Hot off the presses! Feb 01

The Feb 01 issue of the is now up on Pubget (About ): 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:

• The scientist and the smartphone
  - Nature methods 7(2):87 (2010)
  Mobile computing platforms such as the iPhone are beginning to make inroads into the laboratory—serious prospect or fairy tale?
• The author file
  - Nature methods 7(2):89 (2010)
  Adapting optics: techniques for seeing stars scale to cells.
• Genome editing with modularly assembled zinc-finger nucleases
  - Nature methods 7(2):91 (2010)
  To the Editor: In a Correspondence in Nature Methods, some members of the Zinc Finger Consortium reported discouragingly high failure rates for the modular assembly of zinc-finger DNA-binding proteins and concluded that more time-consuming and labor-intensive selection-based methods were "the only publicly available alternatives for academic researchers interested in using ZFN technology". Zinc finger nucleases (ZFNs) are artificial restriction enzymes made by fusing reprogrammable zinc-finger DNA-binding units to the FokI nuclease domain, which efficiently induce, site-specific mutations in higher eukaryotic cells, and thus hold great promise in many fields.
• Reply to "Genome editing with modularly assembled zinc-finger nucleases"
  - Nature methods 7(2):91-92 (2010)
  Joung et al. reply: The publications cited by Kim et al. describing successful construction of zinc-finger nucleases (ZFNs) by modular assembly only further support our original conclusion that this method has a high failure rate for engineering functional zinc-finger arrays. Two of the three reports cited in their Correspondence provide data that enable calculation of failure rates for modular assembly.
• IntOGen: integration and data mining of multidimensional oncogenomic data
  - Nature methods 7(2):92-93 (2010)
  To the Editor: The use of high-throughput techniques has come to the fore in modern cancer research. Several projects collate and analyze multiple datasets from cancer gene studies.
• Systems biology: Big surprises in a little package
  - Nature methods 7(2):95 (2010)
  An in-depth, systems biology approach to analyzing a 'reduced genome' bacterium reveals startling complexity.
• Imaging and visualization: One-shot structure determination
  - Nature methods 7(2):96-97 (2010)
  By sampling a two-dimensional diffraction pattern on a spherical detector, three-dimensional structure determination of single molecules should be possible from a single measurement.
• Genomics: To each his own
  - Nature methods 7(2):96-97 (2010)
  De novo assembly of human genome sequences that are not currently included in the reference genome opens the possibility of a human pan-genome.
• News in brief
  - Nature methods 7(2):97 (2010)
  Gene regulation Mutagenesis screens in human cells The classical mutagenesis approach is a powerful method to determine the genes induced in various biological processes. However, the diploid nature of the human and other mammalian genomes has limited large-scale mutagenesis studies.
• Bioinformatics: Found in translation
  - Nature methods 7(2):98 (2010)
  Annotation of clinical databases using controlled vocabulary permits cross-species comparisons of phenotypes associated with human disease.
• Imaging and visualization: Taking imaging into the red
  - Nature methods 7(2):100 (2010)
  Subtle modifications to a red fluorescent protein make it highly effective for intravital imaging.
• Cell biology: Supporting actors
  - Nature methods 7(2):102 (2010)
  Two GFP-binding peptides, Enhancer and Minimizer, modulate GFP fluorescence and will enable a number of in vivo applications.
• Mind the gaps
  - Nature methods 7(2):105-106 (2010)
  Amid all the excitement about next-generation sequencing, scientists often neglect to mention the problems that are caused by short read lengths. Genome assemblies produced from short reads are far more fragmented than those produced from long reads, with many more gaps and with relatively poor long-range linking information.
• Advancing neurochemical monitoring
  - Nature methods 7(2):106-108 (2010)
  Identifying the neural basis of behavior is a core focus of neuroscience. One prominent methodology in this pursuit is monitoring the neurotransmitters that underlie communication between neurons.
• Correcting distorted optics: back to the basics
  - Nature methods 7(2):108-110 (2010)
  How can optical imperfections that cause image distortion be measured and corrected? This is an important problem in many fields, ranging from imaging very large structures as in astronomy down to the smallest as in high-resolution microscopy. Many often quite complicated ways have been invented to determine exactly how a given optical system differs from perfection.
• Target-enrichment strategies for next-generation sequencing
  - Nature methods 7(2):111-118 (2010)
  We have not yet reached a point at which routine sequencing of large numbers of whole eukaryotic genomes is feasible, and so it is often necessary to select genomic regions of interest and to enrich these regions before sequencing. There are several enrichment approaches, each with unique advantages and disadvantages. Here we describe our experiences with the leading target-enrichment technologies, the optimizations that we have performed and typical results that can be obtained using each. We also provide detailed protocols for each technology so that end users can find the best compromise between sensitivity, specificity and uniformity for their particular project.
• Parallel, tag-directed assembly of locally derived short sequence reads
  - Nature methods 7(2):119-122 (2010)
  We demonstrate subassembly, an in vitro library construction method that extends the utility of short-read sequencing platforms to applications requiring long, accurate reads. A long DNA fragment library is converted to a population of nested sublibraries, and a tag sequence directs grouping of short reads derived from the same long fragment, enabling localized assembly of long fragment sequences. Subassembly may facilitate accurate de novo genome assembly and metagenome sequencing.
• Two-color, two-photon uncaging of glutamate and GABA
  Kantevari S Matsuzaki M Kanemoto Y Kasai H Ellis-Davies GC - Nature methods 7(2):123-125 (2010)
  We developed a caged GABA (γ-aminobutyric acid), which, when combined with an appropriate caged glutamate, allows bimodal control of neuronal membrane potential with subcellular resolution using optically independent two-photon uncaging of each neurotransmitter. We used two-color, two-photon uncaging to fire and block action potentials from rat hippocampal CA1 neurons in brain slices with 720-nm and 830-nm light, respectively. Our method should be generalizable to other chemical messenger pairs.
• Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals
  Clark JJ Sandberg SG Wanat MJ Gan JO Horne EA Hart AS Akers CA Parker JG Willuhn I Martinez V Evans SB Stella N Phillips PE - Nature methods 7(2):126-129 (2010)
  Neurotransmission operates on a millisecond timescale but is changed by normal experience or neuropathology over days to months. Despite the importance of long-term neurotransmitter dynamics, no technique exists to track these changes in a subject from day to day over extended periods of time. Here we describe and characterize a microsensor that can detect the neurotransmitter dopamine with subsecond temporal resolution over months in vivo in rats and mice.
• FRT-seq: amplification-free, strand-specific transcriptome sequencing
  - Nature methods 7(2):130-132 (2010)
  We report an alternative approach to transcriptome sequencing for the Illumina Genome Analyzer, in which the reverse transcription reaction takes place on the flowcell. No amplification is performed during the library preparation, so PCR biases and duplicates are avoided, and because the template is poly(A)+ RNA rather than cDNA, the resulting sequences are necessarily strand-specific. The method is compatible with paired- or single-end sequencing.
• Genome-scale DNA methylation mapping of clinical samples at single-nucleotide resolution
  Gu H Bock C Mikkelsen TS Jäger N Smith ZD Tomazou E Gnirke A Lander ES Meissner A - Nature methods 7(2):133-136 (2010)
  Bisulfite sequencing measures absolute levels of DNA methylation at single-nucleotide resolution, providing a robust platform for molecular diagnostics. We optimized bisulfite sequencing for genome-scale analysis of clinical samples: here we outline how restriction digestion targets bisulfite sequencing to hotspots of epigenetic regulation and describe a statistical method for assessing significance of altered DNA methylation patterns. Thirty nanograms of DNA was sufficient for genome-scale analysis and our protocol worked well on formalin-fixed, paraffin-embedded samples.
• Bright cyan fluorescent protein variants identified by fluorescence lifetime screening
  - Nature methods 7(2):137-139 (2010)
  Optimization of autofluorescent proteins by intensity-based screening of bacteria does not necessarily identify the brightest variant for eukaryotes. We report a strategy to screen excited state lifetimes, which identified cyan fluorescent proteins with long fluorescence lifetimes (>3.7 ns) and high quantum yields (>0.8). One variant, mTurquoise, was 1.5-fold brighter than mCerulean in mammalian cells and decayed mono-exponentially, making it an excellent fluorescence resonance energy transfer (FRET) donor.
• Adaptive optics via pupil segmentation for high-resolution imaging in biological tissues
  Ji N Milkie DE Betzig E - Nature methods 7(2):141-147 (2010)
  Biological specimens are rife with optical inhomogeneities that seriously degrade imaging performance under all but the most ideal conditions. Measuring and then correcting for these inhomogeneities is the province of adaptive optics. Here we introduce an approach to adaptive optics in microscopy wherein the rear pupil of an objective lens is segmented into subregions, and light is directed individually to each subregion to measure, by image shift, the deflection faced by each group of rays as they emerge from the objective and travel through the specimen toward the focus. Applying our method to two-photon microscopy, we could recover near-diffraction–limited performance from a variety of biological and nonbiological samples exhibiting aberrations large or small and smoothly varying or abruptly changing. In particular, results from fixed mouse cortical slices illustrate our ability to improve signal and resolution to depths of 400 μm.
• Systems analysis of EGF receptor signaling dynamics with microwestern arrays
  - Nature methods 7(2):148-155 (2010)
  We describe microwestern arrays, which enable quantitative, sensitive and high-throughput assessment of protein abundance and modifications after electrophoretic separation of microarrayed cell lysates. This method allowed us to measure 91 phosphosites on 67 proteins at six time points after stimulation with five epidermal growth factor (EGF) concentrations in A431 human carcinoma cells. We inferred the connectivities among 15 phosphorylation sites in 10 receptor tyrosine kinases (RTKs) and two sites from Src kinase using Bayesian network modeling and two mutual information-based methods; the three inference methods yielded substantial agreement on the network topology. These results imply multiple distinct RTK coactivation mechanisms and support the notion that small amounts of experimental data collected from phenotypically diverse network states may enable network inference.
• Mass spectrometry for biologists
  - Nature methods 7(2):157-161 (2010)
  Mass spectrometry–based proteomics is still rapidly expanding, not just in terms of the methods and instruments but also the biological questions.

