (, * in TIMING) with the pump, the rephasing pulse and the echo by interfering them on the! detector. The abscissa is the arrival time of the reference pulse relative to the arrival of the rephasing pulse. On the left is the detector signal, showing the interference patterns with the pump, rephasing and echo beams. A moving average has been subtracted to remove the background and laser drift. The pump, rephasing and echo temporal profiles were obtained from the square of these interference patterns, as shown on the right, where the pump beam/rephasing beam time interval, τ12, and the rephasing beam/echo time interval, τ2E, are also shown. Gaussian fits of the pump and rephasing pulses had full-widths at half-maximum intensity of 7.7 ± 1.5 ps, consistent with the inverse spectral width, 0.28%. The echo duration, 27.8 ± 7.6 ps, is somewhat longer than would be expected from the measured inhomogeneous frequency-domain linewidth (~200 μeV). , Echo arrival-time control. Time-resolved cross-correlation experiments similar to those shown in , with a r! ange of pump–rephasing delays, were used to establish values! of the echo delay with respect to the rephasing beam. Within the experimental error, the echo arrives when expected, that is, τ2E = τ12, shown by the black line. The errors in τ2E are standard deviations derived from a Monte Carlo method, and the errors in τ12 represent the uncertainty in the pump–rephasing zero. Because the laser pulse has a Gaussian spatial profile, the effective pulse area for atoms at radius r from the pulse centre is A(r) = APexp(−r2/2r02), where r0 = 0.89 mm and we characterize the size of the pulse by the central area, AP (Methods). , Decay of time-resolved echoes. We show a set of echo profiles for a selection of pump–rephasing delays. The ordinate is the echo power, based on an approximate calibration. The black line is a fit, with time constant Texp = 28.4 ps, showing that the echo intensity decreases exponentially with τ12, as expected. The apparent fluctuations in the echo profile are a result of the smoothing used to process the! data, as in . * Figure 3: Rabi oscillations. The time-integrated photon echo signal, S, as a function of pump peak pulse area, AP, for a rephasing peak pulse area of 0.54π and a pulse length of 6.79 ps. The dashed line is the ideal theoretical result, showing Rabi oscillations. The black line shows the corrected prediction when including the non-uniform spatial profile of the laser beam, and the purple line includes the effect of both photoionization and the beam profile. The lines were calculated using values for μ12, Γ0, and σe that were found from a global fit of many experimental data sets like the one shown here. The experimental results for the same conditions are shown as points. The normalization factor for the ordinate of the experimental result relative to theory was found from a global comparison of many similar experiments with different pulse lengths and rephasing pulse areas (Supplementary Information). The error bars indicate the standard deviation of the normalization factor (systematic for an ind! ividual experiment such the one in this figure) and dominate the statistical errors in the measurements. * Figure 4: Comparison of hydrogen and Si:P, showing spectra and the principal excitation and decoherence mechanisms. The crystal environment leads to an asymmetric effective mass, so that the hydrogen 2p state splits into 2p0 and 2p± states in Si:P. Additionally, the crystal field further splits the hydrogen-like levels into states of cubic symmetry; the splitting of the 1s level into its A, T and E components is shown, but the splitting in the excited states is too small to display here. The main decay channel of the 2p0 state in Si:P, unlike in hydrogen, is phonon decay; furthermore, photoionization of this state is also relatively much stronger than in hydrogen, and because the photoelectrons are confined to the conduction band they can cause decoherence through phase-changing collisions. σ , cross-section of photoionization from upper state or dephasing, as labelled; f, transition oscillator strength in hydrogen; fexp, measured transition oscillator strength in Si:P. Author information * Author information * Supplementary information * Comments Affiliations * London Centre for Nanotechnology and Department of Physics and Astronomy, University College London, London WC1H 0AH, UK * P. T. Greenland, * S. A. Lynch & * G. Aeppli * FOM Institute for Plasma Physics "Rijnhuizen", PO Box 1207, NL-3430 BE Nieuwegein, The Netherlands * A. F. G. van der Meer, * B. Redlich & * N. Q. Vinh * Advanced Technology Institute, University of Surrey, Guildford GU2 7XH, UK * B. N. Murdin * Heriot-Watt University, Department of Physics, Riccarton, Edinburgh EH14 4AS, UK * C. R. Pidgeon * Present address: ITST, Department of Physics, University of California, Santa Barbara, California 93106-4170, USA. * N. Q. Vinh Contributions N.Q.V. and C.R.P. initiated this work; P.T.G., S.A.L., B.N.M., N.Q.V. and G.A. designed the research programme; N.Q.V., P.T.G., S.A.L., A.F.G.v.d.M. and B.R. performed the experiments; P.T.G. performed the theory and analysis; and P.T.G., B.N.M., S.A.L. and G.A. wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * P. T. Greenland (ptg@globalnet.co.uk) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (378K) This file contains Supplementary Information and Data, and Supplementary Figures S1-S4 with legends. Additional data
• Nitrate supply from deep to near-surface waters of the North Pacific subtropical gyre
  - Nature (London) 465(7301):1062 (2010)
  Nature | Letter Nitrate supply from deep to near-surface waters of the North Pacific subtropical gyre * Kenneth S. Johnson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephen C. Riser2 Search for this author in: * NPG journals * PubMed * Google Scholar * David M. Karl3 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1062–1065Date published:(24 June 2010)DOI:doi:10.1038/nature09170Received06 October 2009Accepted29 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Concentrations of dissolved inorganic carbon (DIC) decrease in the surface mixed layers during spring and summer in most of the oligotrophic ocean. Mass balance calculations require that the missing DIC is converted into particulate carbon by photosynthesis1, 2, 3. This DIC uptake represents one of the largest components of net community production in the world ocean2, 4. However, mixed-layer waters in these regions of the ocean typically contain negligible concentrations of plant nutrients such as nitrate and phosphate3, 5. Combined nutrient supply mechanisms including nitrogen fixation, diffusive transport and vertical entrainment are believed to be insufficient to supply the required nutrients for photosynthesis6, 7. The basin-scale potential for episodic nutrient transport by eddy events is unresolved8, 9. As a result, it is not understood how biologically mediated DIC uptake can be supported in the absence of nutrients. Here we report on high-resolution measurements of ! nitrate (NO3−) and oxygen (O2) concentration made over 21 months using a profiling float deployed near the Hawaii Ocean Time-series station in the North Pacific subtropical gyre. Our measurements demonstrate that as O2 was produced and DIC was consumed over two annual cycles, a corresponding seasonal deficit in dissolved NO3− appeared in water at depths from 100 to 250 m. The deep-water deficit in NO3− was in near-stoichiometric balance with the fixed nitrogen exported to depth. Thus, when the water column from the surface to 250 m is considered as a whole, there is near equivalence between nutrient supply and demand. Short-lived transport events (<10 days) that connect deep stocks of nitrate to nutrient-poor surface waters were clearly present in 12 of the 127 vertical profiles. View full text Subject terms: * Earth sciences Figures at a glance * Figure 1: Shipboard observations at HOT station ALOHA. , DIC concentration normalized to salinity 35 in the upper 50 m versus day of year. A linear trend due to increasing atmospheric CO2, noted previously10, was removed from the data. , Nitrate concentration in the upper 50 m measured by chemiluminescence versus day of year. , Dissolved organic nitrogen versus day of year. , Primary production measured with 14C and nitrate versus depth. Data from 1988 to 2007 were downloaded from the HOT Data Organization & Graphical System website (http://hahana.soest.hawaii.edu/hot/hot-dogs/interface.html). Results were binned in 20-d or 20-m intervals and the mean and 95% confidence interval were computed. * Figure 2: Profiling float observations in the upper 300 m. Measurements were made at 5-d intervals and with 5-m vertical resolution above 100 m and 10-m resolution below. , Seawater density anomaly (σ0 = density − 1,000 kg m−3). , Oxygen anomaly (O2 − O2,100%Saturation). , Nitrate. The black line shows sea surface height anomaly (SSHA; http://www.aviso.oceanobs.com/duacs/) at the location of each float profile. The SSHA scale bar is centred on zero and spans −10 cm (top) to 10 cm (bottom). , Preformed nitrate. Data contoured using Ocean Data View 3.4 (Schlitzer, R., http://odv.awi.de). * Figure 3: Profiling float observations over 100 days from 19 December 2008 to 22 March 2009. , Dissolved oxygen. Black dots show the location of each measurement. White line is the 190 μM contour. Vertical transport events discussed in the text are identified