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Sun Apr 24 04:36:28 EDT 2011
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Accidents in waiting - Every researcher and institution should question their own attitudes to safety in the lab after the death of an undergraduate student in a Yale University workshop.

Fix the PhD - No longer a guaranteed ticket to an academic career, the PhD system needs a serious rethink.

Home truths - A new report offers useful insight into the continuing stalemate over global warming.

Reform the PhD system or close it down - There are too many doctoral programmes, producing too many PhDs for the job market. Shut some and change the rest, says Mark C. Taylor.

Ecology: Jonah and the waterfowl - Tiny sea snails can survive a voyage through a duck's gizzard — where prey are typically crushed to death — only a little the worse for wear.Gerhard Cadée at the Royal Netherlands Institute for Sea Research in Texel sifted through the faeces of shelducks,

Astronomy: Sharper cosmic pencils - In order to look back in time, astronomers peer deep into a narrow 'pencil beam' of space. These narrow surveys can be easily confounded by variations in the density of matter on scales larger than the pencil beam.Benjamin Moster, then at the Max Planck

Virology: Stubborn virus grows in sinus - Five years after its discovery, human rhinovirus C, a cold-causing virus that is associated with acute respiratory illness in children, has finally been cultured. This is the first step towards finding the virus's infection mechanisms, as well as possible antiviral targets.Yury Bochkov of the

Stem cells: New ways to change fates - Induced pluripotent stem cells (iPSCs) hold enormous promise for regenerative medicine: they have the potential to develop into cells of any type, just as embryonic stem cells do, but do not require the controversial use of human embryos. Until now, the most efficient way to

Optical Physics: A liquid of photons - For decades, physicists have mused over the theoretical properties of Luttinger liquids, strange one-dimensional quantum states in which charge and magnetic spin of particles are predicted to decouple and move at different speeds.Dimitris Angelakis at the Technical University of Crete, Greece, and his colleagues

Mechanics: A stable, riderless bicycle - A riderless bicycle can travel for some distance without falling — an ability generally assumed to be due to the gyroscopic forces of the spinning front wheel keeping it upright. But this is not the whole story, according to a paper by Andy Ruina of

Behaviour: Diversity beats ability - Can you guess how many marbles are in a jar? Maybe you are a savant or maybe not; either way, odds are that, between them, a group of people will beat your guess.Stefan Krause at the L�beck University of Applied Sciences in Germany and

Cancer Biology: Laying siege to cancer - Tumours can be shrunk by inhibiting a naturally occurring transcription factor called Myc to make the tumour microenvironment inhospitable to invasive cells.Gerard Evan, now at the University of Cambridge, UK, and his team tested the effects of Myc suppression in a mouse model of

Climate Change: Sea ice penguin theory sinks - As sea ice has declined off the West Antarctic Peninsula, scientists expected to see declines in ice-dwelling Ad�lie penguins (pictured left) and increases in chinstrap penguins (right), which forage in ice-free waters. However, Wayne Trivelpiece and his colleagues at the US

Neuroscience: Sleep deprivation: a risky business - What do stock traders, doctors and soldiers have in common? Each often needs to make important decisions on little sleep.Michael Chee of the Duke-NUS Graduate Medical School in Singapore and his colleagues used brain imaging to study how sleep deprivation affects decision-making. They scanned

Seven days: 21 April 2011 - The week in science

US budget a taste of battles to come - Deal leaves science agencies with less but avoids deep cuts.

Canadian research shift makes waves - Agency's focus on industry-driven projects raises concerns that basic science will suffer.

A death in the lab - Fatality adds further momentum to calls for a shake-up in academic safety culture.

Tumour biology: Cancer theory faces doubts - A leading explanation for how disease migrates falls short on clinical evidence.

Nuclear safety chief calls for reform - Laurent Stricker says Japan's nuclear disaster should mark a turning point for the industry.

Education: The PhD factory - The world is producing more PhDs than ever before. Is it time to stop?