Hot off the presses! Jan 28 Neuron

The Jan 28 issue of the Neuron is now up on Pubget (About Neuron): 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:

• Kalzium Ist Nicht Alles
  - Neuron 65(2):143-144 (2010)
  Elevation of cerebral Mg2+ with a novel orally delivered ionophore, magnesium threonate, enhances cognition in young and old rats over a 12-24 day treatment interval, as outlined in a paper by Slutsky et al. in this issue of Neuron. Despite both Mg2+ and Zn2+ blocking the NMDA receptor channel, sustained extracellular Mg2+ elevation mimics sustained synaptic Zn2+ concentrations by increasing hippocampal NR2B expression and bouton density.
• Location, Location, Location: Contrasting Roles of Synaptic and Extrasynaptic NMDA Receptors in Huntington's Disease
  - Neuron 65(2):145-147 (2010)
  Abnormally enhanced N-methyl-D-aspartate (NMDA) receptor function is implicated in Huntington's disease (HD). In this issue of Neuron and a recent issue of Nature Medicine, an abnormal balance between the activity of NMDA receptors at synaptic (prosurvival) and extrasynaptic (proapoptotic) sites has been uncovered in a cellular and a mouse model of HD.
• Excitatory Neuromodulator Reduces Dopamine Release, Enhancing Prolactin Secretion
  - Neuron 65(2):147-149 (2010)
  Hypothalamic dopamine neurons inhibit pituitary prolactin secretion. In this issue of Neuron, Lyons et al. provide evidence for a novel model, whereby the excitatory neuropeptide TRH depolarizes gap-junction-coupled dopamine neurons, leading to a shift in the population pattern of action potentials from phasic burst firing to regular tonic firing, hypothetically reducing dopamine release while increasing total spike number.
• Eye Smarter than Scientists Believed: Neural Computations in Circuits of the Retina
  - Neuron 65(2):150-164 (2010)
  We rely on our visual system to cope with the vast barrage of incoming light patterns and to extract features from the scene that are relevant to our well-being. The necessary reduction of visual information already begins in the eye. In this review, we summarize recent progress in understanding the computations performed in the vertebrate retina and how they are implemented by the neural circuitry. A new picture emerges from these findings that helps resolve a vexing paradox between the retina's structure and function. Whereas the conventional wisdom treats the eye as a simple prefilter for visual images, it now appears that the retina solves a diverse set of specific tasks and provides the results explicitly to downstream brain areas.
• Enhancement of Learning and Memory by Elevating Brain Magnesium
  - Neuron 65(2):165-177 (2010)
  Learning and memory are fundamental brain functions affected by dietary and environmental factors. Here, we show that increasing brain magnesium using a newly developed magnesium compound (magnesium-L-threonate, MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. The pattern completion ability was also improved in aged rats. MgT-treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of hippocampus that were correlated with memory improvement. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced. Our findings suggest th at an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.
• Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice
  - Neuron 65(2):178-190 (2010)
  N-methyl-D-aspartate receptor (NMDAR) excitotoxicity is implicated in the pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder. However, NMDARs are poor therapeutic targets, due to their essential physiological role. Recent studies demonstrate that synaptic NMDAR transmission drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation promotes cell death. We report specifically increased extrasynaptic NMDAR expression, current, and associated reductions in nuclear CREB activation in HD mouse striatum. The changes are observed in the absence of dendritic morphological alterations, before and after phenotype onset, correlate with mutation severity, and require caspase-6 cleavage of mutant huntingtin. Moreover, pharmacological block of extrasynaptic NMDARs with memantine reversed signaling and motor learning deficits. Our data demonstrate elevated extrasynaptic NMDAR activity in an animal model of neurodegenerative diseas e. We provide a candidate mechanism linking several pathways previously implicated in HD pathogenesis and demonstrate successful early therapeutic intervention in mice.
• Hook3 Interacts with PCM1 to Regulate Pericentriolar Material Assembly and the Timing of Neurogenesis
  - Neuron 65(2):191-203 (2010)
  Centrosome functions are important in multiple brain developmental processes. Proper functioning of the centrosome relies on assembly of protein components into the pericentriolar material. This dynamic assembly is mediated by the trafficking of pericentriolar satellites, which are comprised of centrosomal proteins. Here we demonstrate that trafficking of pericentriolar satellites requires the interaction between Hook3 and Pericentriolar Material 1 (PCM1). Hook3, previously shown to link the centrosome and the nucleus in C. elegans, is recruited to pericentriolar satellites through interaction with PCM1, a protein associated with schizophrenia. Disruption of the Hook3-PCM1 interaction in vivo impairs interkinetic nuclear migration, a featured behavior of embryonic neural progenitors. This in turn leads to overproduction of neurons and premature depletion of the neural progenitor pool in the developing neocortex. These results underscore the importance of centrosomal ass embly in neurogenesis and provide potential insights into the etiology of brain developmental diseases related to the centrosome dysfunction.
• Ephexin1 Is Required for Structural Maturation and Neurotransmission at the Neuromuscular Junction
  - Neuron 65(2):204-216 (2010)
  The maturation of neuromuscular junctions (NMJs) requires the topological transformation of postsynaptic acetylcholine receptor (AChR)-containing structures from a simple plaque to an elaborate structure composed of pretzel-like branches. This maturation process results in the precise apposition of the presynaptic and postsynaptic specializations. However, little is known about the molecular mechanisms underlying the plaque-to-pretzel transition of AChR clusters. In this study, we identify an essential role for the RhoGEF ephexin1 in the maturation of AChR clusters. Adult ephexin1−/− mice exhibit severe muscle weakness and impaired synaptic transmission at the NMJ. Intriguingly, when ephexin1 expression is deficient in vivo, the NMJ fails to mature into the pretzel-like shape, and such abnormalities can be rescued by re-expression of ephexin1. We further demonstrate that ephexin1 regulates the stability of AChR clusters in a RhoA-dependent manner. Taken together, ou r findings reveal an indispensible role for ephexin1 in regulating the structural maturation and neurotransmission of NMJs.
• Synchronized Network Oscillations in Rat Tuberoinfundibular Dopamine Neurons: Switch to Tonic Discharge by Thyrotropin-Releasing Hormone
  - Neuron 65(2):217-229 (2010)
  The pituitary hormone, prolactin, triggers lactation in nursing mothers. Under nonlactating conditions, prolactin secretion is suppressed by powerful inhibition from hypothalamic tuberoinfundibular dopamine (TIDA) neurons. Although firing pattern has been suggested as integral to neuroendocrine control, the electrical behavior of TIDA cells remains unknown. We demonstrate that rat TIDA neurons discharge rhythmically in a robust 0.05 Hz oscillation. The oscillation is phase locked between neurons, and while it persists during chemical synaptic transmission blockade, it is abolished by gap junction antagonists. Thyrotropin-releasing hormone (TRH) potently stimulates prolactin release, an effect assumed to take place in the pituitary. In TIDA cells, TRH caused a transition from phasic to tonic firing through combined pre- and postsynaptic effects. These findings suggest a model for prolactin regulation where a TIDA network switch from oscillations to sustained discharge co nverts dopamine from an antagonist at high concentrations to a functional agonist as dopamine output from the network decreases.
• Pathway-Specific Feedforward Circuits between Thalamus and Neocortex Revealed by Selective Optical Stimulation of Axons
  - Neuron 65(2):230-245 (2010)
  Thalamocortical and corticothalamic pathways mediate bidirectional communication between the thalamus and neocortex. These pathways are entwined, making their study challenging. Here we used lentiviruses to express channelrhodopsin-2 (ChR2), a light-sensitive cation channel, in either thalamocortical or corticothalamic projection cells. Infection occurred only locally, but efferent axons and their terminals expressed ChR2 strongly, allowing selective optical activation of each pathway. Laser stimulation of ChR2-expressing thalamocortical axons/terminals evoked robust synaptic responses in cortical excitatory cells and fast-spiking (FS) inhibitory interneurons, but only weak responses in somatostatin-containing interneurons. Strong FS cell activation led to feedforward inhibition in all cortical neuron types, including FS cells. Corticothalamic stimulation excited thalamic relay cells and inhibitory neurons of the thalamic reticular nucleus (TRN). TRN activation triggere d inhibition in relay cells but not in TRN neurons. Thus, a major difference between thalamocortical and corticothalamic processing was the extent to which feedforward inhibitory neurons were themselves engaged by feedforward inhibition.
• Critical Period Plasticity Matches Binocular Orientation Preference in the Visual Cortex
  - Neuron 65(2):246-256 (2010)
  Changes of ocular dominance in the visual cortex can be induced by visual manipulations during a critical period in early life. However, the role of critical period plasticity in normal development is unknown. Here we show that at the onset of this time window, the preferred orientations of individual cortical cells in the mouse are mismatched through the two eyes and the mismatch decreases and reaches adult levels by the end of the period. Deprivation of visual experience during this period irreversibly blocks the binocular matching of orientation preference, but has no effect in adulthood. The critical period of binocular matching can be delayed by long-term visual deprivation from birth, like that of ocular dominance plasticity. These results demonstrate that activity-dependent changes induced by normal visual experience during the well-studied critical period serve to match eye-specific inputs in the cortex, thus revealing a physiological role for critical period pl asticity during normal development.
• Synchronized Activity between the Ventral Hippocampus and the Medial Prefrontal Cortex during Anxiety
  - Neuron 65(2):257-269 (2010)
  The ventral hippocampus, unlike its dorsal counterpart, is required for anxiety-like behavior. The means by which it acts are unknown. We hypothesized that the hippocampus synchronizes with downstream targets that influence anxiety, such as the medial prefrontal cortex (mPFC). To test this hypothesis, we recorded mPFC and hippocampal activity in mice exposed to two anxiogenic arenas. Theta-frequency activity in the mPFC and ventral, but not dorsal, hippocampus was highly correlated at baseline, and this correlation increased in both anxiogenic environments. Increases in mPFC theta power predicted avoidance of the aversive compartments of each arena and were larger in serotonin 1A receptor knockout mice, a genetic model of increased anxiety-like behavior. These results suggest a role for theta-frequency synchronization between the ventral hippocampus and the mPFC in anxiety. They are consistent with the notion that such synchronization is a general mechanism by which the hippocampus communicates with downstream structures of behavioral relevance.
• A Disynaptic Relay from Superior Colliculus to Dorsal Stream Visual Cortex in Macaque Monkey
  - Neuron 65(2):270-279 (2010)
  The superior colliculus (SC) is the first station in a subcortical relay of retinal information to extrastriate visual cortex. Ascending SC projections pass through pulvinar and LGN on their way to cortex, but it is not clear how many synapses are required to complete these circuits or which cortical areas are involved. To examine this relay directly, we injected transynaptic rabies virus into several extrastriate visual areas. We observed disynaptically labeled cells in superficial, retino-recipient SC layers from injections in dorsal stream areas MT and V3, but not the earliest extrastriate area, V2, nor ventral stream area V4. This robust SC-dorsal stream pathway is most likely relayed through the inferior pulvinar and can provide magnocellular-like sensory inputs necessary for motion perception and the computation of orienting movements. Furthermore, by circumventing primary visual cortex, this pathway may also underlie the remaining visual capacities associated wit h blindsight.
• Enhanced Brain Correlations during Rest Are Related to Memory for Recent Experiences
  - Neuron 65(2):280-290 (2010)
  Long-term storage of episodic memories is hypothesized to result from the off-line transfer of information from the hippocampus to neocortex, allowing a hippocampal-independent cortical representation to emerge. However, off-line hippocampal-cortical interactions have not been demonstrated to be linked with long-term memory. Here, using functional magnetic resonance imaging, we examined if hippocampal-cortical BOLD correlations during rest following an associative encoding task are related to later associative memory performance. Our data show enhanced functional connectivity between the hippocampus and a portion of the lateral occipital complex (LO) during rest following a task with high subsequent memory compared to pretask baseline resting connectivity. This effect is not seen during rest following a task with poor subsequent memory. Furthermore, the magnitude of hippocampal-LO correlations during posttask rest predicts individual differences in later associative mem ory. These results demonstrate the importance of postexperience resting brain correlations for memory for recent experiences. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (23044 K)