using the labels 1, 2 and 3?. , Nitrate. White line is the 1 μM contour. Black line is the 24.55 kg m−3 density anomaly contour. , Salinity. White line is the 35.25 contour. , Sea surface height anomaly on 11 February 2009 (407 days after 1 January 2008). The black dot shows the profile location during event 2. Author information * Author information * Supplementary information * Comments Affiliations * Monterey Bay Aquarium Research Institute, Moss Landing, California 95039, USA * Kenneth S. Johnson * School of Oceanography, University of Washington, Seattle, Washington 98195, USA * Stephen C. Riser * School of Ocean and Earth Science and Technology, Center for Microbial Oceanography: Research and Education, University of Hawaii, Honolulu, Hawaii 96822, USA * David M. Karl Contributions S.C.R. and K.S.J. wrote proposals to support incorporation of ISUS into the APEX float and co-lead the engineering effort to complete sensor integration. The system was deployed at the HOT station to take advantage of the background information and hypotheses generated by the HOT program, which was led by D.M.K. The initial data analysis was performed by K.S.J. and all authors contributed to writing the manuscript. Competing financial interests Monterey Bay Aquarium Research Institute and K.S.J. receive small annual licence fees for commercial versions of the ISUS nitrate sensor used in this work. Corresponding author Correspondence to: * Kenneth S. Johnson (johnson@mbari.org) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Figures (498K) This file contains Supplementary Figures 1-5 with legends. Additional data
• Environmental context explains Lévy and Brownian movement patterns of marine predators
  Humphries NE Queiroz N Dyer JR Pade NG Musyl MK Schaefer KM Fuller DW Brunnschweiler JM Doyle TK Houghton JD Hays GC Jones CS Noble LR Wearmouth VJ Southall EJ Sims DW - Nature (London) 465(7301):1066 (2010)
  Nature | Letter Environmental context explains Lévy and Brownian movement patterns of marine predators * Nicolas E. Humphries1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Nuno Queiroz1, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Jennifer R. M. Dyer1 Search for this author in: * NPG journals * PubMed * Google Scholar * Nicolas G. Pade1, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael K. Musyl5 Search for this author in: * NPG journals * PubMed * Google Scholar * Kurt M. Schaefer6 Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel W. Fuller6 Search for this author in: * NPG journals * PubMed * Google Scholar * Juerg M. Brunnschweiler7 Search for this author in: * NPG journals * PubMed * Google Scholar * Thomas K. Doyle8 Search for this author in: * NPG journals * PubMed * Google Scholar * Jonathan D. R. Houghton9 Search for this author in: * NPG journals * PubMed * Google Scholar * Graeme C. Hays10 Search for this author in: * NPG journals * PubMed * Google Scholar * Catherine S. Jones4 Search for this author in: * NPG journals * PubMed * Google Scholar * Leslie R. Noble4 Search for this author in: * NPG journals * PubMed * Google Scholar * Victoria J. Wearmouth1 Search for this author in: * NPG journals * PubMed * Google Scholar * Emily J. Southall1 Search for this author in: * NPG journals * PubMed * Google Scholar * David W. Sims1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1066–1069Date published:(24 June 2010)DOI:doi:10.1038/nature09116Received01 February 2010Accepted21 April 2010Published online09 June 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg An optimal search theory, the so-called Lévy-flight foraging hypothesis1, predicts that predators should adopt search strategies known as Lévy flights where prey is sparse and distributed unpredictably, but that Brownian movement is sufficiently efficient for locating abundant prey2, 3, 4. Empirical studies have generated controversy because the accuracy of statistical methods that have been used to identify Lévy behaviour has recently been questioned5, 6. Consequently, whether foragers exhibit Lévy flights in the wild remains unclear. Crucially, moreover, it has not been tested whether observed movement patterns across natural landscapes having different expected resource distributions conform to the theory's central predictions. Here we use maximum-likelihood methods to test for Lévy patterns in relation to environmental gradients in the largest animal movement data set assembled for this purpose. Strong support was found for Lévy search patterns across 14 species ! of open-ocean predatory fish (sharks, tuna, billfish and ocean sunfish), with some individuals switching between Lévy and Brownian movement as they traversed different habitat types. We tested the spatial occurrence of these two principal patterns and found Lévy behaviour to be associated with less productive waters (sparser prey) and Brownian movements to be associated with productive shelf or convergence-front habitats (abundant prey). These results are consistent with the Lévy-flight foraging hypothesis1, 7, supporting the contention8, 9 that organism search strategies naturally evolved in such a way that they exploit optimal Lévy patterns. View full text Subject terms: * Zoology * Environmental science * Animal behaviour * Applied physics * Engineering Figures at a glance * Figure 1: Examples of good fits to power-law and truncated power-law distributions. , Synthetic power-law and truncated power-law (Pareto) distributions with upper truncations set to 50, 250, 5,000. –, Empirical power-law and truncated power-law fits to dive data from individual blue sharks (Prionace glauca; , ) and an ocean sunfish (Mola mola, ), together with the diving time series for the individual in (over ~8 d; ) and the individual in (over ~4 d; ). The red line indicates a synthetic power law in , a power law in and truncated power-law MLE model fits to empirical data in and . * Figure 2: Behavioural switching between Lévy and Brownian motion in relation to habitat type. , Split moving-window analysis showing significant discontinuities in the dive time series of blue shark 10. Red lines indicate points where the time series was divided into sections (SEC1–SEC5). , MLE analysis with μ values for sections best fitting a truncated power-law distribution: black circles, observed step lengths; red lines, best-fit truncated power law; blue lines, best-fit exponential distribution. , Depth profiles of sea temperature recorded using electronic tags. , , Geo-referenced track sections of blue shark 10 overlaid on chlorophyll a concentrations () and bathymetry (). Section numbers correspond to those in and different data-point colours correspond to different sections: SEC1, black (higher latitude); SEC2, white (higher latitude); SEC3, grey; SEC4, black (lower latitude); SEC5, white (lower latitude). * Figure 3: Spatial occurrence of Lévy and Brownian behaviour types. Frequencies of behaviour types in productive (frontal/shelf) and less productive (off-shelf) habitats in the northeast Atlantic (), and in productive (frontal) and less productive (stratified) habitats in the central eastern Pacific (). Tests of two predictions of the LFF hypothesis (Lévy behaviour where prey is sparse; Brownian movement where prey is abundant and not sparsely distributed) were performed on frequency data (not per cent frequency data). See main text for details of the statistical tests. Author information * Author information * Supplementary information * Comments Affiliations * Marine Biological Association of the United Kingdom, The Laboratory, Citadel Hill, Plymouth PL1 2PB, UK * Nicolas E. Humphries, * Nuno Queiroz, * Jennifer R. M. Dyer, * Nicolas G. Pade, * Victoria J. Wearmouth, * Emily J. Southall & * David W. Sims * Marine Biology and Ecology Research Centre, Marine Institute, School of Marine Sciences and Engineering, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK * Nicolas E. Humphries & * David W. Sims * CIBIO – Universidade do Porto, Campus Agrário de Vairão, Rua Padre Armando Quintas, 4485-668 Vairão, Portugal * Nuno Queiroz * Institute of Biological and Environmental Sciences, School of Biological Sciences, University of Aberdeen, Tillydrone Avenue, Aberdeen AB24 2TZ, UK * Nuno Queiroz, * Nicolas G. Pade, * Catherine S. Jones & * Leslie R. Noble * Joint Institute for Marine and Atmospheric Research, University of Hawaii at Manoa, Kewalo Research Facility/NOAA Fisheries, 1125-B Ala Mona Boulevard, Honolulu, Hawaii 96814, USA * Michael K. Musyl * Inter-American Tropical Tuna Commission, 8604 La Jolla Shores Drive, La Jolla, California 92037-1508, USA * Kurt M. Schaefer & * Daniel W. Fuller * ETH Zurich, Raemistrasse 101, CH-8092 Zurich, Switzerland * Juerg M. Brunnschweiler * Coastal and Marine Resources Centre, ERI, University College Cork, Glucksman Marine Facility, Naval Base, Haulbowline, Cobh, Cork, Ireland * Thomas K. Doyle * School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK * Jonathan D. R. Houghton * Department of Pure and Applied Ecology, Institute of Environmental Sustainability, Swansea University, Singleton Park, Swansea SA2 8PP, UK * Graeme C. Hays Contributions D.W.S. designed the study. N.E.H. and D.W.S. completed data analysis with contributions from N.Q. and J.R.M.D. N.E.H. designed and developed the software for MLE and split moving-window analyses. D.W.S. and N.E.H. wrote the paper and all authors contributed to subsequent drafts. Field data were collected by D.W.S., E.J.S., N.Q., N.G.P., M.K.M., K.M.S., D.W.F., J.M.B., T.K.D., J.D.R.H., G.C.H. and V.J.W. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * David W. Sims (dws@mba.ac.uk) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (5.3M) This file contains Supplementary Methods, Supplementary Results, Supplementary Tables S1-S4, Supplementary Figures S1-S9 with legends and References. Additional data
• Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability
  Grubb MS Burrone J - Nature (London) 465(7301):1070 (2010)
  Nature | Letter Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability * Matthew S. Grubb1 Search for this author in: * NPG journals * PubMed * Google Scholar * Juan Burrone1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:1070–1074Date published:(24 June 2010)DOI:doi:10.1038/nature09160Received01 September 2009Accepted10 May 2010Published online13 June 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg In neurons, the axon initial segment (AIS) is a specialized region near the start of the axon that is the site of action potential initiation1, 2, 3, 4, 5, 6. The precise location of the AIS varies across and within different neuronal types7, 8, and has been linked to cells' information-processing capabilities8; however, the factors determining AIS position in individual neurons remain unknown. Here we show that changes in electrical activity can alter the location of the AIS. In dissociated hippocampal cultures, chronic depolarization with high extracellular potassium moves multiple components of the AIS, including voltage-gated sodium channels, up to 17 μm away from the soma of excitatory neurons. This movement reverses when neurons are returned to non-depolarized conditions, and depends on the activation of T- and/or L-type voltage-gated calcium channels. The AIS also moved distally when we combined long-term LED (light-emitting diode) photostimulation with sparse ne! uronal expression of the light-activated cation channel channelrhodopsin-2; here, burst patterning of activity was successful where regular stimulation at the same frequency failed. Furthermore, changes in AIS position correlate with alterations in current thresholds for action potential spiking. Our results show that neurons can regulate the position of an entire subcellular structure according to their ongoing levels and patterns of electrical activity. This novel form of activity-dependent plasticity may fine-tune neuronal excitability during development. View full text Subject terms: * Neuroscience * Medical research * Cell biology * Biophysics Figures at a glance * Figure 1: Activity-dependent changes in AIS position. , Ankyrin G label in control and 15 mM K+ conditions. Right: fluorescence intensity along the axon. Dotted lines indicate soma. , Ankyrin G positions and length (885 cells, 36 coverslips). , βIV spectrin and PanNav label. , Positions for βIV spectrin (1,065 cells, 44 coverslips), PanNav (95 cells, 4 coverslips), Pan-neurofascin (NF; 96 cells, 4 coverslips) and FGF14 (89 cells, 4 coverslips). , Ankyrin G label after recovery from (K+–control), or continued (K+–K+), depolarization (194 cells, 8 coverslips). , βIV spectrin label in GAD65-positive neurons (200 cells, 8 coverslips). All scale bars indicate 20 μm; *P < 0.05; **P < 0.01; ***P < 0.001. All plots show mean ± s.e.m. * Figure 2: T- and/or L-type calcium channels mediate activity-dependent changes in AIS position. , Ankyrin G label after 12–14 DIV, 15 mM K+ treatment with different voltage-gated ion channel antagonists. Scale bar, 20 μm; dotted line, soma. , Mean ankyrin G positions (TTX, 392 cells, 16 coverslips; Ni2+, 193 cells, 8 coverslips; SNX, 247 cells, 10 coverslips; mibefradil, 246 cells, 10 coverslips; ω-agatoxin-TK, 199 cells, 8 coverslips; ω-conotoxin-GVIA, 199 cells, 8 coverslips; nifedipine, 200 cells, 8 coverslips). *P < 0.05; ***P < 0.001; error bars, s.e.m. * Figure 3: Changes in AIS position with patterned ChR2 photostimulation. , LED photostimulation of ChR2-positive neurons. , Ankyrin G label in ChR2-positive neurons after different photostimulation conditions. Scale bar, 20 μm. , Mean ankyrin G positions for ChR2-positive (green) and ChR2-negative (black) neurons after different photostimulation conditions (0.2 Hz, 133 cells, 4 coverslips; 1 Hz sparse, 274 cells, 8 coverslips; 1 Hz bursts, 310 cells, 8 coverslips; 1 Hz bursts + TTX, 154 cells, 4 coverslips; 1 Hz bursts + mibefradil, 134 cells, 4 coverslips). *P < 0.05; **P < 0.01; error bars, s.e.m. * Figure 4: Differences in AIS position are associated with differences in neuronal excitability. , Current-clamp traces in control and 15 mM K+ conditions. Numbers indicate threshold current (pA) and threshold current density (pA pF−1). , Threshold current, threshold current density and Rm (41 cells, 3 cultures). , , YFP–NavII–III label and current-clamp traces. , AIS end position versus current threshold (control: 24 cells, 3 cultures, AIS end mean 33.51 ± 2.63 µm; 15 mM K+: 26 cells, 1 culture, AIS end mean 37.02 ± 2.40 µm). Lines indicate linear regression. , , Left: biocytin and ankyrin G label. Middle and right panels show current-clamp traces for 10 ms and 500 ms current injections. Numbers indicate input pA pF−1. , AIS start position versus threshold current density for 10 ms current injections (53 cells, 2 cultures). , Current density versus spike number for 500 ms current injections, sample split by AIS start position. , As for , but sample split by Rm. All scale bars indicate 20 μm; *P < 0.05; **P <�! ��0.01; ***P < 0.001. All plots show mean ± s.e.m. Author information * Author information * Supplementary information * Comments Affiliations * MRC Centre for Developmental Neurobiology, King's College London, 4th Floor, New Hunt's House, Guy's Campus, London SE1 1UL, UK * Matthew S. Grubb & * Juan Burrone Contributions M.S.G. planned and performed all experiments and analysis, and wrote the paper. J.B. produced simulation data, planned experiments, supervised the project and wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Matthew S. Grubb (matthew.grubb@kcl.ac.uk) or * Juan Burrone (juan.burrone@kcl.ac.uk) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (10.8M) This file contains Supplementary Figures 1-13 with legends and Supplementary Tables 1-3. Additional data
• Presynaptic activity regulates Na+ channel distribution at the axon initial segment
  Kuba H Oichi Y Ohmori H - Nature (London) 465(7301):1075 (2010)
  Nature | Letter Presynaptic activity regulates Na+ channel distribution at the axon initial segment * Hiroshi Kuba1 Search for this author in: * NPG journals * PubMed * Google Scholar * Yuki Oichi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Harunori Ohmori2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1075–1078Date published:(24 June 2010)DOI:doi:10.1038/nature09087Received30 August 2009Accepted15 April 2010Published online13 June 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Deprivation of afferent inputs in neural circuits leads to diverse plastic changes in both pre- and postsynaptic elements that restore neural activity1. The axon initial segment (AIS) is the site at which neural signals arise2, 3, and should be the most efficient site to regulate neural activity. However, none of the plasticity currently known involves the AIS. We report here that deprivation of auditory input in an avian brainstem auditory neuron leads to an increase in AIS length, thus augmenting the excitability of the neuron. The length of the AIS, defined by the distribution of voltage-gated Na+ channels and the AIS anchoring protein, increased by 1.7 times in seven days after auditory input deprivation. This was accompanied by an increase in the whole-cell Na+ current, membrane excitability and spontaneous firing. Our work demonstrates homeostatic regulation of the AIS, which may contribute to the maintenance of the auditory pathway after hearing loss. Furthermore, pla! sticity at the spike initiation site suggests a powerful pathway for refining neuronal computation in the face of strong sensory deprivation. View full text Subject terms: * Neuroscience * Physiology * Cell biology * Medical research Figures at a glance * Figure 1: Auditory deprivation increased the length of the AIS. , , Immunostaining with VGLUT2 () and Pan-Nav () antibodies seven days after auditory deprivation. NM, nucleus magnocellularis. , Enlarged views of the boxed regions in . Arrowheads indicate AISs in this figure and in Fig. 2. , , Histograms and cumulative plots of length () and width () of Nav channel clusters in (Methods). , Nav channel clusters (red) are located on the axons of labelled nucleus magnocellularis neurons (green). , , Distance () and length () of Nav channel clusters in 14. Circles indicate values from individual cells. Error bars, s.e.; **P < 0.01. , , Ankyrin-G () and Nav1.6 () (green) are co-localized with Pan-Nav (red). n, number of cells. * Figure 2: Elongation of the AIS is activity dependent and develops within several days. , Immunostaining with Pan-Nav antibody at various times (as indicated in days after deprivation) after auditory deprivation. , Cumulative plots of length of Nav channel clusters from animals in . , Time course of relative length of control and deprived sides. Data from 4, 5, 5, 9, 3 animals (left to right). Statistical analysis was made against day-one data. , , Effects of different levels of auditory input on the length of the AIS (Methods and Supplementary Fig. 5). Relative length could be increased by