Hot off the presses! Apr 30 Nature

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Latest Articles Include:

• Time to act
  - Nature 458(7242):1077-1078 (2009)
  Without a solid commitment from the world's leaders, innovative ways to combat climate change are likely to come to nothing.
• Authorship policies
  - Nature 458(7242):1078 (2009)
  We are clarifying the duties of lead authors and making author-contribution statements mandatory.
• Fluid dynamics: Dynamics of a dance
  - Nature 458(7242):1080 (2009)
  
• Chemistry: Fuel from thin air
  - Nature 458(7242):1080 (2009)
  
• Biochemistry: DNA base maker
  - Nature 458(7242):1080 (2009)
  
• Stem-cell biology: New stem-cell formula
  - Nature 458(7242):1080 (2009)
  
• Photonics: E-ink goes colour
  - Nature 458(7242):1080 (2009)
  
• Chemical biology: Getting the glow
  - Nature 458(7242):1081 (2009)
  
• Materials: Improving on nature
  - Nature 458(7242):1081 (2009)
  
• Genomics: X-linked mysteries
  - Nature 458(7242):1081 (2009)
  
• Climate: Ground truths
  - Nature 458(7242):1081 (2009)
  
• Journal club
  - Nature 458(7242):1081 (2009)
  
• Swine flu goes global
  - Nature 458(7242):1082-1083 (2009)
  
• California in clean-fuel drive
  - Nature 458(7242):1083 (2009)
  
• Japan goes for the sun
  - Nature 458(7242):1084-1085 (2009)
  
• Basic researchers protest UK budget
  - Nature 458(7242):1084-1085 (2009)
  
• Obama says more money
  - Nature 458(7242):1085 (2009)
  
• Funding cut for US nuclear waste dump
  - Nature 458(7242):1086-1087 (2009)
  
• Brain imaging skewed
  - Nature 458(7242):1087 (2009)
  
• Fake Facebook pages spin web of deceit
  - Nature 458(7242):1089 (2009)
  
• Close shave for Austrian science budget
  - Nature 458(7242):1090 (2009)
  
• Nobel laureate celebrates her centenary
  - Nature 458(7242):1090 (2009)
  
• Japan cuts red tape holding up stem-cell work
  - Nature 458(7242):1090 (2009)
  
• New UK coal must be partly 'clean'
  - Nature 458(7242):1090 (2009)
  
• Texas agencies sue over national disease lab
  - Nature 458(7242):1090 (2009)
  
• Researchers rally to support animal studies
  - Nature 458(7242):1090 (2009)
  
• Correction
  - Nature 458(7242):1090 (2009)
  
• Climate crunch: A burden beyond bearing
  - Nature 458(7242):1091-1094 (2009)
  
• Sucking it up
  - Nature 458(7242):1094-1097 (2009)
  
• Great white hope
  - Nature 458(7242):1097-1100 (2009)
  
• Stem-cell treatments for spinal-cord injury may be worth the risk
  - Nature 458(7242):1101 (2009)
  In his Correspondence 'Caution urged in trial of stem cells to treat spinal-cord injury' (Nature 458, 29; 2009), Yves Barde questions the wisdom of testing oligodendrocyte precursors derived from embryonic stem (ES) cells in patients, despite the promise that such cells hold for repairing these injuries in rodents.
• A lesson or two from a regional economic argument
  - Nature 458(7242):1101 (2009)
  In his Commentary on how to survive the recession, 'Work for the greater good' (Nature 457, 959–960; 2009), Eric Rauchway discusses the role that science and technology had in improving living conditions in the Tennessee Valley in the 1930s.
• Romanian funding cuts call for more stringent criteria
  - Nature 458(7242):1101 (2009)
  The Lisbon summit in 2000 persuaded many governments that it was in the interest of Europe's long-term economic growth to restore priorities in science and research expenditure; this would also help found the next generation of researchers, innovators and technicians. But these laudable aims are being undermined by the current economic crisis, which disproportionately affects the Eastern European economies.
• Overshoot, adapt and recover
  - Nature 458(7242):1102-1103 (2009)
  We will probably overshoot our current climate targets, so policies of adaptation and recovery need much more attention, say Martin Parry, Jason Lowe and Clair Hanson.
• The worst-case scenario
  - Nature 458(7242):1104-1105 (2009)
  Stephen Schneider explores what a world with 1,000 parts per million of CO2 in its atmosphere might look like.
• Could climate change capitalism?
  - Nature 458(7242):1107-1108 (2009)
  Economist Nicholas Stern's latest book is a rare and masterly synthesis of climate-change science and economics. His 'global deal' could change capitalism for the better, says Robert Costanza.
• New in Paperback
  - Nature 458(7242):1107-1116 (2009)
  