Hot off the presses! Jan 28 Nature

The Jan 28 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:

• Learning to share
  - Nature 463(7280):401 (2010)
  By opening up its database of potential malaria drugs, GlaxoSmithKline has blazed a path that other pharmaceutical companies should follow.
• Valid concerns
  - Nature 463(7280):401 (2010)
  The reporting of candidate biomarkers for disease must be rigorous to drive translational research.
• False alarms
  - Nature 463(7280):402 (2010)
  British scientists must adopt a positive tone if they hope to protect their gains in funding.
• Genetics: Protein's billion-year history
  - Nature 463(7280):404 (2010)
  
• Material science: Speedy silk imprinting
  - Nature 463(7280):404 (2010)
  
• Biomaterials: Super snail shells
  - Nature 463(7280):404 (2010)
  
• Regenerative biology: New nerve cells connect
  - Nature 463(7280):404 (2010)
  
• Vascular biology: Hearty hormones
  - Nature 463(7280):404 (2010)
  
• Astronomy: Hot spectra
  - Nature 463(7280):405 (2010)
  
• Neurobiology: Prions at work
  - Nature 463(7280):405 (2010)
  
• Atmospheric science: Stronger storms
  - Nature 463(7280):405 (2010)
  
• Cancer biology: Weighted cancer risk
  - Nature 463(7280):405 (2010)
  
• Journal club
  - Nature 463(7280):405 (2010)
  