elongation on the operated side and/or shortening on the non-operated side. Data from 5, 7, 10, 9, 3, 7 animals (, left to right). Circles in indicate values from individual animals. The lengths of Nav channel clusters in were plotted cumulatively for each group (). Data from 7, 31, 5, 7, 10, 19 animals (, top to bottom). Acoustic attenuation shifts the curves rightwards. Coch dep, cochlea deprivation; colum dep, columella deprivation; colum fix, columella fixation; tymp pun! c, tympanic membrane puncture. Error bars, s.e.; *P < 0.05; **P < 0.01. * Figure 3: Auditory deprivation increased axonal INa and excitability of neurons. , , INa recorded under whole-cell () and cell-attached () conditions from the soma. , , Auditory deprivation increased whole-cell () but not cell-attached () INa. , Action potentials in response to depolarizing current steps. Threshold current is indicated in grey and threshold potential is indicated by arrowheads (Methods). Symbols indicate points where conductance was calculated (Supplementary Fig. 8). , Auditory deprivation increased amplitude () and maximum dV/dt (), and decreased threshold potential () and threshold current () of spikes. , Spontaneous firing of nucleus magnocellularis neurons in slices after auditory deprivation; inset, firing frequency. Circles indicate values from individual cells. Error bars, s.e.; *P < 0.05; **P < 0.01. * Figure 4: Auditory deprivation has little effect on synaptic transmission. , VGLUT2 immunolabelling declined within one day after auditory deprivation. , Evoked excitatory postsynaptic currents (eEPSCs). Four traces of different stimulus intensities are superimposed. Insets, amplitudes as functions of stimulus intensity. , Ensemble averaged traces of spontaneous excitatory postsynaptic current (sEPSCs). Insets, the relationship between the 10–90% rise time and the amplitude of sEPSCs did not show any differences between the distribution on the control side (541 sEPSCs from 7 cells) and that on the deprived side (523 sEPSCs from 8 cells). , Amplitudes (), 10–90% rise times () and half-amplitude widths () of eEPSCs and sEPSCs. , Frequency of sEPSCs. Error bars, s.e.; *P < 0.05. Author information * Author information * Supplementary information * Comments Affiliations * Career-Path Promotion Unit for Young Life Scientists, * Hiroshi Kuba & * Yuki Oichi * Department of Physiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan * Harunori Ohmori Contributions H.K. designed and carried out all experiments and wrote the paper. Y.O. carried out preliminary experiments. H.O. helped with acoustic stimulation. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Hiroshi Kuba (kuba@nbiol.med.kyoto-u.ac.jp) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (4.1M) This file contains Supplementary Figures 1-8 with legends and References. Additional data
• Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus
  - Nature (London) 465(7301):1079 (2010)
  Nature | Letter Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus * Matteo Iannacone1, 2, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * E. Ashley Moseman1, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Elena Tonti1 Search for this author in: * NPG journals * PubMed * Google Scholar * Lidia Bosurgi1 Search for this author in: * NPG journals * PubMed * Google Scholar * Tobias Junt3 Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah E. Henrickson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sean P. Whelan4 Search for this author in: * NPG journals * PubMed * Google Scholar * Luca G. Guidotti2 Search for this author in: * NPG journals * PubMed * Google Scholar * Ulrich H. von Andrian1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorsJournal name:NatureVolume:465,Pages:1079–1083Date published:(24 June 2010)DOI:doi:10.1038/nature09118Received01 January 2010Accepted22 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Lymph nodes (LNs) capture microorganisms that breach the body's external barriers and enter draining lymphatics, limiting the systemic spread of pathogens1. Recent work has shown that CD11b+CD169+ macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for the clearance of viruses from the lymph and for initiating antiviral humoral immune responses2, 3, 4. Here we show, using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the central nervous system (CNS). On local depletion of LN macrophages, about 60% of mice developed ascending paralysis and died 7–10 days after subcutaneous infection with a small dose of VSV, whereas macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system through peripheral nerves in macrophage-depleted LNs. In contrast! , within macrophage-sufficient LNs VSV replicated preferentially in SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but decreased type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I-producing plasmacytoid dendritic cells to the SCS and in addition were a major source of IFN-I themselves. Experiments in bone marrow chimaeric mice revealed that IFN-I must act on both haematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal infection with VSV. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral invasion of the nervous system on peripheral infection. View full text Subject terms: * Immunology * Virology Figures at a glance * Figure 1: Lymph node macrophages confer resistance to fatal invasion of the CNS on peripheral low-dose infection with VSV. , Survival curves of control mice (n = 68) and mice that received ipsilateral (n = 77) or contralateral (n = 10) injection of CLLs before infection with VSV. Ipsilateral CLLs versus control, P < 0.0001. , VSV titres in the brain of control and CLL-treated mice, 7 days after infection. Red squares identify paralytic animals. P = 0.024. , Survival curves of CD11c-DTR mice (n = 8); P = 0.0256. , Survival curves of control and CLL-treated mice after intravenous VSV infection (n = 10). , Survival curves of CLL-treated VSV-infected mice after ipsilateral (n = 10) or contralateral (n = 7) sciatic nerve resection. P = 0.007. , FACS plots of digested footpads (top) and the popliteal LNs (bottom) of control and CLL footpad-injected or calf-injected mice. Numbers show the percentages of CD45+ cells within each gate. Plots are representative of two experiments (n = 3 mice per experiment). , Survival curves in control (n = 10) and calf CLL-treated mice (n = 11). P = 0.0411. * Figure 2: SCS macrophages are the primary targets for lymph-borne VSV and prevent infection of adjacent nerves. –, Representative confocal micrographs of macrophage-sufficient (, ) and CLL-treated () popliteal LNs after VSV–eGFP infection. Scale bars, 150 μm (, ) and 20 μm (). –, Representative multiphoton micrographs of whole mounts of uninfected () or VSV–eGFP-infected LNs (, ). VSV–eGFP infection of macrophage-sufficient LNs () induced GFP expression in macrophages but not in nerves (red), whereas nerves in CLL-treated LNs () expressed GFP (Supplementary Movies 1 and 2). Scale bars, 100 μm. Blue shows the second harmonic signal from collagen in the LN capsule. , Ratio of mean fluorescent intensity (MFI) in the green (488 nm) and red (568 nm) channel, depicting GFP expression and β3-tubulin staining, respectively, in peripheral nerves. n = 3, P < 0.0001 (VSV versus CLLs + VSV). , VSV titres in popliteal LNs of control and CLL-treated mice. n = 4, P = 0.0010 (6 h), P < 0.0001 (12 h), P = 0.1043 (24 h), P = 0.0765 (36 h). , Serum-neutralizin! g immunoglobulin titres in control and CLL-treated infected mice. n = 4, P = 0.0053 (day 4), P = 0.0138 (day 7), P = 0.0022 (day 10), P = 0.0054 (day 26). Error bars show s.e.m. * Figure 3: Regulation of VSV-induced IFN-I production by SCS macrophages. , VSV-induced IFN-α production in LNs (n = 3). Asterisk, P < 0.05; two asterisks, P < 0.001 versus uninfected. NS, not significant. , , IFN-α concentrations in supernatants of FACS-sorted LN cells after VSV–eGFP infection (Supplementary Fig. 9a, b). Results are from one representative experiment of three. –, Micrographs of popliteal LN sections from bone-marrow chimaeric mice with 30% GFP+ pDCs (Supplementary Fig. 10) that were either left untreated () or killed 8 h after VSV infection (–) without (, ) or with () pretreatment with CLLs. Scale bars, 150 μm (, , ) and 20 μm (). , pDC frequency in the T-cell area (n = 4 mice per group). Two asterisks, P < 0.001 versus control. , Relative pDC frequency distribution in LN cross-sections (Supplementary Fig. 12). VSV versus control, P < 0.05. , Effect of depletion of LN macrophages, pDCs or both on survival on VSV infection; anti-PDCA1 versus control, NS; CLLs versus CLLs + anti-PDCA1, NS. , Surv! ival curves of wild-type (WT), IFN-αβR−/− or irradiated IFN-αβR−/− mice that were reconstituted with WT bone marrow (BM) on VSV infection. n = 8. WT BM→IFN-αβR−/− versus WT + CLLs, NS; WT BM→IFN-αβR−/− versus IFN-αβR−/−, P = 0.0001. Error bars show s.e.m. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Matteo Iannacone & * E. Ashley Moseman Affiliations * Immune Disease Institute and Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA * Matteo Iannacone, * E. Ashley Moseman, * Elena Tonti, * Lidia Bosurgi, * Sarah E. Henrickson & * Ulrich H. von Andrian * Department of Immunology, Infectious Diseases and Transplantation, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy * Matteo Iannacone & * Luca G. Guidotti * Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland * Tobias Junt * Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA * Sean P. Whelan Contributions M.I., E.A.M. and U.H.v.A. designed the study. M.I., E.A.M., E.T., L.B. and T.J. performed experiments. M.I., E.A.M., E.T. and L.B. collected and analysed data. S.P.W. provided reagents and performed the RT–PCR experiment. S.E.H. contributed to the nerve imaging. L.G.G. provided mice and gave conceptual advice. M.I., E.A.M. and U.H.v.A. wrote the manuscript. M.I. and E.A.M contributed equally to this work. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Ulrich H. von Andrian (uva@hms.harvard.edu) or * Matteo Iannacone (Matteo_Iannacone@hms.harvard.edu) Supplementary information * Author information * Supplementary information * Comments Movies * Supplementary Movie 1 (12.6M) This movie shows a three-dimensional rotation view followed by Z-stack projection of the MP-IVM stack used to generate Fig. 2e (see Supplementary Information file for full legend). * Supplementary Movie 2 (8.7M) This movie shows a three-dimensional rotation view followed by Z-stack projection of the MP-IVM stack used to generate Fig. 2f (see Supplementary Information file for full legend). PDF files * Supplementary Information (1.1M) This file contains Supplementary Figures 1-13 with legends and legends for Supplementary Movies 1-2. Additional data
• Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
  - Nature (London) 465(7301):1084 (2010)
  Nature | Letter Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2 * Sergio E. Alvarez1, 3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Kuzhuvelil B. Harikumar1, 3 Search for this author in: * NPG journals * PubMed * Google Scholar * Nitai C. Hait1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeremy Allegood1 Search for this author in: * NPG journals * PubMed * Google Scholar * Graham M. Strub1 Search for this author in: * NPG journals * PubMed * Google Scholar * Eugene Y. Kim1 Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Maceyka1 Search for this author in: * NPG journals * PubMed * Google Scholar * Hualiang Jiang2 Search for this author in: * NPG journals * PubMed * Google Scholar * Cheng Luo2 Search for this author in: * NPG journals * PubMed * Google Scholar * Tomasz Kordula1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sheldon Milstien1 Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah Spiegel1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1084–1088Date published:(24 June 2010)DOI:doi:10.1038/nature09128Received11 November 2009Accepted26 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Tumour-necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is a key component in NF-κB signalling triggered by TNF-α1, 2. Genetic evidence indicates that TRAF2 is necessary for the polyubiquitination of receptor interacting protein 1 (RIP1)3 that then serves as a platform for recruitment and stimulation of IκB kinase, leading to activation of the transcription factor NF-κB. Although TRAF2 is a RING domain ubiquitin ligase, direct evidence that TRAF2 catalyses the ubiquitination of RIP1 is lacking. TRAF2 binds to sphingosine kinase 1 (SphK1)4, one of the isoenzymes that generates the pro-survival lipid mediator sphingosine-1-phosphate (S1P) inside cells. Here we show that SphK1 and the production of S1P is necessary for lysine-63-linked polyubiquitination of RIP1, phosphorylation of IκB kinase and IκBα, and IκBα degradation, leading to NF-κB activation. These responses were mediated by intracellular S1P independently of its cell surface G-protein-coupled rece! ptors. S1P specifically binds to TRAF2 at the amino-terminal RING domain and stimulates its E3 ligase activity. S1P, but not dihydro-S1P, markedly increased recombinant TRAF2-catalysed lysine-63-linked, but not lysine-48-linked, polyubiquitination of RIP1 in vitro in the presence of the ubiquitin conjugating enzymes (E2) UbcH13 or UbcH5a. Our data show that TRAF2 is a novel intracellular target of S1P, and that S1P is the missing cofactor for TRAF2 E3 ubiquitin ligase activity, indicating a new paradigm for the regulation of lysine-63-linked polyubiquitination. These results also highlight the key role of SphK1 and its product S1P in TNF-α signalling and the canonical NF-κB activation pathway important in inflammatory, antiapoptotic and immune processes. View full text Subject terms: * Biochemistry * Immunology Figures at a glance * Figure 1: SphK1 and intracellular S1P are necessary for NF-κB activation by TNF-α independently of S1P receptors. , HEK 293 cells transfected with siControl or siSphK1 were treated with TNF-α and analysed by immunoblotting. , A7 cells were pre-treated with SK1-I (10 μM) and stimulated with TNF-α or S1P (100 nM). , Sphk1+/+ and Sphk1−/− MEFs were stimulated with TNF-α. , Sphk1+/+ or Sphk1−/− MEFs transfected with V5-SphK1 or catalytically inactive SphK1(G82D) (CI-SphK1) were treated with TNF-α, stained with Hoechst (blue), and p65 (red) and V5 (green) antibodies, and visualized by confocal microscopy. Scale bar, 20 μm. Percentages of cells with p65 positive nuclei are shown. *P < 0.01. , NF-κB reporter activity was determined in A7 cells stimulated with TNF-α, 100 nM S1P or dihydro-S1P (DHS1P). *P < 0.01. , A7 cells were stimulated with TNF-α (1 ng ml−1) or S1P (100 nM or 10 µM) for 10 min. , HeLa cells were stimulated with TNF-α (1 ng ml−1), 10 μM S1P or dihydro-S1P. , Sphingolipids were analysed by LC-ESI-MS/MS. *P < 0.01. , NF-κ! B reporter activity was determined in HeLa cells stimulated with TNF-α (1 ng ml−1), S1P (10 µM), or both. *P < 0.01 compared to 'none'. n = 3. Data are representative of two or more independent experiments and are means and s.d. of triplicates (, , , ). * Figure 2: SphK1 is required for TNF-α-induced Lys-63-linked polyubiquitination of RIP1. , A7 cells transfected with siControl or siSphK1 were stimulated with TNF-α (10 ng ml−1). Proteins were immunoblotted (IB) with anti-RIP1 or anti-p65 antibodies. , Lysates were immunoprecipitated (IP) with anti-RIP1 antibody and analysed with anti-ubiquitin antibody. , Lysates from cells transfected with haemagglutinin (HA)–Ub and stimulated with TNF-α were immunoprecipitated with anti-RIP1 antibody and analysed with HA antibody. , Lysates were immunoprecipitated with anti-RIP1 antibody and proteins analysed with Lys-63-specific polyubiquitin antibody. , HEK 293 cells transfected with siControl or siSphK1 were transfected with Flag–TRAF2 and stimulated with TNF-α. Proteins were pulled down with anti-Flag beads and analysed with anti-TRAF2 antibody. * Figure 3: S1P is required for TRAF2-mediated Lys-63-linked polyubiquitination of RIP1 in vitro. , In vitro ubiquitination of purified RIP1 was carried out with ATP, E1, Ubc13–Uev1a, ubiquitin and TRAF2 with the indicated lipids (100 nM) and examined with anti-RIP1 antibody. , , Ubiquitination reactions were carried out with purified wild-type (WT) TRAF2 or TRAF2(ΔRING) in the presence of UbcH13–Uev1a () or UbcH5a–Uev1a () as E2s and ubiquitin proteins (wild type, Lys 63 only, or Lys 48 only), without or with 100 nM S1P. RIP1 ubiquitination was determined with anti-RIP1 antibody and TRAF2 input with anti-TRAF2 antibody. * Figure 4: Specific binding of S1P to TRAF2. , Lysates from HEK 293 cells transfected with Flag–TRAF2 were incubated with control (no lipid), S1P, LPA, or sphingosine affinity matrices. , Lysates from naive cells were pre-treated with 10 µM S1P, followed by pull down with control (no lipid), S1P, or sphingosine affinity matrices and bound proteins analysed by immunoblotting. , Lysates from vector or Flag–TRAF2-transfected cells were incubated with anti-Flag agarose beads. Beads were washed and incubated with [32P]S1P (0.1 nM) in the absence or presence of 1 µM unlabelled S1P, dihydro-S1P, sphingosine or LPA, and [32P]S1P bound to TRAF2 was eluted with Flag peptide and radioactivity determined. The insert shows a blot of eluted TRAF2. c.p.m., counts per minute. , Naive cells were stimulated with TNF-α. Lysates were immunoprecipitated with anti-TRAF2 antibody or control IgG and bound sphingolipids determined by LC-ESI-MS/MS. Of all of the sphingolipids present in these cells (Supplementary Table 1), only S1P! was detected in the immunocomplexes. , , Cells transfected with vector, Flag–TRAF2, or Flag–TRAF2(ΔRING) were stimulated with TNF-α. Lysates were immunoprecipitated with anti-Flag antibody. , Bound S1P determined by LC-ESI-MS/MS. , Immunoblot with anti-Flag antibody. , Docking of S1P into the pocket of the RING domain of TRAF2. Surface contour of the binding site with S1P was coloured by electrostatic potential. –, Data are means and s.d. of triplicates. Author information * Author information * Supplementary information * Comments Primary authors * These authors contributed equally to this work. * Sergio E. Alvarez & * Kuzhuvelil B. Harikumar Affiliations * Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, 1101 E. Marshall Street, Richmond, Virginia 23298, USA * Sergio E. Alvarez, * Kuzhuvelil B. Harikumar, * Nitai C. Hait, * Jeremy Allegood, * Graham M. Strub, * Eugene Y. Kim, * Michael Maceyka, * Tomasz Kordula, * Sheldon Milstien & * Sarah Spiegel * State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China * Hualiang Jiang & * Cheng Luo * Present address: IMIBIO-SL CONICET, Ejército de los Andes 950, San Luis 5700, Argentina. * Sergio E. Alvarez Contributions S.E.A. and K.B.H. planned and performed most experiments, with assistance from N.C.H., G.M.S., E.Y.K., J.A. and M.M.; C.L. and H.J. performed molecular docking; T.K. contributed to the planning of the experiments; S.M. and S.S. conceived the study, contributed to planning of the experiments and wrote the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Sarah Spiegel (sspiegel@vcu.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (4.8M) This file contains Supplementary Table 1 and Supplementary Tables 1-10 w Additional data