• Why inequality is fatal
  - Nature 458(7242):1109-1110 (2009)
  
• Fiction beyond the grave
  - Nature 458(7242):1110 (2009)
  
• Genes, games and the sexes
  - Nature 458(7242):1111-1112 (2009)
  
• Managing nature as Earth warms
  - Nature 458(7242):1112-1113 (2009)
  
• Tales of top models
  - Nature 458(7242):1113-1114 (2009)
  
• A billionaire's vision for India
  - Nature 458(7242):1114-1115 (2009)
  
• An eye on the Universe
  - Nature 458(7242):1116 (2009)
  
• Climate change: Too much of a bad thing
  - Nature 458(7242):1117-1118 (2009)
  There are various — and confusing — targets to limit global warming due to emissions of greenhouse gases. Estimates based on the total slug of carbon emitted are possibly the most robust, and are worrisome.
• Cell biology: Another way to get rid of fat
  - Nature 458(7242):1118-1119 (2009)
  When starved, cells resort to breaking down their assets — proteins, lipids and even whole organelles. An investigation of lipid metabolism indicates that one process — autophagy — targets all three cellular components.
• X-ray astronomy: When appearances are deceptive
  - Nature 458(7242):1119-1121 (2009)
  The sharpest X-ray image ever obtained of a portion of the Milky Way resolves a seemingly diffuse X-ray emission into discrete sources. These sources are likely to be stars of the 'garden variety' in the Sun's vicinity.
• Miniature devices: Voyage of the microrobots
  - Nature 458(7242):1121-1122 (2009)
  Nanobots — tiny robots that can be injected into the body to perform medical procedures — are the stuff of science fiction. Swimming microrobots propelled by artificial flagella bring that fantasy closer to reality.
• Ecology: Speciation affects ecosystems
  - Nature 458(7242):1122-1123 (2009)
  Evidence that speciation and adaptive radiation can change the properties of an ecosystem is a reminder of the pressing need to integrate ecosystems science and evolutionary biology.
• Solid-state physics: Lost magnetic moments
  - Nature 458(7242):1123-1124 (2009)
  A neat study gives clear-cut evidence that when a wire made of a magnetic material such as iron is squashed to the atomic scale, the material's magnetism disappears via an exotic physical process.
• Neuroscience: A social hub for worms
  - Nature 458(7242):1124-1125 (2009)
  There are more connections in the human brain than there are stars in the Milky Way, so scientists use simple organisms to search for universal neural-circuit motifs. Their latest find is a neuron for social behaviour.
• Correction
  - Nature 458(7242):1125 (2009)
  filled circle In the News & Views article "Quantum chemistry: The little molecules that could" by Cris H. Greene (Nature 458, 975–976; 2009
• Cytoplasmic functions of the tumour suppressor p53
  - Nature 458(7242):1127-1130 (2009)
  The principal tumour-suppressor protein, p53, accumulates in cells in response to DNA damage, oncogene activation and other stresses. It acts as a nuclear transcription factor that transactivates genes involved in apoptosis, cell cycle regulation and numerous other processes. An emerging area of research unravels additional activities of p53 in the cytoplasm, where it triggers apoptosis and inhibits autophagy. These previously unknown functions contribute to the mission of p53 as a tumour suppressor.
• Autophagy regulates lipid metabolism
  - Nature 458(7242):1131-1135 (2009)
  The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that co! uld have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
• Structural basis for leucine-rich nuclear export signal recognition by CRM1
  - Nature 458(7242):1136-1141 (2009)
  CRM1 (also known as XPO1 and exportin 1) mediates nuclear export of hundreds of proteins through the recognition of the leucine-rich nuclear export signal (LR-NES). Here we present the 2.9 Å structure of CRM1 bound to snurportin 1 (SNUPN). Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal LR-NES and its nucleotide-binding domain. The LR-NES is a combined alpha-helical-extended structure that occupies a hydrophobic groove between two CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin 1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Si! milar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport.
• Discrete sources as the origin of the Galactic X-ray ridge emission
  - Nature 458(7242):1142-1144 (2009)