• News briefing: 28 January 2010
  - Nature 463(7280):406 (2010)
  The week in science This article is best viewed as a PDF Policy|Research|Events|People|Business|Business watch|The week ahead|Number crunch|Sound bites Israel's National Council for Research and Development has suspended its activities. The group advises the government on research and development policy, but its budget is controlled by the ministry of science. In a 20 January letter to Prime Minister Binyamin Netanyahu, council chairman Oded Abramsky — a medical neurologist — said the group would not perform its functions until it was granted statutory independence. The decision follows the rejection last month by the Knesset, Israel's parliament, of a bill that would have given the council independent budgetary and administrative standing (see Nature 463, 14–15; 2010). A 1996 US law that orders the privatization of the helium market by selling off a national reserve is hurting science, according to a report released on 22 January by the US National Research Council. Researchers often use liquid helium, an exhaustible resource, to cool experiments close to absolute zero. The report finds that the sell-off of an underground reserve in Texas has destabilized the market price for helium, and warns that the United States could become a net importer of helium within 15 years. France's government has outlined plans to amend its tax on carbon dioxide emissions. A 29 December court ruling had stopped an earlier scheme because it exempted 93% of industrial emissions besides fuel use and unfairly penalized households. On 20 January, the government said that it would consult widely to draft a revised version, which would enter into force in July. It would maintain the tax at €17 (US$24) per tonne, but compromises might include compensation for households and variable tax rates for energy-intensive sectors. The US$4 million that the United States spends annually to detect near-Earth objects is not enough, according to the 22 January report of a US National Research Council committee. In 2005, the US Congress set NASA a deadline of 2020 to characterize 90% of near-Earth objects bigger than 140 metres — the size thought to pose a significant risk if asteroids or comets hit urban areas. A new space mission could help to meet the target by 2022, and funding must also be assured for future ground-based facilities, such as the Large Synoptic Survey Telescope, the report said. Delegates at a conference in London on 18–20 January began hammering out a new strategy for the Convention on Biological Diversity. In the first of many talks leading up to an October meeting in Nagoya, Japan, policy-makers and scientists called for an ambitious long-term vision, which could include halting extinctions by 2050. On 19 January, the European Commission laid out four possible visions for European Union biodiversity this decade — three of which include halting the loss of EU biodiversity by 2020. See go.nature.com/asCFvn for more. Researchers from Italy's Institute for Environmental Protection and Research (ISPRA) have ended a two-month rooftop protest after winning a reprieve against job cuts. The lay-offs had been announced by the Italian government as part of its attempt to cut public research funds and restructure the civil service. Around 200 scientists at ISPRA — itself formed by a 2008 merger of three environmental institutes — would have lost their short-term, renewable work contracts. In an agreement signed on 20 January, Italian environment minister Stefania Prestigiacomo promised to renew all threatened contracts for one year, and to appoint new positions in the near future. The US Chemical Safety Board is to investigate an explosion on 7 January at Texas Tech University in Lubbock that injured a graduate student. The board is an independent federal agency that usually investigates chemical explosions and leaks at industrial facilities; this will be the first time that it has investigated an academic laboratory. "We see serious accidents in high school and university labs every year, including a tragic fatality a year ago at UCLA [University of California, Los Angeles]," said the board's chairman John Bresland in a 19 January statement. "I believe it is time to begin examining these accidents." A medical school and a hospital have teamed up for a US$65-million project to sequence the genomes of normal and cancerous cells from more than 600 children with cancer. St Jude Children's Research Hospital in Memphis, Tennessee, and the School of Medicine at Washington University in St Louis, Missouri, announced the partnership on 25 January. The privately funded three-year project will generate "the most significant set of data we can imagine in paediatric cancer", says Francis Collins, head of the National Institutes of Health, which plans to do such sequencing in adults. ARIZONA FISH & GAME DEPT An Arizona study that led to the death of the last known wild jaguar in the United States has been sharply criticized. A 19 January report by the Department of the Interior cited evidence gathered in an ongoing criminal investigation suggesting that Arizona officials and a subcontractor intentionally snared the jaguar (pictured), while trapping black bears and mountain lions. It also claimed they did not have a permit to cover even an accidental capture, as required under the US Endangered Species Act. The cat, called Macho B, was released, but fell ill and was killed after recapture. Officials from Arizona's Game and Fish Department say they had a valid permit and followed all laws. The agency that judges the effectiveness of medicines in Germany will lose its director later this year. Peter Sawicki, the founding director of the Institute for Quality and Efficiency in Health Care (IQWiG) in Cologne, will be replaced when his contract is up at the end of August, IQWiG's board announced on 22 January. Critics have questioned his management of IQWiG and its drug-evaluation process. See go.nature.com/UcpVlk for more. Fotis Kafatos, the president of the European Research Council (ERC), which funds cutting-edge research in Europe, will leave his post on 1 March. His four-year term as president was due to end in February 2011, but announcing the move on 22 January, he said he wanted to devote more time to his research. Kafatos holds the chair in insect immunogenomics at Imperial College London. He will remain on the ERC's 22-member scientific council, which will elect a new president from its ranks next month. G. OSAN/AP Rajendra Pachauri (pictured), the chairman of the Intergovernmental Panel on Climate Change (IPCC), has been facing a storm of criticism after conceding that a mistake was made in the IPCC's 2007 synthesis report. The IPCC admitted that it was wrong to state that Himalayan glaciers were likely to melt by 2035, and that the claim was based on "poorly substantiated estimates", not rigorous evidence (see Nature 463, 276–277; 2010). Despite calls from the media and some climate scientists that the IPCC's leadership should be reformed, Pachauri said he would not resign. "I am not going to stand down, I am going to stand up," he said. Two months after filing for bankruptcy, the 14-year-old genomics company deCODE Genetics, based in Reykjavik, has been resurrected as a newly financed private company. Research will be headed by deCODE's founder, neuroscientist Kári Stefánsson, and the company will continue to develop gene-based diagnostics, perform personal genome scans, and contract with pharmaceutical firms, while abandoning its in-house drug-discovery efforts. The rebirth was orchestrated by the US venture-capital consortium Saga Investments, which purchased deCODE's drug-discovery and development programmes, as well as its subsidiary Íslensk Erfđagreining, with the approval of a Delaware bankruptcy court. SOURCE: DOW JONES VENTURESOURCE Biotechnology and pharmaceutical companies were perhaps the least affected by last year's collapse in US venture-capital spending, according to market tracker Dow Jones VentureSource. Venture capitalists invested $21.4 billion in US companies last year, a 31% drop from 2008. But spending on biopharmaceutical companies (those involved in biotech, drug delivery or pharmaceuticals) dropped by just 11%, helping the health-care industry to become the leading venture-capital investment sector for the first time (see chart). "I was surprised to see how resilient biotech has been," says Jessica Canning, VentureSource's global research director. She ascribes the sector's hardiness to US investors scenting industry change ahead of anticipated health-care reforms in the nation and the loss of patent protection for a series of blockbuster drugs. In the longer term, the retiring baby-boom generation is expected to create a new market for treatments. Although 2009 saw just three initial public offerings (IPOs) by US biotech firms, by December, ten more companies in the sector have now filed their intention, says Canning. Biotech firms accounted for one-third of all IPO registrations in 2009. US President Barack Obama announces his proposed federal budget for 2011. In New York, a federal judge will consider a lawsuit that challenges the patents on human breast-cancer genes held by Myriad Genetics of Salt Lake City, Utah. The case will either receive judgement or be referred to public trial (see page 413). The strongest gust of wind ever recorded that was not related to a tornado. It happened during Tropical Cyclone Olivia at Barrow Island, Australia, in April 1996. Source: World Meteorological Organization review, 22 January UN climate chief Yvo de Boer says that countries will be able to back the Copenhagen climate-change accord after 31 January — the date by which they were supposed to sign the document and list non-binding national emissions targets. Source: AP 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.
• Icy hunt for old air
  - Nature 463(7280):408 (2010)
  Antarctic drilling project aims for a definitive record of climate. Kendrick Taylor looks over the WAIS drill.C. FIRESTONE "We're checking out history books made of ice," says Kendrick Taylor. A palaeoclimatologist at the Desert Research Institute in Reno, Nevada, Taylor is the chief scientist of the West Antarctic Ice Sheet (WAIS) Divide drilling project, which is now three-quarters of the way towards pulling up the most temporally precise record of carbon dioxide for the past 100,000 years. The highly anticipated ice core promises to improve climatologists' understanding of the dynamic global climate system, and has already begun to illuminate how humans can affect it. On 25 January, drillers finished the season at a depth of 2,561 metres, about a kilometre off the project's final goal. Relentless winds and poor visibility at the WAIS Divide camp, about 1,170 kilometres from the South Pole, had permitted only 35 days of drilling this year. But bad weather is precisely why researchers chose this desolate stretch of ice. Snowfall accumulation here, about half a metre per year, is an order of magnitude greater than at the sites of other Antarctic cores covering the same time span. The heavy precipitation produces annual layers of ice 22 centimetres thick near the surface, allowing palaeoclimatologists to collect season-by-season data further back in time than any other Antarctic core. "This is the best spot on the planet to get the record we're looking for." The drill site is perched atop an ice divide that sends ice flowing in opposite directions. There is little lateral flow on the divide itself, ensuring that ice sampled here has not travelled in from elsewhere on the ice sheet and scrambled the climate record. "This is simply the best spot on the planet to get the record we're looking for," says Taylor. "This is where the library is." That record should yield annual data for the past 40,000 years. It will extend back another 60,000 years, but annual layers cannot be reliably identified for that period because the weight of overlying ice has compressed them, making them too thin. Thirty-seven investigators lead 27 projects at the WAIS Divide, funded by the US National Science Foundation, studying everything from trace elements in the ice to the potential for life deep in the core. The bubbles in the ice are a special prize. Although temperatures at the camp are well below freezing, four refrigeration units in the drilling facility keep the cores below −20 °C, the temperature at which the bubbles can leak out. Their contents are precious: they trap air from the time of snowfall, offering snapshots of ancient atmospheric conditions. Last November, for instance, palaeoclimatologist Richard Alley and his colleagues at Pennsylvania State University in University Park reported the isotopic composition of methane extracted from the top layers of the WAIS core, representing the past 1,000 years1. They found an increase in heavy methane — a by-product of biomass burning and other human activity — around the sixteenth century, which Alley attributes to Native Americans razing forests to expand their territory as the Americas experienced a population boom. This peak recedes as quickly as it rises, corresponding to widespread deaths as Europeans arrived with their diseases and weapons. The imprint shows up in the ice record