• Hormonal control of the shoot stem-cell niche
  - Nature (London) 465(7301):1089 (2010)
  Nature | Letter Hormonal control of the shoot stem-cell niche * Zhong Zhao1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Stig U. Andersen2, 6 Search for this author in: * NPG journals * PubMed * Google Scholar * Karin Ljung3 Search for this author in: * NPG journals * PubMed * Google Scholar * Karel Dolezal3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Andrej Miotk1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Sebastian J. Schultheiss2, 5 Search for this author in: * NPG journals * PubMed * Google Scholar * Jan U. Lohmann1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1089–1092Date published:(24 June 2010)DOI:doi:10.1038/nature09126Received17 March 2010Accepted20 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The classic phytohormones cytokinin and auxin play essential roles in the maintenance of stem-cell systems embedded in shoot and root meristems, and exhibit complex functional interactions1, 2, 3, 4. Here we show that the activity of both hormones directly converges on the promoters of two A-type ARABIDOPSIS RESPONSE REGULATOR (ARR) genes, ARR7 and ARR15, which are negative regulators of cytokinin signalling5 and have important meristematic functions3. Whereas ARR7 and ARR15 expression in the shoot apical meristem (SAM) is induced by cytokinin, auxin has a negative effect, which is, at least in part, mediated by the AUXIN RESPONSE FACTOR5/MONOPTEROS (MP) transcription factor6. Our results provide a mechanistic framework for hormonal control of the apical stem-cell niche and demonstrate how root and shoot stem-cell systems differ in their response to phytohormones. View full text Subject terms: * Stem cells * Plant sciences * Developmental biology * Genetics * Genomics Figures at a glance * Figure 1: ARR15 and ARR7 have important roles for SAM regulation. –, AlcA::GUS control plants (GUS). –, AlcA::AM7/15 plants (AM7/15). Silencing of ARR7 and ARR15 caused disturbed phyllotaxis (, ), enlarged shoot apical meristems (P < 0.0001; AM7/15: mean = 80 µm, n = 16; GUS: mean = 60 µm, n = 10) (, , ) and strong reduction of CLV3 expression (, ), whereas WUS expression was mildly increased (, ). , Meristem expansion after ARR7 and ARR15 silencing in clv3 (P < 0.05. AM7/15-clv3: mean = 1126 µm, n = 20; clv3: mean = 968 µm, n = 20). , ARR15 and () ARR7 expression in wild type. Scale bars, 25 μm, except in and (100 μm). * Figure 2: Interaction of ARR7 and ARR15 with auxin signalling. , Modulation of auxin and cytokinin responses by ARR7 and ARR15 visualized by PCA. The two components shown represent 22% and 17% of the total variance, respectively. C, cytokinin; A, auxin; C+A, co-treatment. , ARR7 and ARR15 expression in response to auxin (50 μM NAA) and NPA (100 μM) and loss of auxin synthesis in yuc mutants. –, Changes in ARR15 expression patterns in auxin mutants. Error bars, s.d.; scale bars, 50 μm. * Figure 3: Regulatory and functional interaction of ARR15 and ARF5/MONOPTEROS. , Quantitative real-time PCR of ARR15 and ARR7 mRNA in arf mutants. , Enrichment of ARR15 promoter fragments after ChIP. , EMSA using MP. Asterisk, specific interaction. , MP/ARF5 RNA expression. , MP-GFP distribution. , ARR15 expression in mp. , ARR15::GUS, with five () or a single () mutated AuxRE-like motif. Black boxes, AuxRE-like motifs (TGTC); red boxes, mutated motifs (TGGC). , Quantification of MP misexpression phenotypes. CLV3::GUS: n = 50; CLV3::MP: n = 30; WUS::MP: n = 40. Quantification () of phenotypes () after silencing ARR7 and ARR15 in mp; mp: n = 77; mp + ethanol (EtOH): n = 81; mp-AM7/15: n = 52; mp-AM7/15 + EtOH: n = 58. Scale bars: –, 50 μm; , 200 μm. Error bars, s.d. * Figure 4: Cross talk between auxin and cytokinin affects the stem-cell niche. Expression of ARR15 (, ), ARR7 (, ), CLV3 (, ) and WUS (, ) in mock- (–) and NPA- (–) treated plants. –, Expression of CLV3 in AM7/15 plants. , Mock treatment. , ARR silencing. , NPA treatment. , ARR silencing and NPA treatment. , TCS::GUS in wild type. , Wild-type and mutated ARR15::GUS () after cytokinin treatment. Black box, 35S minimal promoter; green boxes, B-type ARR-binding sites (AGATT); red box, mutated binding site (ACATT). , Hypothetical interactions of auxin and cytokinin with the WUS/CLV3 network. Scale bars, 50 μm. Author information * Author information * Supplementary information * Comments Affiliations * Department of Stem Cell Biology, University of Heidelberg, D-69120 Heidelberg, Germany * Zhong Zhao, * Andrej Miotk & * Jan U. Lohmann * Max Planck Institute for Developmental Biology, D-72076 Tübingen, Germany * Zhong Zhao, * Stig U. Andersen, * Andrej Miotk, * Sebastian J. Schultheiss & * Jan U. Lohmann * Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, S-901 83 Umeå, Sweden * Karin Ljung & * Karel Dolezal * Laboratory of Growth Regulators, Palacký University and Institute of Experimental Botany Academy of Sciences of the Czech Republic, 783 71 Olomouc-Holice, Czech Republic * Karel Dolezal * Machine Learning in Biology, Friedrich Miescher Laboratory of the Max Planck Society, D-72076 Tübingen, Germany * Sebastian J. Schultheiss * Present address: Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10, 8000 Aarhus C, Denmark. * Stig U. Andersen Contributions S.U.A. established the AM7/15 line and performed the microarray experiment, K.L. and K.D. quantified cytokinin content, A.M. performed ChIP experiments, S.J.S performed bioinformatic analyses and Z.Z. performed all other experiments. Z.Z and J.U.L. designed experiments and wrote the paper. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Jan U. Lohmann (jlohmann@meristemania.org) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (4.1M) This file contains Supplementary Figures 1-16 with legends, Supplementary Table 1 and a Reference. Additional data
• Activation of autophagy during cell death requires the engulfment receptor Draper
  - Nature (London) 465(7301):1093 (2010)
  Nature | Letter Activation of autophagy during cell death requires the engulfment receptor Draper * Christina K. McPhee1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Mary A. Logan3 Search for this author in: * NPG journals * PubMed * Google Scholar * Marc R. Freeman3, 4 Search for this author in: * NPG journals * PubMed * Google Scholar * Eric H. Baehrecke1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1093–1096Date published:(24 June 2010)DOI:doi:10.1038/nature09127Received06 January 2010Accepted23 April 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Autophagy degrades cytoplasmic components that are required for cell survival in response to starvation1. Autophagy has also been associated with cell death, but it is unclear how this is distinguished from autophagy during cell survival. Drosophila salivary glands undergo programmed cell death that requires autophagy genes2, and engulfment of salivary gland cells by phagocytes does not appear to occur3. Here we show that Draper (Drpr), the Drosophilamelanogaster orthologue of the Caenorhabditis elegans engulfment receptor CED-1, is required for autophagy during cell death. Null mutations in, and salivary gland-specific knockdown of, drpr inhibit salivary gland degradation. Knockdown of drpr prevents the induction of autophagy in dying salivary glands, and expression of the Atg1 autophagy regulator in drpr mutants suppresses the failure in degradation of salivary glands. Surprisingly, drpr is required in the same dying salivary gland cells in which it regulates autophagy ind! uction, but drpr knockdown does not prevent starvation-induced autophagy in the fat body, which is associated with survival. In addition, components of the conserved engulfment pathway are required for clearance of dying salivary glands. To our knowledge, this is the first example of an engulfment factor that is required for self-clearance of cells. Further, Drpr is the first factor that distinguishes autophagy that is associated with cell death from autophagy associated with cell survival. View full text Subject terms: * Cell biology * Genetics * Genomics * Developmental biology * Molecular biology Figures at a glance * Figure 1: Draper is required for salivary gland cell degradation. , Protein extracts from drpr null (w; drprΔ5/drprΔ5) pupae at puparium formation (0 h) and wild-type (Canton-S) salivary glands 6 h, 12 h and 14 h after puparium formation, analysed by western blotting with anti-Drpr antibody. , Samples from control animals (+/w; +/drprΔ5), n = 12, and drpr null mutants (w; drprΔ5/drprΔ5), n = 47, analysed by histology for the presence of salivary gland material (red circles) 24 h after puparium formation. , Quantification of data from and . , Samples from control animals (+/w; +/UAS-drprIR), n = 11, and those with salivary gland-specific knockdown of drpr (fkh–Gal4/w; UAS-drprIR/+), n = 19, analysed by histology for the presence of salivary gland material (red circles) 24 h after puparium formation. , Control animals (+/w; +/UAS-drpr-IIR), n = 9, and those with salivary gland-specific knockdown of drpr-I (fkh–Gal4/w; UAS-drpr-IIR/+), n = 20, analysed by histology for the presence of salivary gland material (red circles)! 