  An unresolved X-ray glow (at energies above a few kiloelectronvolts) was discovered about 25 years ago and found to be coincident with the Galactic disk—the Galactic ridge X-ray emission1, 2. This emission3, 4, 5, 6, 7, 8, 9, 10 has a spectrum characteristic of a approx108 K optically thin thermal plasma, with a prominent iron emission line at 6.7 keV. The gravitational well of the Galactic disk, however, is far too shallow to confine such a hot interstellar medium; instead, it would flow away at a velocity of a few thousand kilometres per second, exceeding the speed of sound in the gas. To replenish the energy losses requires a source of 1043 erg s-1, exceeding by orders of magnitude all plausible energy sources in the Milky Way11. An alternative is that the hot plasma is bound to a multitude of faint sources12, which is supported by the recently observed similarities in the X-ray and near-infrared surface brightness distributions13, 14 (the latter traces the Galact! ic stellar distribution). Here we report that at energies of approx6–7 keV, more than 80 per cent of the seemingly diffuse X-ray emission is resolved into discrete sources, probably accreting white dwarfs and coronally active stars.
• Serial time-encoded amplified imaging for real-time observation of fast dynamic phenomena
  - Nature 458(7242):1145-1149 (2009)
  Ultrafast real-time optical imaging is an indispensable tool for studying dynamical events such as shock waves1, 2, chemical dynamics in living cells3, 4, neural activity5, 6, laser surgery7, 8, 9 and microfluidics10, 11. However, conventional CCDs (charge-coupled devices) and their complementary metal–oxide–semiconductor (CMOS) counterparts are incapable of capturing fast dynamical processes with high sensitivity and resolution. This is due in part to a technological limitation—it takes time to read out the data from sensor arrays. Also, there is the fundamental compromise between sensitivity and frame rate; at high frame rates, fewer photons are collected during each frame—a problem that affects nearly all optical imaging systems. Here we report an imaging method that overcomes these limitations and offers frame rates that are at least 1,000 times faster than those of conventional CCDs. Our technique maps a two-dimensional (2D) image into a serial time-domain! data stream and simultaneously amplifies the image in the optical domain. We capture an entire 2D image using a single-pixel photodetector and achieve a net image amplification of 25 dB (a factor of 316). This overcomes the compromise between sensitivity and frame rate without resorting to cooling and high-intensity illumination. As a proof of concept, we perform continuous real-time imaging at a frame speed of 163 ns (a frame rate of 6.1 MHz) and a shutter speed of 440 ps. We also demonstrate real-time imaging of microfluidic flow and phase-explosion effects that occur during laser ablation.
• The Kondo effect in ferromagnetic atomic contacts
  - Nature 458(7242):1150-1153 (2009)
  Iron, cobalt and nickel are archetypal ferromagnetic metals. In bulk, electronic conduction in these materials takes place mainly through the s and p electrons, whereas the magnetic moments are mostly in the narrow d-electron bands, where they tend to align. This general picture may change at the nanoscale because electrons at the surfaces of materials experience interactions that differ from those in the bulk. Here we show direct evidence for such changes: electronic transport in atomic-scale contacts of pure ferromagnets (iron, cobalt and nickel), despite their strong bulk ferromagnetism, unexpectedly reveal Kondo physics, that is, the screening of local magnetic moments by the conduction electrons below a characteristic temperature1. The Kondo effect creates a sharp resonance at the Fermi energy, affecting the electrical properties of the system; this appears as a Fano–Kondo resonance2 in the conductance characteristics as observed in other artificial nanostructur! es3, 4, 5, 6, 7, 8, 9, 10, 11. The study of hundreds of contacts shows material-dependent log-normal distributions of the resonance width that arise naturally from Kondo theory12. These resonances broaden and disappear with increasing temperature, also as in standard Kondo systems4, 5, 6, 7. Our observations, supported by calculations, imply that coordination changes can significantly modify magnetism at the nanoscale. Therefore, in addition to standard micromagnetic physics, strong electronic correlations along with atomic-scale geometry need to be considered when investigating the magnetic properties of magnetic nanostructures.
• The ITQ-37 mesoporous chiral zeolite
  - Nature 458(7242):1154-1157 (2009)