because methane circulates around the globe in a matter of years. Yet of all the gases within the WAIS ice, Alley sees the most promise in CO2. "We're going to get the highest-resolution, best-dated CO2 record ever," he says. "That's what gets me really excited." High-resolution ice cores have been extracted before: Greenland's GRIP and GISP2 cores, drilled in the early 1990s, have the same season-by-season detail as those from the WAIS Divide, and have been the gold standard for palaeoclimatology in the Northern Hemisphere. But dust blown in from exposed land nearby interacted with acids in Greenland's ice to produce extra CO2, which has stymied attempts to establish a reliable CO2 record there. Most of what is known about past CO2 levels thus comes from the dust-free Antarctic ice. "WAIS will combine the high time resolution we see in Greenland with a record only retrievable in Antarctica," Taylor says. Click to enlarge. A question of timing The gas record may help researchers to better understand the precise timing of past increases in CO2 and temperature. Palaeoclimatologists already know that these changes have taken place roughly in step in the past, but which rises first, the thermometer or the greenhouse gas? "All the analysis everyone has done suggests that CO2 lags temperature on timescales of several hundred years," says Ed Brook, a palaeoclimatologist at Oregon State University in Corvallis. The rising CO2 presumably acts as an amplifier to drive the temperature up further, but the margin of error in deep Antarctic cores is too large to nail down the timing of that relationship precisely. "The uncertainty is of the same order as the actual lag," says Brook. "WAIS Divide should help us solve that problem." The CO2 record could also help to solve a recently discovered climate puzzle. Other cores have shown that past temperature changes in the Arctic are inversely coupled to changes in the Antarctic, such that hot and cold periods 'seesaw' between the poles2,3. One driver is the oceanic 'Atlantic conveyor belt', in which cool, salty water sinks in the North Atlantic and flows southward. Abrupt changes in heat or salinity can disrupt the flow; warm periods in the Arctic, for example, are thought to have led icebergs to dump fresh water into the North Atlantic, decreasing the salinity and density of northern seawater and preventing it from sinking. The cold water stays in the Arctic, cooling it down, while Antarctica does not receive the cold water it normally would, shifting southern temperatures up. That, at least, is the theory. But temperature can be exchanged between the poles through other channels, including the atmosphere, which moves heat faster than ocean currents do, says Bo Vinther, a postdoc at the University of Copenhagen, who has worked on coring projects in Greenland and Antarctica. If palaeoclimatologists see long lags between temperature changes at the poles when they stack the WAIS cores up against those from Greenland, that evidence would suggest a lead role for the ocean in the bipolar seesaw. But a shorter lag would suggest a more prominent role for the atmosphere. The CO2 record will help to answer this question, too: CO2 from deep in the ocean, where large masses of organic matter have decomposed, has a different isotopic signature from terrestrial or atmospheric CO2. Heavier CO2 in the WAIS record would suggest that ocean circulation bringing up deep water was largely responsible for the bipolar seesaw. ADVERTISEMENT With about a kilometre of ice left to pull up, Taylor is hopeful that the core will be complete by the end of the next drilling season. But the final metres can be the toughest to dig up because the drill's descent grows longer with each segment of extracted core. "We can get it all done next season if everything goes perfectly," he says. "But this is Antarctica. Every day is a surprise." * References * Mischler, J. A.et al. Glob. Biogeochem. Cycles23, GB4024 (2009). * Blunier, T. & Brook, E. J.Science291, 109-112 (2001). * EPICA Community MembersNature444, 195-198 (2006). 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.
• Altered microbe makes biofuel
  - Nature 463(7280):409 (2010)
  Bacterium could work directly on grass or crop waste. Switch grass could be made into diesel cleanly and quickly.PVSTOCK.COM/ALAMY In a bid to overcome the drawbacks of existing biofuels, researchers have engineered a bacterium that can convert a form of raw plant biomass directly into clean, road-ready diesel. So far, biofuels have largely been limited to ethanol, which is harder to transport than petrol and is made from crop plants such as maize (corn) and sugarcane, putting vehicles in competition with hungry mouths. In this week's Nature, researchers from the University of California, Berkeley, and the biotech firm LS9 of South San Francisco, California, among others describe a potential solution: a modified Escherichia coli bacterium that can make biodiesel directly from sugars or hemicellulose, a component of plant fibre (see page 559). The method can be tailored to produce a host of high-value chemicals, including molecules that mimic standard petrol, and could be expanded to work on tougher cellulosic materials, the researchers say. The work identifies a potentially cost-effective way of converting grass or crop waste directly into fuel, filling gas tanks without raising global food prices or increasing hunger and deforestation in far-flung locales. Moreover, the process is much more climate friendly than manufacturing ethanol from maize, and produces higher-energy fuels that are interchangeable with current petroleum products. The next step is to scale the process up and adapt it to cellulose, which makes up the bulk of plant material. "The process has a lot of promise for actually being commercialized." "It's a nice milestone in the field of biofuels, and it has a lot of promise for actually being commercialized," says James Liao, a metabolic engineer and synthetic biologist at the University of California, Los Angeles. LS9's calculations, performed with the help of the Argonne National Laboratory in Illinois, show that the biodiesel that it is preparing to market reduces greenhouse-gas emissions by 85% compared with standard diesel. That calculation is based on using Brazilian sugarcane, which is a much more efficient feedstock than maize; LS9 says that the shift from sugars to biomass as a feedstock would reduce greenhouse gases even further. The company has been working to convert sugars into tailored molecules for several years, says co-author Stephen del Cardayre, LS9's vice-president for research and development. However, their university collaborators went two steps further, eliminating the need for additives and then folding in the ability to use hemicellulose as a feedstock. "This paper is a representation of the types of efforts that are going to move us to biomass," he says. The researchers basically amplified and then short-circuited E. coli's internal machinery for producing large fatty-acid molecules, enabling them to convert precursor molecules directly into fuels and other chemicals. The team then inserted genes from other bacteria to produce enzymes able to break down hemicellulose. In all, the authors report more than a dozen genetic modifications. ADVERTISEMENT The results could buoy LS9, says Mark Bünger, a research director at business consultancy Lux Research in San Francisco. Like its competitors, including Amyris of Emeryville, California, and South San Francisco-based Solazyme, LS9 struggled for funding in 2008 and early 2009 because of the drop in oil prices and the economic downturn, Bünger says. But LS9 made it through, securing US$25 million in new funding from various sources, including a strategic partnership with oil giant Chevron last September. The company plans to open a commercial-scale demonstration plant later this 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.
• Debt crisis threatens UK science
  - Nature 463(7280):410 (2010)
  Gabriel Aeppli has spent decades probing the nanostructure of materials, but today it is financial woes that are on his mind. As director of the London Centre for Nanotechnology, Aeppli is responsible for making sure the laboratory continues to bring in funding at the current level of about £10 million (US$16 million) each year. There are currently no comments.
• Stem-cell line given the nod
  - Nature 463(7280):411 (2010)
  US stem-cell researchers had reason to celebrate last week. The uncertain fate of human embryonic stem-cell lines from the George W. There are currently no comments.
• Lawsuit rekindles gene-patent debate
  - Nature 463(7280):413 (2010)
  A court case in New York next week could have widespread implications for gene patenting. The judge will consider a lawsuit over a discovery that was made in university labs and ended as a lucrative test monopoly for a diagnostics company. There are currently no comments.
• What will the next solar cycle bring?
  - Nature 463(7280):414 (2010)
  Orbiting mission will probe the Sun's activity. Solar activity is on the rise.NASA/lMSAL The Sun is rousing from an unusually heavy slumber. On 19 January, the otherwise calm and quiet Sun erupted in a violent blast of light and energy — an M-class solar flare, the largest observed in nearly two years. Over the next 24 hours, four more M-class flares erupted from the same sunspot, each more powerful than the one before. It was a welcome bit of excitement for solar physicists, who have been languishing during the quietest period of solar activity in nearly a century. Sunspots, flares and the plasma-spewing eruptions known as coronal mass ejections typically wax and wane on an 11-year cycle, but the most recent solar cycle has lasted for 12.5 years. "A number of my colleagues were wondering if there would even be a new cycle," says solar physicist David Hathaway of NASA's Marshall Space Flight Center in Huntsville, Alabama. On 9 February, NASA plans to launch its Solar Dynamics Observatory (SDO), just in time to watch the Sun's activity. Using a suite of imaging instruments, the SDO will probe the inner workings of the Sun, including how material flowing within it helps to generate its magnetic field and how that energy is released. The findings could help researchers to improve their understanding of the fluctuations in solar activity that can, at their peak, scramble electricity grids and throw Global-Positioning-System devices off by dozens of metres. "The Sun is getting much more interesting to look at," says Frank Eparvier, a solar physicist at the University of Colorado at Boulder. "We really want to get the SDO up there to watch the rise to the next maximum." Eparvier is one of 13 scientists charged with combing through dozens of predictions and issuing the official prediction of the timing and strength of the upcoming solar cycle, cycle 24. In April 2009, the group reached a consensus that the solar maximum would arrive relatively late, in May 2013, and be less intense than average, with only 90 sunspots per day at its peak (see graphic). But there was a notable dissenter: Mausumi Dikpati at the National Center for Atmospheric Research in Boulder thinks that cycle 24 will have at least 150 sunspots at its maximum. The last solar cycle peaked at around 120 sunspots. Strength to strength Click for larger image The difference for cycle 24 boils down to the different methods used to predict solar activity. Historically, the most reliable prediction methods have been 'precursor' techniques that rely on the strength of the magnetic field during the previous minimum. A number of precursor models all suggest that the peak for solar cycle 24 will be small. But Dikpati uses a different method, a solar-dynamo model that incorporates theories of how material within the Sun travels from its poles toward the equator. She argues that the material can take decades, not a few years, to make this journey — meaning that the last maximum doesn't say much, if anything, about what the next one will be like. Dikpati says that her model has retrospectively predicted the past eight cycles with 96% accuracy. Those earlier cycles, however, were also used to calibrate the model, and the model has not been used yet to predict future activity. "The true test we want to see is to make a prediction before [the cycle] has actually happened," says Doug Biesecker of the National Oceanic and Atmospheric Administration's Space Environment Center in Boulder, Colorado. The predictions of other solar-dynamo models have differed from Dikpati's. ADVERTISEMENT The SDO may help to clear up the confusion by giving the deepest look yet at the flow fields inside the Sun. It will also measure the magnetic field at the surface, take high-resolution images of the corona and measure the Sun's extreme ultraviolet output. From an orbit offset from Earth's equator, the observatory will take images every 10 seconds for 5 years, giving astronomers their first near-continuous look at the Sun's activity. Currently astronomers only take one to two images a day, and they can only see the part of the Sun that faces Earth. 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.
• Aid fund faces cash crunch
  - Nature 463(7280):415 (2010)