24 h after puparium formation. , Quantification of data from . , Samples from drpr null animals (+/w; +/UAS-Drpr-I; drprΔ5/drprΔ5), n = 9, and those with salivary gland-specific expression of Drpr-I (fkh–Gal4/w; UAS-Drpr-I/+; drprΔ5/drprΔ5), n = 20, analysed by histology for the presence of salivary gland material (red circles) 24 h after puparium formation. , Quantification of data from . * Figure 2: Draper functions downstream or in parallel to caspases during salivary gland cell death. , Samples from animals with salivary gland-specific expression of p35 (fkh–Gal4/+; UAS-p35/+), n = 18 (left), drpr null animals (+/w; +/UAS-p35; drprΔ5/drprΔ5), n = 10 (middle), and drpr null animals with salivary gland-specific expression of p35 (fkh–Gal4/w; UAS-p35/+; drprΔ5/drprΔ5), n = 16 (right), analysed by histology for the presence of salivary gland material 24 h after puparium formation. Red circles, cell fragments; yellow circle, gland fragments. , Quantification of data from . , Salivary glands dissected from animals expressing drprIR specifically in GFP-marked clone cells (heat shock (hs)flp/w; UAS-drprIR/+; act Gal4, UAS-GFP/+) 6 h and 14 h after puparium formation. Stained with GFP antibody (green), to label cells expressing drpr IR, and Lamin antibody (red). * Figure 3: Draper is required for the induction of autophagy in dying salivary gland cells. , Samples from animals with salivary gland-specific knockdown of Atg12 (fkh–Gal4/w; UAS-Atg12IR/+), n = 21, and those with salivary gland-specific knockdown of both Atg12 and drpr-I (fkh–Gal4/w; UAS-Atg12IR/+; UAS-drpr-IIR/+), n = 19, analysed by histology for the presence of salivary gland material (red circles) 24 h after puparium formation. , Quantification of data from . , GFP–LC3 was expressed in salivary glands of control animals (+/w; UAS-GFP–LC3/+; fkh–Gal4/+) and those with salivary gland-specific knockdown of drpr (w; UAS-drprIR/UAS-GFP–LC3; fkh–Gal4/+). Salivary glands were dissected 6 h and 14 h after puparium formation, imaged for GFP–LC3, and LC3 puncta were quantified using Zeiss Automeasure software. , Quantification of data from . Error bars represent s.e.m.; n ≥ 10; p < 0.0000001. , LAMP1–GFP was expressed in control animals (tub-LAMP–GFP/w; +/fkh–Gal4) and those with salivary gland-specific knockdown of drpr (tub-LAMP�! ��GFP/w; UAS-drprIR/+; fkh–Gal4/+). Salivary glands were dissected 14 h after puparium formation, imaged for LAMP–GFP, and LAMP puncta were quantified using Zeiss Automeasure software. , Quantification of data from . Error bars represent s.e.m.; n ≥ 10; p < 0.05. , Samples from drpr mutant animals (+/w; +/UAS-Atg16A; drprΔ5/drprΔ5), n = 10, and those with salivary gland-specific expression of Atg16A (fkh–Gal4/w; UAS-Atg16A/+; drprΔ5/drprΔ5), n = 16, analysed by histology for the presence of salivary gland material (red circles) 24 h after puparium formation. , Quantification of data from . * Figure 4: Drpr is cell-autonomously required for autophagy in dying salivary glands, but not in response to starvation in the fat body. , Protein extracts from drpr null (w; drprΔ5/drprΔ5) pupae at puparium formation (0 h) and from the fat bodies of wild-type (Canton-S) third-instar larvae were analysed by western blotting with anti-Drpr antibody. Third-instar larvae were either fed or starved for 4 h. , We either fed Wild-type (Canton-S) third-instar larvae or starved them for 4 h, and dissected fat bodies, stained them with anti-Drpr antibody, and imaged them for Drpr (green). We stained nuclei with 4′,6-diamidino-2-phenylindole (DAPI) (blue). , We starved third-instar larvae expressing GFP–Atg8a in all cells, and drprIR specifically in dsRed-marked clone cells (hsflp/w; UAS-drprIR/+; hsGFPAtg8a, act Gal4, UAS-dsRed/+), for 4 h. We dissected larval fat bodies and imaged them for GFP–Atg8a (green) and dsRed (red). , Salivary glands of animals expressing GFP–Atg8a in all cells, and drprIR specifically in dsRed-marked clone cells (hsflp/w; UAS-drprIR/+; hsGFPAtg8a, act Gal4, UAS-dsRed/+), dissected 14 h after puparium formation. Imaged for GFP–Atg8a (green) and dsRed (red). We stained nuclei with Hoechst (blue). Author information * Author information * Supplementary information * Comments Affiliations * Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA * Christina K. McPhee & * Eric H. Baehrecke * Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA * Christina K. McPhee * Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA * Mary A. Logan & * Marc R. Freeman * Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA * Marc R. Freeman Contributions All the experiments were performed by C.K.M., and were designed by C.K.M and E.H.B. M.L. and M.R.F. provided critical DNA constructs and transgenic flies. All authors wrote and discussed the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Eric H. Baehrecke (Eric.Baehrecke@umassmed.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (2.3M) This file contains Supplementary Table 1 and Supplementary Figures 1-4 with legends. Additional data
• Small regulatory RNAs inhibit RNA polymerase II during the elongation phase of transcription
  Guang S Bochner AF Burkhart KB Burton N Pavelec DM Kennedy S - Nature (London) 465(7301):1097 (2010)
  Nature | Letter Small regulatory RNAs inhibit RNA polymerase II during the elongation phase of transcription * Shouhong Guang1 Search for this author in: * NPG journals * PubMed * Google Scholar * Aaron F. Bochner1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kirk B. Burkhart1 Search for this author in: * NPG journals * PubMed * Google Scholar * Nick Burton1 Search for this author in: * NPG journals * PubMed * Google Scholar * Derek M. Pavelec2 Search for this author in: * NPG journals * PubMed * Google Scholar * Scott Kennedy1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:465,Pages:1097–1101Date published:(24 June 2010)DOI:doi:10.1038/nature09095Received04 December 2009Accepted16 April 2010Published online13 June 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Eukaryotic cells express a wide variety of endogenous small regulatory RNAs that regulate heterochromatin formation, developmental timing, defence against parasitic nucleic acids and genome rearrangement. Many small regulatory RNAs are thought to function in nuclei1, 2. For instance, in plants and fungi, short interfering RNA (siRNAs) associate with nascent transcripts and direct chromatin and/or DNA modifications1, 2. To understand further the biological roles of small regulatory RNAs, we conducted a genetic screen to identify factors required for RNA interference (RNAi) in Caenorhabditis elegans nuclei3. Here we show that the gene nuclear RNAi defective-2 (nrde-2) encodes an evolutionarily conserved protein that is required for siRNA-mediated silencing in nuclei. NRDE-2 associates with the Argonaute protein NRDE-3 within nuclei and is recruited by NRDE-3/siRNA complexes to nascent transcripts that have been targeted by RNAi. We find that nuclear-localized siRNAs direct an ! NRDE-2-dependent silencing of pre-messenger RNAs (pre-mRNAs) 3′ to sites of RNAi, an NRDE-2-dependent accumulation of RNA polymerase (RNAP) II at genomic loci targeted by RNAi, and NRDE-2-dependent decreases in RNAP II occupancy and RNAP II transcriptional activity 3′ to sites of RNAi. These results define NRDE-2 as a component of the nuclear RNAi machinery and demonstrate that metazoan siRNAs can silence nuclear-localized RNAs co-transcriptionally. In addition, these results establish a novel mode of RNAP II regulation: siRNA-directed recruitment of NRDE factors that inhibit RNAP II during the elongation phase of transcription. View full text Subject terms: * Genetics * Genomics * Molecular biology Figures at a glance * Figure 1: The gene nrde-2 encodes a conserved and nuclear-localized protein that is required for nuclear RNAi. , Light microscopy of embryos of about six cells with or without GFP RNAi subjected to in situ hybridization detecting pes-10::gfp RNA. , nrde-2(−) animals fail to silence the lin-15b/lin15a and lir-1/lin-26 nuclear-localized RNAs (n = 4; bars, s.d.). An eri-1(−) genetic background was used for this analysis. , Predicted domain structure of NRDE-2. Yellow, serine/arginine domain; green, DUF1740; red, potential HAT-like repeats. , Fluorescent microscopy of an embryo of about 200 cells expressing a rescuing GFP::NRDE-2 fusion protein. * Figure 2: NRDE-2 is recruited by NRDE-3/siRNA complexes to pre-mRNAs that have been targeted by RNAi. , Animals were exposed to unc-15 dsRNA and scored for uncoordinated phenotypes (Unc) (n = 3; bars, s.d.). rde-1(ne219) animals are defective for RNAi12. , Top panels: fluorescent microscopy of a seam cell expressing GFP::NRDE-3. Arrows indicate nuclei. eri-1(mg366) animals fail to express endo-siRNAs and consequently NRDE-3 is mislocalized to the cytoplasm3, 13, 14. Bottom panels: FLAG::NRDE-3 co-precipitating RNAs radiolabelled with 32P and analysed by polyacrylamide gel electrophoresis. , NRDE-2 co-precipitates with nuclear-localized NRDE-3 (Methods) (n = 3). , rtPCR quantification of NRDE-2/3 co-precipitating pre-mRNA. Throughout this paper, pre-mRNA levels are quantified with exon–intron or intron–intron primer pairs. Data are expressed as ratios of co-precipitating pre-mRNA with or without lin-15b RNAi (n = 4 for NRDE-2 IP, n = 2 for NRDE-3 IP; bars, s.e.m.). Δ, fold change. * Figure 3: C. elegans siRNAs direct an NRDE-2/3-dependent co-transcriptional gene silencing program. , Animals were exposed to one part lir-1 dsRNA expressing bacteria and six parts vector control, nrde-2/3 or rpb-7 dsRNA expressing bacteria. The percentage of animals that failed to exhibit lir-1 RNAi phenotypes is indicated. , ChIP with H3K9me3 antibody (Upstate, 07-523). Data are expressed as the ratio of H3K9me3 co-precipitating DNA with or without lin-15b RNAi (n = 2; bars = s.d.). , Total RNA was isolated and lin-15b pre-mRNA was quantified with rtPCR. Data are expressed as ratios with or without lin-15b RNAi. The genetic background was eri-1(−) (bars = s.d.). , FLAG::NRDE-2/3 co-precipitating dpy-28 pre-mRNA. Data are expressed as ratios with or without dpy-28 RNAi (n = 4; bars, s.d.). , ChIP of AMA-1/Rpb1 with α-AMA-1 antibody (Covance, 8WG16). Data are expressed as ratios of AMA-1 co-precipitating DNA with or without lin-15b RNAi (n = 3; bars, s.d.). The genetic background was eri-1(−). * Figure 4: siRNAs direct an NRDE-2/3-dependent inhibition of RNAP II during the elongation phase of transcription. , AMA-1 co-precipitating pre-mRNA. Data are expressed as ratio with or without lin-15b RNAi (n = 3; bars, s.d.). , A crude preparation of nuclei was subjected to nuclear run-on analysis (see Methods). Transcription detected from wild-type (WT) nuclei was defined as one (n = 3; bars, s.d.). , , RNAi inhibits RNAP II activity 3′ to sites of RNAi. An eri-1(−) genetic background was used for these analyses. Nuclei isolated from animals treated with lin-15b () or lir-1 () RNAi were subjected to run-on analysis. Data are expressed as ratio of transcription detected in nrde-3(+)/nrde-3(−) nuclei () or nrde-2(+)/nrde-2(−) nuclei () (n = 5 for , n = 3 for ; bars, s.e.m.). Author information * Author information * Supplementary information * Comments Affiliations * Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706, USA * Shouhong Guang, * Aaron F. Bochner, * Kirk B. Burkhart, * Nick Burton & * Scott Kennedy * Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, USA * Derek M. Pavelec & * Scott Kennedy Contributions S.G. performed genetic screening, generated constructs and contributed to Figs 1a, 2b, c, 3b, e, 4a and Supplementary Figs 2, 6, 7 and 9–12. A.F.B. mapped nrde-2, generated transgenic lines and contributed to Fig. 1c, d and Supplementary Figs 3 and 5. K.B.B. contributed to Fig. 1b and Supplementary Figs 3 and 8. N.B. contributed to Fig. 3a and Supplementary Fig. 8. D.M.P. contributed to Fig. 2a. S.K. wrote the paper and contributed to Figs 2d, 3c, d, 4b–d and Supplementary Figs 1, 2, 13 and 14. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Scott Kennedy (sgkennedy@wisc.edu) Supplementary information * Author information * Supplementary information * Comments PDF files * Supplementary Information (8.7M) This file contains Supplementary Figures S1-S14 with legends and References. Additional data
• A science-fiction fantasy
  - Nature (London) 465(7301):1110 (2010)
  Nature | Futures A science-fiction fantasy * Paul Di Filippo1 Search for this author in: * NPG journals * PubMed * Google ScholarJournal name:NatureVolume:465,Page:1110Date published:(24 June 2010)DOI:doi:10.1038/4651110aPublished online23 June 2010 The magic of the written word. Article tools * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Making a Case for Morrisian Fiction: Why Heroic Epic Fantasy Is So Rare (University of Syrtis Major Press, 2011) Some academics have nothing better to do with their time than fruitlessly to argue 'What if?' Of course, as any literate person knows, this mode of thought experiment is perfectly suited to science fiction, and in fact is one of the main tools of that all-encompassing literature that so dominates today's bookstores, cinemas, classrooms and canonical journals. But professors seeking seriously to examine matters of literary history should restrict themselves to more scholarly tools and approaches, and avoid speculative avenues. We scholars cannot, after all, compete with the likes of such living masters as Bester, Sterling, Atwood and Weinbaum. For the first half of his book, however, Professor McCafferty does hew to the straight and narrow in impeccable fashion. This portion of his study forms a useful primer on the roots and brief efflorescence of a minor genre of fiction that nowadays is as dead as the epistolary novel. Professor McCafferty traces the birth of what he terms "Heroic Epic Fantasy" or "Morrisian Fiction" back to the late Victorian period, specifically the "prose romances" of William Morris. He follows its haphazard development in the works of such forgotten authors as George MacDonald, William Hope Hodgson and Lord Dunsany. McCafferty's analysis of the themes, tropes and styles of this kind of fiction are cogent and exhibit a keen intellect. He makes a particularly telling point when he focuses on the fact that the majority of these fictions took place in invented worlds, "secondary creations" with no apparent ties to our own continuum. It was this tragic flaw, we learn, that would ultimately doom the genre. JACEY In the twentieth century, during the era of the pulp magazines, there were minor eruptions of such fiction, most notably in the magazine Weird Tales. For instance, in 1932, the famous writer Robert E. Howard published his one and only story concerning a barbarian named Conan: 'The Phoenix on the Sword'. But this abortive foray into what McCafferty labels "blades and black magic" fiction was not to be repeated. Howard — who died just last year at the lamentably early age of 105 on his Texas ranch — was tapped to pen the exploits of the pulp science hero Doc Savage, and turned all his energies in that direction. And Weird Tales, under the inexpert editorship of H. P. Lovecraft, went bankrupt the next year, sending Lovecraft himself into a non-literary career. (Yes, that beloved national institution, Lovecraft's Yankee Ice Cream Company, was founded by the same fellow.) The subsequent several decades saw sporadic and limited incursions of such fiction, cropping up like occasional cuckoo eggs in the pages of various science-fiction pulps: works by de Camp and Pratt, Hubbard, Leiber and Brackett. But without a committed editor or dedicated venue to serve as a centre for their efforts, Morrisian writers did not prosper. Then, of course, the Second World War intervened. The dire events of that global calamity — can anyone forget such atrocities as the Nazi fire-bombing of Oxford, which wiped out so many promising scholars, C. Lewis, J. Tolkien and a visiting Jos. Campbell among them? — concentrated the minds of both writers and readers on hard reality. Tales set in "secondary creations" held no allure: they seemed to smell of shirking one's duty, of a wilful, unpatriotic refusal to face tough facts and deal with them. 'Escapism' became a taunt and slur. Technology and science fiction, however, went hand in hand, the literature serving as a playful and entertaining, utopian laboratory to explicate and inspire the modern, scientific path of progress — admittedly, with no little allegiance to the military-industrial complex. With the end of war, and the advent of the Western–Soviet détente, conditions became even less hospitable for the Morrisian writers. During the post-conflagration Renaissance, all the world's attention was concentrated on such shared human enterprises as space exploration, undersea mining, macro-engineering and the construction of nuclear fusion power plants. Science education flourished at all levels, with competitive Knowledge Bowls — both domestic and between friendly rival countries — coming to overwhelm professional sports. International polls revealed that the majority of citizens experienced utmost satisfaction and zest with their daily lives, their careers and civic challenges. The Age of the New Frontiers had dawned, and science fiction was the perfect embodiment of it, eventually coming to dominate the literary world as it still does to this day. It is at this point in his narrative that Professor McCafferty goes off the rails of history and into a speculative terra incognita. He spins out an improbable scenario by which Morrisian fantasy — an unlikely and repugnant blend of megalomaniacal delusions; crude bipolar divisions of the world into good and evil; infantile narcissistic Messianic beliefs; contravention of the laws of physics and cosmology; retrogressive privileging of monarchies and feudalism; deliberate ignorance and suppression of the harsh crudity of pre-technological living conditions; and a reliance on clichéd supernatural entities — could have become a best-selling mode of fiction. So morbidly and upsettingly vivid is McCafferty's portrayal of this ridiculous scenario — a world in which readers stick their heads, ostrich-like, into overblown and endlessly protracted multivolume tales of schools for wizards, omnipotent rings and battles between vampires and werewolves, rather than creatively face! the real issues of the day and solve them — that one almost suspects the good professor has gained illicit access to the Large Hadron Collider's Multiversal Viewing Scanner, and has actually seen a warped timeline where such a sordid state of affairs is the hideous norm. Author information * Author information * Comments Affiliations * Paul Di Filippo's new novel, Roadside Bodhisattva, will be available in spring 2010. He continues to review for various venues. Additional data