  The synthesis of crystalline molecular sieves with pore dimensions that fill the gap between microporous and mesoporous materials is a matter of fundamental and industrial interest1, 2, 3. The preparation of zeolitic materials with extralarge pores and chiral frameworks would permit many new applications. Two important steps in this direction include the synthesis4 of ITQ-33, a stable zeolite with 18 times 10 times 10 ring windows, and the synthesis5 of SU-32, which has an intrinsically chiral zeolite structure and where each crystal exhibits only one handedness. Here we present a germanosilicate zeolite (ITQ-37) with extralarge 30-ring windows. Its structure was determined by combining selected area electron diffraction (SAED) and powder X-ray diffraction (PXRD) in a charge-flipping algorithm6. The framework follows the SrSi2 (srs) minimal net7 and forms two unique cavities, each of which is connected to three other cavities to form a gyroidal channel system. These ca! vities comprise the enantiomorphous srs net of the framework. ITQ-37 is the first chiral zeolite with one single gyroidal channel. It has the lowest framework density (10.3 T atoms per 1,000 Å3) of all existing 4-coordinated crystalline oxide frameworks, and the pore volume of the corresponding silica polymorph would be 0.38 cm3 g-1.
• Greenhouse-gas emission targets for limiting global warming to 2 °C
  - Nature 458(7242):1158-1162 (2009)
  More than 100 countries have adopted a global warming limit of 2 °C or below (relative to pre-industrial levels) as a guiding principle for mitigation efforts to reduce climate change risks, impacts and damages1, 2. However, the greenhouse gas (GHG) emissions corresponding to a specified maximum warming are poorly known owing to uncertainties in the carbon cycle and the climate response. Here we provide a comprehensive probabilistic analysis aimed at quantifying GHG emission budgets for the 2000–50 period that would limit warming throughout the twenty-first century to below 2 °C, based on a combination of published distributions of climate system properties and observational constraints. We show that, for the chosen class of emission scenarios, both cumulative emissions up to 2050 and emission levels in 2050 are robust indicators of the probability that twenty-first century warming will not exceed 2 °C relative to pre-industrial temperatures. Limiting cumulative C! O2 emissions over 2000–50 to 1,000 Gt CO2 yields a 25% probability of warming exceeding 2 °C—and a limit of 1,440 Gt CO2 yields a 50% probability—given a representative estimate of the distribution of climate system properties. As known 2000–06 CO2 emissions3 were approx234 Gt CO2, less than half the proven economically recoverable oil, gas and coal reserves4, 5, 6 can still be emitted up to 2050 to achieve such a goal. Recent G8 Communiqués7 envisage halved global GHG emissions by 2050, for which we estimate a 12–45% probability of exceeding 2 °C—assuming 1990 as emission base year and a range of published climate sensitivity distributions. Emissions levels in 2020 are a less robust indicator, but for the scenarios considered, the probability of exceeding 2 °C rises to 53–87% if global GHG emissions are still more than 25% above 2000 levels in 2020.
• Warming caused by cumulative carbon emissions towards the trillionth tonne
  - Nature 458(7242):1163-1166 (2009)
  Global efforts to mitigate climate change are guided by projections of future temperatures1. But the eventual equilibrium global mean temperature associated with a given stabilization level of atmospheric greenhouse gas concentrations remains uncertain1, 2, 3, complicating the setting of stabilization targets to avoid potentially dangerous levels of global warming4, 5, 6, 7, 8. Similar problems apply to the carbon cycle: observations currently provide only a weak constraint on the response to future emissions9, 10, 11. Here we use ensemble simulations of simple climate-carbon-cycle models constrained by observations and projections from more comprehensive models to simulate the temperature response to a broad range of carbon dioxide emission pathways. We find that the peak warming caused by a given cumulative carbon dioxide emission is better constrained than the warming response to a stabilization scenario. Furthermore, the relationship between cumulative emissions an! d peak warming is remarkably insensitive to the emission pathway (timing of emissions or peak emission rate). Hence policy targets based on limiting cumulative emissions of carbon dioxide are likely to be more robust to scientific uncertainty than emission-rate or concentration targets. Total anthropogenic emissions of one trillion tonnes of carbon (3.67 trillion tonnes of CO2), about half of which has already been emitted since industrialization began, results in a most likely peak carbon-dioxide-induced warming of 2 °C above pre-industrial temperatures, with a 5–95% confidence interval of 1.3–3.9 °C.