  Does the Global Fund to Fight AIDS, Tuberculosis and Malaria risk becoming a victim of its own success? With demand for its programmes outstripping donor contributions, the fund will convene an informal retreat of board members next week to address a potential cash crisis. Unless sufficient extra money can be raised, the eight-year-old fund may be forced for the first time to reject otherwise-solid new proposals from recipient countries, and trim others. There are currently no comments.
• Correction
  - Nature 463(7280):415 (2010)
  The Editorial 'Self-inflicted damage' (Nature 463, 270; 2010) incorrectly stated that Rita Levi-Montalcini intends to appoint a new commissioner at the European Brain Research Institute in Rome. In fact, if her plans go ahead, the appointment would be made by the local prefecture. In addition, the Editorial spoke of Italy's "none-too-good scientific image". This was meant to refer to the nation's image problem in terms of reliability as a scientific partner; it was not intended to call into question Italy's scientific skills and ability. 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.
• Literature mining: Speed reading
  - Nature 463(7280):416 (2010)
  In 2002, when he began to make the transition from basic cell biology to research into Alzheimer's disease, Virgil Muresan found himself all but overwhelmed by the sheer volume of literature on the disease. He and his wife, Zoia, both now at the University of Medicine and Dentistry of New Jersey in Newark, were hoping to test an idea that they had developed about the formation of the protein plaques in the brains of people with Alzheimer's disease. There are currently no comments.
• Planetary science: A whiff of mystery on Mars
  - Nature 463(7280):420 (2010)
  For the past decade, NASA's mantra for exploring Mars has been to 'follow the water'. The agency based its aqueous obsession on the idea that finding evidence of past or present water would yield clues to whether life once graced the planet — or still exists there. There are currently no comments.
• Translational research: Talking up translation
  - Nature 463(7280):422 (2010)
  A short, laminated article has fallen off the wall of press cuttings outside Alan Ashworth's London office. It is an editorial published in 2000 by Britain's widely read and notoriously opinionated tabloid newspaper, The Sun — and it is praising geneticists who study cancer. There are currently no comments.
• Local priorities can be too parochial for biodiversity
  - Nature 463(7280):424 (2010)
  I cannot accept the provocative point made by R. J.
• Psychiatry: medicine benefits from cultural and personal insights
  - Nature 463(7280):424 (2010)
  Anthropology is a valuable component of the multidisciplinary research effort into psychiatric disorders that is recommended in your Editorial (Nature 463, 9; 2010).Since the 1920s, anthropologists have helped psychiatrists consider the cultural factors influencing their patients, and psychiatrists have helped anthropologists focus on the individual in their societal studies.
• Psychiatry: Brazil debates dismantling all mental hospitals
  - Nature 463(7280):424 (2010)
  Your Editorial on psychiatric disorders (Nature 463, 9; 2010) mentions the misplaced stigma often associated with them. In Brazil, there is strong opposition within certain social sectors to the idea of mental-health interventions.
• Mind the gap: future depends on sciences and humanities
  - Nature 463(7280):425 (2010)
  Why do we continue to undermine Earth's life-support system, on which our survival depends, despite a wealth of information documenting its deterioration? Your Editorial on the need for a more productive relationship between natural and social scientists is timely (Nature 462, 825–826; 2009
• Mind the gap: social sciences can reveal community needs
  - Nature 463(7280):425 (2010)
  The benefits you detail in your Editorial from collaboration between social and natural sciences (Nature 462, 825–826; 2009) can be extended to people like me.
• Safeguarding the integrity of protein archive
  - Nature 463(7280):425 (2010)
  Your News story 'Fraud rocks protein community' (Nature462, 970; 2009) discusses allegations that 12 Protein Data Bank (PDB) entries are based on fabricated data. Pending verdicts on these entries from the US Department of Health and Human Services Office for Research Integrity, we wish to clarify PDB policies and actions.
• Science friction as fantasy irritates religious sensibilities
  - Nature 463(7280):425 (2010)
  I was amazed to read the story 'Divine diseases' in your Futures science-fiction section (Nature 462, 1088; 2009). I am not a Catholic and I do not believe in transubstantiation, but this gratuitously offensive junk has no place in a serious scientific journal.
• Research on global sun block needed now
  - Nature 463(7280):426 (2010)
  Geoengineering studies of solar-radiation management should begin urgently, argue David W. Keith, Edward Parson and M. Granger Morgan — before a rogue state decides to act alone.
• On the shoulders of giants
  - Nature 463(7280):429 (2010)
  A volume of essays celebrating 350 years of Britain's Royal Society highlights the continuing gulf between science and the public, says John Gribbin.
• Brainy reads
  - Nature 463(7280):430 (2010)
  Some of our biggest decisions are made without conscious awareness, argues Washington Post columnist Shankar Vedantam in The Hidden Brain (Spiegel & Grau, 2010). Using powerful case studies, Vedantam examines with a light touch unconscious bias and sexism; why we seem to care more about animal welfare than genocide; and how decisions taken by those on the 88th and 89th floors of the World Trade Center's South Tower on 11 September 2001 determined whether they lived or died.
• Deciphering the printed word
  - Nature 463(7280):430 (2010)
  Reading is a vital portal to knowledge. Unique to humans, this evolutionarily recent invention intertwines language and vision in such a new way that years of education are needed to become fluent.
• Across the cultural divide
  - Nature 463(7280):431 (2010)
  The history of neuroaesthetics might be described as an epic war that has been fought between scientists and artists since the days of Freudian psychology and surrealism. Both sides — one hopeful, one fearful — posit that science might eventually explain away the arts.
• Tricks of the stage
  - Nature 463(7280):432 (2010)
  A restored imperial theatre in China reveals how Western techniques of visual perspective brought by the Jesuits were adopted by an eighteenth-century Chinese emperor, explains Martin Kemp.
• Biomechanics: Barefoot running strikes back
  - Nature 463(7280):433 (2010)
  Detailed analyses of foot kinematics and kinetics in barefoot and shod runners offer a refined understanding of bipedalism in human evolution. This research will also prompt fresh studies of running injuries.
• Immunology: The expanding TH2 universe
  - Nature 463(7280):434 (2010)
  TH2 growth factors, which are involved in allergy and in defence against parasites, are produced by many different cell types, including a newly identified population found in fat-associated lymph clusters in the abdomen.
• Organometallic chemistry: Carbon–carbon bonds get a break
  - Nature 463(7280):435 (2010)
  As a rule of thumb, carbon–carbon bonds are not easily broken. But a tungsten complex has been found to break a particularly strong carbon–carbon bond, opening up fresh opportunities for organic synthesis.
• 50 & 100 years ago
  - Nature 463(7280):436 (2010)
  In order to study the influence of the fat content of food on the occurrence of thrombosis in the arterial and venous system, a group of 133 hospital patients aged 65–90 years were treated with a diet in which butterfat, margarine and lard were replaced by vegetable oils (unhydrogenated corn oil and soybean oil) ... For comparison, a control group of the same size and composition who received an ordinary hospital diet containing about 80 gm. animal fats (including about 40 gm.
• Cell biology: Stability in times of stress
  - Nature 463(7280):436 (2010)
  Damaged lysosomes, the principal degradative organelles, can kill a cell. A stress-induced protein controls lysosome stability, providing a potential target to treat lysosome-related diseases and cancer.
• Carbon cycle: Degrees of climate feedback
  - Nature 463(7280):438 (2010)
  A probabilistic analysis of climate variation during the period AD 1050–1800 refines available estimates of the influence of temperature change on the concentration of carbon dioxide in the atmosphere.
• Fluid dynamics: Supersonic splash
  - Nature 463(7280):439 (2010)
  Throwing a coin into a wishing well might not bring you your heart's desire, but it could cause an astonishing physical effect — a supersonic jet of air. That's if you follow the instructions of Stephan Gekle and colleagues at the University of Twente in the Netherlands and the University of Seville in Spain.
• Biophysics: Joint effort bends membrane
  - Nature 463(7280):439 (2010)
  The curvature of cellular membranes is generated by proteins and lipids. A synthetic experimental system allows the interplay between protein- and lipid-generated bending mechanisms to be studied directly.
• Physics: Quantum computing
  - Nature 463(7280):441 (2010)
  The race is on to build a computer that exploits quantum mechanics. Such a machine could solve problems in physics, mathematics and cryptography that were once thought intractable, revolutionizing information technology and illuminating the foundations of physics. But when?
• Building a Cell
  - Nature 463(7280):445 (2010)
  All organisms, from bacteria to humans, face the daunting task of replicating, packaging and segregating up to two metres (about 6 × 109 base pairs) of DNA when each cell divides. This task is carried out up to a trillion times during the development of a human from a single fertilized cell. The strategy by which DNA is replicated is now well understood. But when it comes to packaging and segregating a genome, the mechanisms are only beginning to be understood and are often as variable as the organisms in which they are studied.
• Towards building a chromosome segregation machine
  - Nature 463(7280):446 (2010)
  All organisms, from bacteria to humans, face the daunting task of replicating, packaging and segregating up to two metres (about 6 × 109 base pairs) of DNA when each cell divides. This task is carried out up to a trillion times during the development of a human from a single fertilized cell. The strategy by which DNA is replicated is now well understood. But when it comes to packaging and segregating a genome, the mechanisms are only beginning to be understood and are often as variable as the organisms in which they are studied.
• Expansion of the eukaryotic proteome by alternative splicing
  - Nature 463(7280):457 (2010)
  The collection of components required to carry out the intricate processes involved in generating and maintaining a living, breathing and, sometimes, thinking organism is staggeringly complex. Where do all of the parts come from? Early estimates stated that about 100,000 genes would be required to make up a mammal; however, the actual number is less than one-quarter of that, barely four times the number of genes in budding yeast. It is now clear that the 'missing' information is in large part provided by alternative splicing, the process by which multiple different functional messenger RNAs, and therefore proteins, can be synthesized from a single gene.
• The endocytic matrix
  - Nature 463(7280):464 (2010)
  Endocytosis has long been thought of as simply a way for cells to internalize nutrients and membrane-associated molecules. But an explosive growth in knowledge has given a new dimension to our understanding of this process. It now seems that endocytosis is a master organizer of signalling circuits, with one of its main roles being the resolution of signals in space and time. Many of the functions of endocytosis that are emerging from recent research cannot yet be reconciled with the canonical view of intracellular trafficking but, instead, point to endocytosis being integrated at a deeper level in the cellular 'master plan' (the cellular network of signalling circuits that lie at the base of the cell's make-up). Deconvolution of this level, which we call the 'endocytic matrix', might uncover a fundamental aspect of how a cell is built.
• Chromatin remodelling during development
  - Nature 463(7280):474 (2010)
  New methods for the genome-wide analysis of chromatin are providing insight into its roles in development and their underlying mechanisms. Current studies indicate that chromatin is dynamic, with its structure and its histone modifications undergoing global changes during transitions in development and in response to extracellular cues. In addition to DNA methylation and histone modification, ATP-dependent enzymes that remodel chromatin are important controllers of chromatin structure and assembly, and are major contributors to the dynamic nature of chromatin. Evidence is emerging that these chromatin-remodelling enzymes have instructive and programmatic roles during development. Particularly intriguing are the findings that specialized assemblies of ATP-dependent remodellers are essential for establishing and maintaining pluripotent and multipotent states in cells.