Education: Rethinking PhDs - Fix it, overhaul it or skip it completely — institutions and individuals are taking innovative approaches to postgraduate science training.

Seven ages of the PhD - Scientists share memories of doing doctorates in different decades, disciplines and locations, from the hunt for the structure of DNA to deciphering the human genome.

The art of conservation - As the World Wide Fund for Nature (WWF) turns 50, Henry Nicholls traces how the evolution of conservation practice has been echoed in the various incarnations of WWF's iconic pandas, and other conservation logos.

Conservation: Bringing back wildlife - A scholarly history of the WWF highlights the gap between advocacy and action, finds Nancy Lee Nash.

Books in brief - Energy policy has failed, according to law professor Michael Graetz. Pulling no punches, he argues that we must overcome the delusion we've lived with for 40 years that power is plentiful and cheap. By accepting inappropriate pricing of gas and oil, and being unwilling to

Climate change: A dose of reality - Tony McMichael welcomes an overview of an under-recognized climate issue: the threat to human health.

Art: Grime and punishment - Daniel Cressey finds there is more to dirt than disease at a London exhibition.

Q&A: Animal distractions - Isabella Rossellini, star of films including Blue Velvet (1986) and Big Night (1996), has made a series of short films on the mating rituals of insects and sea creatures. As her latest humorous biopic debuts in the United States, Rossellini explains why she is fascinated by animals.

Doing the maths on the green economy - In their 21 February report Towards a Green Economy, the United Nations Environment Programme (UNEP) claims that “a green economy grows faster than a [conventional] brown economy, while maintaining and restoring natural capital”. We contend that this claim is founded on flawed assumptions.First,

Academia resists clean-up in Romania - A law to reform Romania's education system, approved in February (Nature469, 142–143; 10.1038/469142a 2011), is already floundering. University staff seem willing to compromise their academic standards when it comes to political matters.The law bans members of parliament

Science failed to self-regulate - As initiators of the open letter that contributed to the resignation of the German defence minister Karl-Theodor zu Guttenberg after allegations of scientific misconduct (Nature471, 135–136; 10.1038/471135b2011), we find the reaction of the scientific community disappointing.Only

Fund biodiversity collections - Universities are crucial for holding specimen collections in megabiodiverse, developing regions such as Brazil (see Nature471, 164–165; 2011). Only local institutions can gather information with the necessary resolution to answer biological questions at a regional scale. But such collections

Jürg Tschopp (1951–2011) - Immunologist whose discoveries transformed patients' lives.

Start-ups: In search of venture capital - To secure elusive funding, entrepreneurs must understand the financial landscape and the motivations of investing firms.

What is a PhD really worth? - To secure elusive funding, entrepreneurs must understand the financial landscape and the motivations of investing firms.

Test of faith - The heat is on.

Corrections - The news story 'China faces up to 'terrible' state of its ecosystems' (Nature 471, 19; 2011) stated that more than 25% of China's grasslands have been lost in the past decade. The percentage should have been 2.5%.The Editorial 'Universal truths' (

Correction - In the Comment article 'NASA: what now?' (Nature472, 27–29; 2011), the picture of the space shuttle Challenger disaster in 1986 was wrongly identified as that of Columbia in 2003.

Developmental biology: Remarkable role for the placenta - The placenta does not only act as the essential link between the developing embryo and its mother. Unexpectedly, it is also a source of serotonin — a neurotransmitter that is crucial for embryonic brain development. See Letter p.347

Materials chemistry: Spot-on healing - Rubbery polymers have been made in which damage is healed by exposure to light. The healing mechanism allows localized, on-demand repair, and might help to extend the lifetimes of materials for many applications. See Letter p.334

Evolutionary biology: Light sense - Evidence that a larval brachiopod has ciliary photoreceptors that are directionally selective, and therefore may function as eyes, bears on an enduring puzzle about photoreceptor evolution in animals.