• Evolutionary diversification in stickleback affects ecosystem functioning
  - Nature 458(7242):1167-1170 (2009)
  Explaining the ecological causes of evolutionary diversification is a major focus of biology, but surprisingly little has been said about the effects of evolutionary diversification on ecosystems1, 2, 3. The number of species in an ecosystem and their traits are key predictors of many ecosystem-level processes, such as rates of productivity, biomass sequestration and decomposition4, 5. Here we demonstrate short-term ecosystem-level effects of adaptive radiation in the threespine stickleback (Gasterosteus aculeatus) over the past 10,000 years. These fish have undergone recent parallel diversification in several lakes in coastal British Columbia, resulting in the formation of two specialized species (benthic and limnetic) from a generalist ancestor6. Using a mesocosm experiment, we demonstrate that this diversification has strong effects on ecosystems, affecting prey community structure, total primary production, and the nature of dissolved organic materials that regulat! e the spectral properties of light transmission in the system. However, these ecosystem effects do not simply increase in their relative strength with increasing specialization and species richness; instead, they reflect the complex and indirect consequences of ecosystem engineering by sticklebacks. It is well known that ecological factors influence adaptive radiation7, 8. We demonstrate that adaptive radiation, even over short timescales, can have profound effects on ecosystems.
• A hub-and-spoke circuit drives pheromone attraction and social behaviour in C. elegans
  - Nature 458(7242):1171-1175 (2009)
  Innate social behaviours emerge from neuronal circuits that interpret sensory information on the basis of an individual's own genotype, sex and experience. The regulated aggregation behaviour of the nematode Caenorhabditis elegans, a simple animal with only 302 neurons, is an attractive system to analyse these circuits. Wild social strains of C. elegans aggregate in the presence of specific sensory cues, but solitary strains do not1, 2, 3, 4. Here we identify the RMG inter/motor neuron as the hub of a regulated circuit that controls aggregation and related behaviours. RMG is the central site of action of the neuropeptide receptor gene npr-1, which distinguishes solitary strains (high npr-1 activity) from wild social strains (low npr-1 activity); high RMG activity is essential for all aspects of social behaviour. Anatomical gap junctions connect RMG to several classes of sensory neurons known to promote aggregation, and to ASK sensory neurons, which are implicated in ma! le attraction to hermaphrodite pheromones5. We find that ASK neurons respond directly to pheromones, and that high RMG activity enhances ASK responses in social strains, causing hermaphrodite attraction to pheromones at concentrations that repel solitary hermaphrodites. The coordination of social behaviours by RMG suggests an anatomical hub-and-spoke model for sensory integration in aggregation, and points to functions for related circuit motifs in the C. elegans wiring diagram.
• Toxin B is essential for virulence of Clostridium difficile
  - Nature 458(7242):1176-1179 (2009)
  Clostridium difficile is the leading cause of infectious diarrhoea in hospitals worldwide, because of its virulence, spore-forming ability and persistence1, 2. C. difficile-associated diseases are induced by antibiotic treatment or disruption of the normal gastrointestinal flora3, 4. Recently, morbidity and mortality resulting from C. difficile-associated diseases have increased significantly due to changes in the virulence of the causative strains and antibiotic usage patterns1, 2, 5, 6. Since 2002, epidemic toxinotype III NAP1/027 strains1, 2, which produce high levels of the major virulence factors, toxin A and toxin B, have emerged. These toxins have 63% amino acid sequence similarity7 and are members of the large clostridial glucosylating toxin family, which are monoglucosyltransferases that are pro-inflammatory, cytotoxic