• Cell mechanics and the cytoskeleton
  - Nature 463(7280):485 (2010)
  The ability of a eukaryotic cell to resist deformation, to transport intracellular cargo and to change shape during movement depends on the cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins. Recent work has demonstrated that both internal and external physical forces can act through the cytoskeleton to affect local mechanical properties and cellular behaviour. Attention is now focused on how cytoskeletal networks generate, transmit and respond to mechanical signals over both short and long timescales. An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.
• Systemic signals regulate ageing and rejuvenation of blood stem cell niches
  - Nature 463(7280):495 (2010)
  Ageing in multicellular organisms typically involves a progressive decline in cell replacement and repair processes, resulting in several physiological deficiencies, including inefficient muscle repair, reduced bone mass, and dysregulation of blood formation (haematopoiesis). Although defects in tissue-resident stem cells clearly contribute to these phenotypes, it is unclear to what extent they reflect stem cell intrinsic alterations or age-related changes in the stem cell supportive microenvironment, or niche. Here, using complementary in vivo and in vitro heterochronic models, we show that age-associated changes in stem cell supportive niche cells deregulate normal haematopoiesis by causing haematopoietic stem cell dysfunction. Furthermore, we find that age-dependent defects in niche cells are systemically regulated and can be reversed by exposure to a young circulation or by neutralization of the conserved longevity regulator, insulin-like growth factor-1, in the ma! rrow microenvironment. Together, these results show a new and critical role for local and systemic factors in signalling age-related haematopoietic decline, and highlight a new model in which blood-borne factors in aged animals act through local niche cells to induce age-dependent disruption of stem cell function.
• Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors
  - Nature 463(7280):501 (2010)
  In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr–Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr–Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr–Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr–Abl activity can be achieved with ! inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.
• Structure of a bacterial homologue of vitamin K epoxide reductase
  - Nature 463(7280):507 (2010)
  Vitamin K epoxide reductase (VKOR) generates vitamin K hydroquinone to sustain γ-carboxylation of many blood coagulation factors. Here, we report the 3.6 Å crystal structure of a bacterial homologue of VKOR from Synechococcus sp. The structure shows VKOR in complex with its naturally fused redox partner, a thioredoxin-like domain, and corresponds to an arrested state of electron transfer. The catalytic core of VKOR is a four transmembrane helix bundle that surrounds a quinone, connected through an additional transmembrane segment with the periplasmic thioredoxin-like domain. We propose a pathway for how VKOR uses electrons from cysteines of newly synthesized proteins to reduce a quinone, a mechanism confirmed by in vitro reconstitution of vitamin K-dependent disulphide bridge formation. Our results have implications for the mechanism of the mammalian VKOR and explain how mutations can cause resistance to the VKOR inhibitor warfarin, the most commonly used oral anti! coagulant.
• A relativistic type Ibc supernova without a detected γ-ray burst
  - Nature 463(7280):513 (2010)
  Long duration γ-ray bursts (GRBs) mark1 the explosive death of some massive stars and are a rare sub-class of type Ibc supernovae. They are distinguished by the production of an energetic and collimated relativistic outflow powered2 by a central engine (an accreting black hole or neutron star). Observationally, this outflow is manifested3 in the pulse of γ-rays and a long-lived radio afterglow. Until now, central-engine-driven supernovae have been discovered exclusively through their γ-ray emission, yet it is expected4 that a larger population goes undetected because of limited satellite sensitivity or beaming of the collimated emission away from our line of sight. In this framework, the recovery of undetected GRBs may be possible through radio searches5, 6 for type Ibc supernovae with relativistic outflows. Here we report the discovery of luminous radio emission from the seemingly ordinary type Ibc SN 2009bb, which requires a substantial relativistic outflow powere! d by a central engine. A comparison with our radio survey of type Ibc supernovae reveals that the fraction harbouring central engines is low, about one per cent, measured independently from, but consistent with, the inferred7 rate of nearby GRBs. Independently, a second mildly relativistic supernova has been reported8.
• A mildly relativistic radio jet from the otherwise normal type Ic supernova 2007gr
  - Nature 463(7280):516 (2010)
  The class of type Ic supernovae have drawn increasing attention since 1998 owing to their sparse association (only four so far) with long duration γ-ray bursts (GRBs)1, 2, 3, 4. Although both phenomena originate from the core collapse of a massive star, supernovae emit mostly at optical wavelengths, whereas GRBs emit mostly in soft γ-rays or hard X-rays. Though the GRB central engine generates ultra-relativistic jets, which beam the early emission into a narrow cone, no relativistic outflows have hitherto been found in type Ib/c supernovae explosions, despite theoretical expectations5, 6, 7 and searches8. Here we report radio (interferometric) observations that reveal a mildly relativistic expansion in a nearby type Ic supernova, SN 2007gr. Using two observational epochs 60 days apart, we detect expansion of the source and establish a conservative lower limit for the average apparent expansion velocity of 0.6c. Independently, a second mildly relativistic supernova ! has been reported9. Contrary to the radio data, optical observations10, 11, 12, 13 of SN 2007gr indicate a typical type Ic supernova with ejecta velocities ~6,000 km s-1, much lower than in GRB-associated supernovae. We conclude that in SN 2007gr a small fraction of the ejecta produced a low-energy mildly relativistic bipolar radio jet, while the bulk of the ejecta were slower and, as shown by optical spectropolarimetry14, mildly aspherical.
• Broken rotational symmetry in the pseudogap phase of a high-Tc superconductor
  - Nature 463(7280):519 (2010)
  The nature of the pseudogap phase is a central problem in the effort to understand the high-transition-temperature (high-Tc) copper oxide superconductors1. A fundamental question is what symmetries are broken when the pseudogap phase sets in, which occurs when the temperature decreases below a value T*. There is evidence from measurements of both polarized neutron diffraction2, 3 and the polar Kerr effect4 that time-reversal symmetry is broken, but at temperatures that differ significantly from one another. Broken rotational symmetry was detected from both resistivity measurements5 and inelastic neutron scattering6, 7, 8 at low doping, and from scanning tunnelling spectroscopy9, 10 at low temperature, but showed no clear relation to T*. Here we report the observation of a large in-plane anisotropy of the Nernst effect in YBa2Cu3Oy that sets in precisely at T* throughout the doping phase diagram. We show that the CuO chains of the orthorhombic lattice are not responsibl! e for this anisotropy, which is therefore an intrinsic property of the CuO2 planes. We conclude that the pseudogap phase is an electronic state that strongly breaks four-fold rotational symmetry. This narrows the range of possible states considerably, pointing to stripe or nematic order11, 12.
• Cleaving carbon–carbon bonds by inserting tungsten into unstrained aromatic rings
  - Nature 463(7280):523 (2010)
  The cleavage of C–H and C–C bonds by transition metal centres is of fundamental interest and plays an important role in the synthesis of complex organic molecules from petroleum feedstocks1, 2, 3, 4, 5, 6. But while there are many examples for the oxidative addition of C–H bonds to a metal centre, transformations that feature oxidative addition of C–C bonds are rare. The paucity of transformations that involve the cleavage of C–C rather than C–H bonds is usually attributed to kinetic factors arising from the greater steric hindrance and the directional nature of the spn hybrids that form the C–C bond, and to thermodynamic factors arising from the fact that M–C bonds are weaker than M–H bonds2, 3, 4, 5. Not surprisingly, therefore, most examples of C–C bond cleavage either avoid the kinetic limitations by using metal compounds in which the C–C bond is held in close proximity to the metal centre, or avoid the thermodynamic limitations by using organ! ic substrates in which the cleavage is accompanied by either a relief of strain energy or the formation of an aromatic system2, 3, 4, 5. Here, we show that a tungsten centre can be used to cleave a strong C–C bond that is a component of an unstrained 6-membered aromatic ring. The cleavage is enabled by the formation of an unusual chelating di(isocyanide) ligand, which suggests that other metal centres with suitable ancillary ligands could also accomplish the cleavage of strong C–C bonds of aromatic substrates and thereby provide new ways of functionalizing such molecules.
• Ensemble reconstruction constraints on the global carbon cycle sensitivity to climate
  - Nature 463(7280):527 (2010)
  The processes controlling the carbon flux and carbon storage of the atmosphere, ocean and terrestrial biosphere are temperature sensitive1, 2, 3, 4 and are likely to provide a positive feedback leading to amplified anthropogenic warming3. Owing to this feedback, at timescales ranging from interannual to the 20–100-kyr cycles of Earth's orbital variations1, 5, 6, 7, warming of the climate system causes a net release of CO2 into the atmosphere; this in turn amplifies warming. But the magnitude of the climate sensitivity of the global carbon cycle (termed γ), and thus of its positive feedback strength, is under debate, giving rise to large uncertainties in global warming projections8, 9. Here we quantify the median γ as 7.7 p.p.m.v. CO2 per °C warming, with a likely range of 1.7–21.4 p.p.m.v. CO2 per °C. Sensitivity experiments exclude significant influence of pre-industrial land-use change on these estimates. Our results, based on the coupling of a probabilis! tic approach with an ensemble of proxy-based temperature reconstructions and pre-industrial CO2 data from three ice cores, provide robust constraints for γ on the policy-relevant multi-decadal to centennial timescales. By using an ensemble of >200,000 members, quantification of γ is not only improved, but also likelihoods can be assigned, thereby providing a benchmark for future model simulations. Although uncertainties do not at present allow exclusion of γ calculated from any of ten coupled carbon–climate models, we find that γ is about twice as likely to fall in the lowermost than in the uppermost quartile of their range. Our results are incompatibly lower (P < 0.05) than recent pre-industrial empirical estimates of ~40 p.p.m.v. CO2 per °C (refs 6, 7), and correspondingly suggest ~80% less potential amplification of ongoing global warming.
• Foot strike patterns and collision forces in habitually barefoot versus shod runners
  - Nature 463(7280):531 (2010)
  Humans have engaged in endurance running for millions of years1, but the modern running shoe was not invented until the 1970s. For most of human evolutionary history, runners were either barefoot or wore minimal footwear such as sandals or moccasins with smaller heels and little cushioning relative to modern running shoes. We wondered how runners coped with the impact caused by the foot colliding with the ground before the invention of the modern shoe. Here we show that habitually barefoot endurance runners often land on the fore-foot (fore-foot strike) before bringing down the heel, but they sometimes land with a flat foot (mid-foot strike) or, less often, on the heel (rear-foot strike). In contrast, habitually shod runners mostly rear-foot strike, facilitated by the elevated and cushioned heel of the modern running shoe. Kinematic and kinetic analyses show that even on hard surfaces, barefoot runners who fore-foot strike generate smaller collision forces than shod re! ar-foot strikers. This difference results primarily from a more plantarflexed foot at landing and more ankle compliance during impact, decreasing the effective mass of the body that collides with the ground. Fore-foot- and mid-foot-strike gaits were probably more common when humans ran barefoot or in minimal shoes, and may protect the feet and lower limbs from some of the impact-related injuries now experienced by a high percentage of runners.
• Chimpanzee and human Y chromosomes are remarkably divergent in structure and gene content
  - Nature 463(7280):536 (2010)