Atomic physics: A route to quantum magnetism - The trend towards using ultracold atoms as simulators of condensed-matter and many-body phenomena is gaining momentum. These systems can now be used to simulate quantum magnetism. See Article p.307

Cancer: Macrophages limit chemotherapy - A major hurdle to successful cancer treatment is tumour resistance to chemotherapy. White blood cells called macrophages often infiltrate tumours in large numbers, and now appear to promote tumour chemoresistance.

50 & 100 years ago - 50 Years AgoIn Nature of October 12, 1957 ... we were glad and proud to congratulate the scientists and technologists of the U.S.S.R. on the successful launching of the first artificial Earth satellite (Sputnik I). Less than a month afterwards ...

Electronics: Power surfing on waves - Wavy strips of piezoelectric materials on stretchable substrates can both withstand larger applied mechanical strain without cracking and harvest energy more efficiently than their flat counterparts.

Immunology: TRIM5 does double duty - TRIM5 proteins limit retroviral infection by targeting the viral coat. It now seems that these proteins can also serve as pattern-recognition receptors, which initiate cellular innate immune responses. See Letter p.361

Quantum simulation of antiferromagnetic spin chains in an optical lattice - Understanding exotic forms of magnetism in quantum mechanical systems is a central goal of modern condensed matter physics, with implications for systems ranging from high-temperature superconductors to spintronic devices. Simulating magnetic materials in the vicinity of a quantum phase transition is computationally intractable on classical

Catecholamine receptor polymorphisms affect decision-making in C. elegans - Innate behaviours are flexible: they change rapidly in response to transient environmental conditions, and are modified slowly by changes in the genome. A classical flexible behaviour is the exploration–exploitation decision, which describes the time at which foraging animals choose to abandon a depleting food supply.

Caspase signalling controls microglia activation and neurotoxicity - Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell

Crystal structure of inhibitor of κB kinase β - Inhibitor of κB (IκB) kinase (IKK) phosphorylates IκB proteins, leading to their degradation and the liberation of nuclear factor κB for gene transcription. Here we report the crystal structure of IKKβ in complex with an inhibitor, at a resolution of 3.6 Å. The structure reveals a

The auroral footprint of Enceladus on Saturn - Although there are substantial differences between the magnetospheres of Jupiter and Saturn, it has been suggested that cryovolcanic activity at Enceladus could lead to electrodynamic coupling between Enceladus and Saturn like that which links Jupiter with Io, Europa and Ganymede. Powerful field-aligned electron beams associated with the Io–Jupiter coupling, for example, create an auroral footprint in Jupiter’s ionosphere. Auroral ultraviolet emission associated with Enceladus–Saturn coupling is anticipated to be just a few tenths of a kilorayleigh (ref. 12), about an order of magnitude dimmer than Io’s footprint and below the observable threshold, consistent with its non-detection. Here we report the detection of magnetic-field-aligned ion and electron beams (offset several moon radii downstream from Enceladus) with sufficient power to stimulate detectable aurora, and the subsequent discovery of Enceladus-associated aurora in a few per cent of the scans of the moon’s footprint. The footprint varies in emission magnitude more than can plausibly be explained by changes in magnetospheric parameters—and as such is probably indicative of variable plume activity.

Optically healable supramolecular polymers - Polymers with the ability to repair themselves after sustaining damage could extend the lifetimes of materials used in many applications. Most approaches to healable materials require heating the damaged area. Here we present metallosupramolecular polymers that can be mended through exposure to light. They consist of telechelic, rubbery, low-molecular-mass polymers with ligand end groups that are non-covalently linked through metal-ion binding. On exposure to ultraviolet light, the metal–ligand motifs are electronically excited and the absorbed energy is converted into heat. This causes temporary disengagement of the metal–ligand motifs and a concomitant reversible decrease in the polymers’ molecular mass and viscosity, thereby allowing quick and efficient defect healing. Light can be applied locally to a damage site, so objects can in principle be healed under load. We anticipate that this approach to healable materials, based on supramolecular polymers and a light–heat conversion step, can be applied to a wide range of supramolecular materials that use different chemistries.