and enterotoxic in the human colon8, 9, 10. Inside host cells, both toxins catalyse the transfer of glucose onto the Rho family of GTPases, lea! ding to cell death8, 11. However, the role of these toxins in the context of a C. difficile infection is unknown. Here we describe the construction of isogenic tcdA and tcdB (encoding toxin A and B, respectively) mutants of a virulent C. difficile strain and their use in the hamster disease model to show that toxin B is a key virulence determinant. Previous studies showed that purified toxin A alone can induce most of the pathology observed after infection of hamsters with C. difficile 8, 9, 12 and that toxin B is not toxic in animals unless it is co-administered with toxin A, suggesting that the toxins act synergistically12. Our work provides evidence that toxin B, not toxin A, is essential for virulence. Furthermore, it is clear that the importance of these toxins in the context of infection cannot be predicted exclusively from studies using purified toxins, reinforcing the importance of using the natural infection process to dissect the role of toxins in disease.
• Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation
  - Nature 458(7242):1180-1184 (2009)
  Gene silencing by double-stranded RNA, denoted RNA interference, represents a new paradigm for rational drug design1. However, the transformative therapeutic potential of short interfering RNA (siRNA) has been stymied by a key obstacle—safe delivery to specified target cells in vivo 2. Macrophages are particularly attractive targets for RNA interference therapy because they promote pathogenic inflammatory responses in diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and diabetes3. Here we report the engineering of beta1,3-d-glucan-encapsulated siRNA particles (GeRPs) as efficient oral delivery vehicles that potently silence genes in mouse macrophages in vitro and in vivo. Oral gavage of mice with GeRPs containing as little as 20 mug kg-1 siRNA directed against tumour necrosis factor alpha (Tnf-alpha) depleted its messenger RNA in macrophages recovered from the peritoneum, spleen, liver and lung, and lowered serum Tnf-alpha levels. Sc! reening with GeRPs for inflammation genes revealed that the mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) is a previously unknown mediator of cytokine expression. Importantly, silencing Map4k4 in macrophages in vivo protected mice from lipopolysaccharide-induced lethality by inhibiting Tnf-alpha and interleukin-1beta production. This technology defines a new strategy for oral delivery of siRNA to attenuate inflammatory responses in human disease.
• Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay
  Matsushita K Takeuchi O Standley DM Kumagai Y Kawagoe T Miyake T Satoh T Kato H Tsujimura T Nakamura H Akira S - Nature 458(7242):1185-1190 (2009)
  Toll-like receptors (TLRs) recognize microbial components, and evoke inflammation and immune responses1, 2, 3. TLR stimulation activates complex gene expression networks that regulate the magnitude and duration of the immune reaction. Here we identify the TLR-inducible gene Zc3h12a as an immune response modifier that has an essential role in preventing immune disorders. Zc3h12a-deficient mice suffered from severe anaemia, and most died within 12 weeks. Zc3h12a -/- mice also showed augmented serum immunoglobulin levels and autoantibody production, together with a greatly increased number of plasma cells, as well as infiltration of plasma cells to the lung. Most Zc3h12a -/- splenic T cells showed effector/memory characteristics and produced interferon-gamma in response to T-cell receptor stimulation. Macrophages from Zc3h12a -/- mice showed highly increased production of interleukin (IL)-6 and IL-12p40 (also known as IL12b), but not TNF, in response to TLR ligands. Altho! ugh the activation of TLR signalling pathways was normal, Il6 messenger RNA decay was severely impaired in Zc3h12a -/- macrophages. Overexpression of Zc3h12a accelerated Il6 mRNA degradation via its 3'-untranslated region (UTR), and destabilized RNAs with 3'-UTRs for genes including Il6, Il12p40 and the calcitonin receptor gene Calcr. Zc3h12a contains a putative amino-terminal nuclease domain, and the expressed protein had RNase activity, consistent with a role in the decay of Il6 mRNA. Together, these results indicate that Zc3h12a is an essential RNase that prevents immune disorders by directly controlling the stability of a set of inflammatory genes.
• The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex
  - Nature 458(7242):1191-1195 (2009)
  The lipopolysaccharide (LPS) of Gram negative bacteria is a well-known inducer of the innate immune response1. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules. To understand the ligand specificity and receptor activation mechanism of the TLR4–MD-2–LPS complex we determined its crystal structure. LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4–MD-2–LPS complex arranged symmetrically. LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2, forming a hydrophobic interaction with the conserved phenylalanines of TLR4. The F126 loop of MD-2 undergoes localized structural change and supports this core hydrophobic interfac! e by making hydrophilic interactions with TLR4. Comparison with the structures of tetra-acylated antagonists bound to MD-2 indicates that two other lipid chains in LPS displace the phosphorylated glucosamine backbone by approx5 Å towards the solvent area2, 3. This structural shift allows phosphate groups of LPS to contribute to receptor multimerization by forming ionic interactions with a cluster of positively charged residues in TLR4 and MD-2. The TLR4–MD-2–LPS structure illustrates the remarkable versatility of the ligand recognition mechanisms employed by the TLR family4, 5, which is essential for defence against diverse microbial infection.
• A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range
  - Nature 458(7242):1196-1200 (2009)
  Brachydactyly type A1 (BDA1) was the first recorded disorder of the autosomal dominant Mendelian trait in humans, characterized by shortened or absent middle phalanges in digits. It is associated with heterozygous missense mutations in indian hedgehog (IHH)1, 2. Hedgehog proteins are important morphogens for a wide range of developmental processes3, 4. The capacity and range of signalling is thought to be regulated by its interaction with the receptor PTCH1 and antagonist HIP1. Here we show that a BDA1 mutation (E95K) in Ihh impairs the interaction of IHH with PTCH1 and HIP1. This is consistent with a recent paper showing that BDA1 mutations cluster in a calcium-binding site essential for the interaction with its receptor and cell-surface partners5. Furthermore, we show that in a mouse model that recapitulates the E95K mutation, there is a change in the potency and range of signalling. The mice have digit abnormalities consistent with the human disorder.
• Embryonic stem cells use ZFP809 to silence retroviral DNAs
  - Nature 458(7242):1201-1204 (2009)
  Embryonic stem cells (ESCs) and other primitive stem cells of mice have been known for more than 30 years to potently block retrovirus replication1. Infection of ESCs by the murine leukaemia viruses (MLVs) results in the normal establishment of integrated proviral DNA, but this DNA is then transcriptionally silenced, preventing further viral spread. The repression is largely mediated by trans-acting factors that recognize a conserved sequence element termed the primer binding site, an 18-base pair sequence complementary to the 3' end of a cellular transfer RNA2, 3, 4, 5, 6. A specific tRNA is annealed to the primer binding site sequence of the viral genomic RNA, and is used to prime DNA synthesis7. This same sequence in the context of the integrated proviral DNA is targeted for silencing in ESCs. We have recently shown that a large protein complex binding to the primer binding site in ESCs contains TRIM28 (refs 8, 9), a well-characterized transcriptional co-repressor10! , 11, 12. An important question remains as to the identity of the factor that directly recognizes integrated retroviral DNAs and recruits TRIM28 to mediate their specific silencing. Here we identify the zinc finger protein ZFP809 as the recognition molecule that bridges the integrated proviral DNA and TRIM28. We show that expression of ZFP809 is sufficient to render even differentiated cells highly resistant to MLV infection. Furthermore, we demonstrate that ZFP809 is able to potently block transcription from DNA constructs of human T-cell lymphotropic virus-1 (HTLV-1), which use the same primer tRNA. These results identify ZFP809 as a DNA-binding factor that specifically recognizes a large subset of mammalian retroviruses and retroelements, targeting them for transcriptional silencing. We propose that ZFP809 evolved as a stem-cell-specific retroviral restriction factor, and therefore constitutes a new component of the intrinsic immune system of stem cells.
• En passant
  - Nature 458(7242):1212 (2009)
  Family ties.