  The human Y chromosome began to evolve from an autosome hundreds of millions of years ago, acquiring a sex-determining function and undergoing a series of inversions that suppressed crossing over with the X chromosome1, 2. Little is known about the recent evolution of the Y chromosome because only the human Y chromosome has been fully sequenced. Prevailing theories hold that Y chromosomes evolve by gene loss, the pace of which slows over time, eventually leading to a paucity of genes, and stasis3, 4. These theories have been buttressed by partial sequence data from newly emergent plant and animal Y chromosomes5, 6, 7, 8, but they have not been tested in older, highly evolved Y chromosomes such as that of humans. Here we finished sequencing of the male-specific region of the Y chromosome (MSY) in our closest living relative, the chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. By comparing the MSYs of the two species we show ! that they differ radically in sequence structure and gene content, indicating rapid evolution during the past 6 million years. The chimpanzee MSY contains twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. We suggest that the extraordinary divergence of the chimpanzee and human MSYs was driven by four synergistic factors: the prominent role of the MSY in sperm production, 'genetic hitchhiking' effects in the absence of meiotic crossing over, frequent ectopic recombination within the MSY, and species differences in mating behaviour. Although genetic decay may be the principal dynamic in the evolution of newly emergent Y chromosomes, wholesale renovation is the paramount theme in the continuing evolution of chimpanzee, human and perhaps other older MSYs.
• Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells
  Moro K Yamada T Tanabe M Takeuchi T Ikawa T Kawamoto H Furusawa JI Ohtani M Fujii H Koyasu S - Nature 463(7280):540 (2010)
  Innate immune responses are important in combating various microbes during the early phases of infection. Natural killer (NK) cells are innate lymphocytes that, unlike T and B lymphocytes, do not express antigen receptors but rapidly exhibit cytotoxic activities against virus-infected cells and produce various cytokines1, 2. Here we report a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity. These cells do not express lineage (Lin) markers but do express c-Kit, Sca-1 (also known as Ly6a), IL7R and IL33R. Similar lymphoid clusters were found in both human and mouse mesentery and we term this tissue 'FALC' (fat-associated lymphoid cluster). FALC Lin-c-Kit+Sca-1+ cells are distinct from lymphoid progenitors3 and lymphoid tissue inducer cells4. These cells proliferate in response to IL2 and produce large amounts of TH2 cytokines such as IL5, IL6 and IL13. IL5 and IL6 regulate B-cell antibody pro! duction and self-renewal of B1 cells5, 6, 7. Indeed, FALC Lin-c-Kit+Sca-1+ cells support the self-renewal of B1 cells and enhance IgA production. IL5 and IL13 mediate allergic inflammation and protection against helminth infection8, 9. After helminth infection and in response to IL33, FALC Lin-c-Kit+Sca-1+ cells produce large amounts of IL13, which leads to goblet cell hyperplasia—a critical step for helminth expulsion. In mice devoid of FALC Lin-c-Kit+Sca-1+ cells, such goblet cell hyperplasia was not induced. Thus, FALC Lin-c-Kit+Sca-1+ cells are TH2-type innate lymphocytes, and we propose that these cells be called 'natural helper cells'.
• Interaction between RasV12 and scribbled clones induces tumour growth and invasion
  - Nature 463(7280):545 (2010)
  Human tumours have a large degree of cellular and genetic heterogeneity1. Complex cell interactions in the tumour and its microenvironment are thought to have an important role in tumorigenesis and cancer progression2. Furthermore, cooperation between oncogenic genetic lesions is required for tumour development3; however, it is not known how cell interactions contribute to oncogenic cooperation. The genetic techniques available in the fruitfly Drosophila melanogaster allow analysis of the behaviour of cells with distinct mutations4, making this the ideal model organism with which to study cell interactions and oncogenic cooperation. In Drosophila eye-antennal discs, cooperation between the oncogenic protein RasV12 (ref. 5) and loss-of-function mutations in the conserved tumour suppressor scribbled (scrib)6, 7 gives rise to metastatic tumours that display many characteristics observed in human cancers8, 9, 10, 11. Here we show that clones of cells bearing different muta! tions can cooperate to promote tumour growth and invasion in Drosophila. We found that the RasV12 and scrib- mutations can also cause tumours when they affect different adjacent epithelial cells. We show that this interaction between RasV12 and scrib- clones involves JNK signalling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines, a compensatory growth mechanism for tissue homeostasis. The development of RasV12 tumours can also be triggered by tissue damage, a stress condition that activates JNK signalling. Given the conservation of the pathways examined here, similar cooperative mechanisms could have a role in the development of human cancers.
• Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology
  - Nature 463(7280):549 (2010)
  Heat shock protein 70 (Hsp70) is an evolutionarily highly conserved molecular chaperone that promotes the survival of stressed cells by inhibiting lysosomal membrane permeabilization1, 2, 3, 4, 5, a hallmark of stress-induced cell death6, 7, 8, 9, 10. Clues to its molecular mechanism of action may lay in the recently reported stress- and cancer-associated translocation of a small portion of Hsp70 to the lysosomal compartment1, 11. Here we show that Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential co-factor for lysosomal sphingomyelin metabolism12, 13, 14. In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of acid sphingomyelinase (ASM). The inhibition of the Hsp70–BMP interaction by BMP antibodies or a point mutation in Hsp70 (Trp90Phe), as well as the pharmacological and genetic inhibition of ASM, effectively re! vert the Hsp70-mediated stabilization of lysosomes. Notably, the reduced ASM activity in cells from patients with Niemann–Pick disease (NPD) A and B—severe lysosomal storage disorders caused by mutations in the sphingomyelin phosphodiesterase 1 gene (SMPD1) encoding for ASM15—is also associated with a marked decrease in lysosomal stability, and this phenotype can be effectively corrected by treatment with recombinant Hsp70. Taken together, these data open exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway.
• A role for the elongator complex in zygotic paternal genome demethylation
  - Nature 463(7280):554 (2010)
  The life cycle of mammals begins when a sperm enters an egg. Immediately after fertilization, both the maternal and paternal genomes undergo dramatic reprogramming to prepare for the transition from germ cell to somatic cell transcription programs1. One of the molecular events that takes place during this transition is the demethylation of the paternal genome2, 3. Despite extensive efforts, the factors responsible for paternal DNA demethylation have not been identified4. To search for such factors, we developed a live cell imaging system that allows us to monitor the paternal DNA methylation state in zygotes. Through short-interfering-RNA-mediated knockdown in mouse zygotes, we identified Elp3 (also called KAT9), a component of the elongator complex5, to be important for paternal DNA demethylation. We demonstrate that knockdown of Elp3 impairs paternal DNA demethylation as indicated by reporter binding, immunostaining and bisulphite sequencing. Similar results were als! o obtained when other elongator components, Elp1 and Elp4, were knocked down. Importantly, injection of messenger RNA encoding the Elp3 radical SAM domain mutant, but not the HAT domain mutant, into MII oocytes before fertilization also impaired paternal DNA demethylation, indicating that the SAM radical domain is involved in the demethylation process. Our study not only establishes a critical role for the elongator complex in zygotic paternal genome demethylation, but also indicates that the demethylation process may be mediated through a reaction that requires an intact radical SAM domain.
• Microbial production of fatty-acid-derived fuels and chemicals from plant biomass
  - Nature 463(7280):559 (2010)
  Increasing energy costs and environmental concerns have emphasized the need to produce sustainable renewable fuels and chemicals1. Major efforts to this end are focused on the microbial production of high-energy fuels by cost-effective 'consolidated bioprocesses'2. Fatty acids are composed of long alkyl chains and represent nature's 'petroleum', being a primary metabolite used by cells for both chemical and energy storage functions. These energy-rich molecules are today isolated from plant and animal oils for a diverse set of products ranging from fuels to oleochemicals. A more scalable, controllable and economic route to this important class of chemicals would be through the microbial conversion of renewable feedstocks, such as biomass-derived carbohydrates. Here we demonstrate the engineering of Escherichia coli to produce structurally tailored fatty esters (biodiesel), fatty alcohols, and waxes directly from simple sugars. Furthermore, we show engineering ! of the biodiesel-producing cells to express hemicellulases, a step towards producing these compounds directly from hemicellulose, a major component of plant-derived biomass.
• DNMT1 maintains progenitor function in self-renewing somatic tissue
  Sen GL Reuter JA Webster DE Zhu L Khavari PA - Nature 463(7280):563 (2010)
  Progenitor cells maintain self-renewing tissues throughout life by sustaining their capacity for proliferation while suppressing cell cycle exit and terminal differentiation1, 2. DNA methylation3, 4, 5 provides a potential epigenetic mechanism for the cellular memory needed to preserve the somatic progenitor state through repeated cell divisions. DNA methyltransferase 1 (DNMT1)6, 7 maintains DNA methylation patterns after cellular replication. Although dispensable for embryonic stem cell maintenance8, the role for DNMT1 in maintaining the progenitor state in constantly replenished somatic tissues, such as mammalian epidermis, is unclear. Here we show that DNMT1 is essential for epidermal progenitor cell function. DNMT1 protein was found enriched in undifferentiated cells, where it was required to retain proliferative stamina and suppress differentiation. In tissue, DNMT1 depletion led to exit from the progenitor cell compartment, premature differentiation and eventual ! tissue loss. Genome-wide analysis showed that a significant portion of epidermal differentiation gene promoters were methylated in self-renewing conditions but were subsequently demethylated during differentiation. Furthermore, UHRF1 (refs 9, 10), a component of the DNA methylation machinery that targets DNMT1 to hemi-methylated DNA, is also necessary to suppress premature differentiation and sustain proliferation. In contrast, Gadd45A11, 12 and B13, which promote active DNA demethylation, are required for full epidermal differentiation gene induction. These data demonstrate that proteins involved in the dynamic regulation of DNA methylation patterns are required for progenitor maintenance and self-renewal in mammalian somatic tissue.
• Self versus non-self discrimination during CRISPR RNA-directed immunity
  - Nature 463(7280):568 (2010)
  All immune systems must distinguish self from non-self to repel invaders without inducing autoimmunity. Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci protect bacteria and archaea from invasion by phage and plasmid DNA through a genetic interference pathway1, 2, 3, 4, 5, 6, 7, 8, 9. CRISPR loci are present in ~40% and ~90% of sequenced bacterial and archaeal genomes, respectively10, and evolve rapidly, acquiring new spacer sequences to adapt to highly dynamic viral populations1, 11, 12, 13. Immunity requires a sequence match between the invasive DNA and the spacers that lie between CRISPR repeats1, 2, 3, 4, 5, 6, 7, 8, 9. Each cluster is genetically linked to a subset of the cas (CRISPR-associated) genes14, 15, 16 that collectively encode >40 families of proteins involved in adaptation and interference. CRISPR loci encode small CRISPR RNAs (crRNAs) that contain a full spacer flanked by partial repeat sequences2, 17, 18, 19. CrRNA spacers are t! hought to identify targets by direct Watson–Crick pairing with invasive 'protospacer' DNA2, 3, but how they avoid targeting the spacer DNA within the encoding CRISPR locus itself is unknown. Here we have defined the mechanism of CRISPR self/non-self discrimination. In Staphylococcus epidermidis, target/crRNA mismatches at specific positions outside of the spacer sequence license foreign DNA for interference, whereas extended pairing between crRNA and CRISPR DNA repeats prevents autoimmunity. Hence, this CRISPR system uses the base-pairing potential of crRNAs not only to specify a target, but also to spare the bacterial chromosome from interference. Differential complementarity outside of the spacer sequence is a built-in feature of all CRISPR systems, indicating that this mechanism is a broadly applicable solution to the self/non-self dilemma that confronts all immune pathways.
• Quinquereme of Nineveh
  - Nature 463(7280):578 (2010)
  The perils of long-haul travel.