Thermal history of Mars inferred from orbital geochemistry of volcanic provinces - Reconstruction of the geological history of Mars has been the focus of considerable attention over the past four decades, with important discoveries being made about variations in surface conditions. However, despite a significant increase in the amount of data related to the morphology, mineralogy and chemistry of the martian surface, there is no clear global picture of how magmatism has evolved over time and how these changes relate to the internal workings and thermal evolution of the planet. Here we present geochemical data derived from the Gamma Ray Spectrometer on board NASA’s Mars Odyssey spacecraft, focusing on twelve major volcanic provinces of variable age. Our analysis reveals clear trends in composition that are found to be consistent with varying degrees of melting of the martian mantle. There is evidence for thickening of the lithosphere (17–25 km Gyr−1) associated with a decrease in mantle potential temperature over time (30–40 K Gyr−1). Our inferred thermal history of Mars, unlike that of the Earth, is consistent with simple models of mantle convection.

Metabolic trade-offs and the maintenance of the fittest and the flattest - How is diversity maintained? Environmental heterogeneity is considered to be important, yet diversity in seemingly homogeneous environments is nonetheless observed. This, it is assumed, must either be owing to weak selection, mutational input or a fitness advantage to genotypes when rare. Here we demonstrate the possibility of a new general mechanism of stable diversity maintenance, one that stems from metabolic and physiological trade-offs. The model requires that such trade-offs translate into a fitness landscape in which the most fit has unfit near-mutational neighbours, and a lower fitness peak also exists that is more mutationally robust. The ‘survival of the fittest’ applies at low mutation rates, giving way to ‘survival of the flattest’ at high mutation rates. However, as a consequence of quasispecies-level negative frequency-dependent selection and differences in mutational robustness we observe a transition zone in which both fittest and flattest coexist. Although diversity maintenance is possible for simple organisms in simple environments, the more trade-offs there are, the wider the maintenance zone becomes. The principle may be applied to lineages within a species or species within a community, potentially explaining why competitive exclusion need not be observed in homogeneous environments. This principle predicts the enigmatic richness of metabolic strategies in clonal bacteria and questions the safety of lethal mutagenesis as an antimicrobial treatment.

A transient placental source of serotonin for the fetal forebrain - Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal–fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1−/− (also called Fev) mice in which most dorsal raphe neurons lack 5-HT. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal–placental–fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.

Neuronal activity is required for the development of specific cortical interneuron subtypes - Electrical activity has been shown to regulate development in a variety of species and in various structures, including the retina, spinal cord and cortex. Within the mammalian cortex specifically, the development of dendrites and commissural axons in pyramidal cells is activity-dependent. However, little is known about the developmental role of activity in the other major cortical population of neurons, the GABA-producing interneurons. These neurons are morphologically and functionally heterogeneous and efforts over the past decade have focused on determining the mechanisms that contribute to this diversity. It was recently discovered that 30% of all cortical interneurons arise from a relatively novel source within the ventral telencephalon, the caudal ganglionic eminence (CGE). Owing to their late birth date, these interneurons populate the cortex only after the majority of other interneurons and pyramidal cells are already in place and have started to functionally integrate. Here we demonstrate in mice that for CGE-derived reelin (Re)-positive and calretinin (Cr)-positive (but not vasoactive intestinal peptide (VIP)-positive) interneurons, activity is essential before postnatal day 3 for correct migration, and that after postnatal day 3, glutamate-mediated activity controls the development of their axons and dendrites. Furthermore, we show that the engulfment and cell motility 1 gene (Elmo1), a target of the transcription factor distal-less homeobox 1 (Dlx1), is selectively expressed in Re+ and Cr+ interneurons and is both necessary and sufficient for activity-dependent interneuron migration. Our findings reveal a selective requirement for activity in shaping the cortical integration of specific neuronal subtypes.

Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration - Coordinated migration of neurons in the developing and adult brain is essential for its proper function. The secreted glycoprotein Reelin (also known as RELN) guides migration of neurons by binding to two lipoprotein receptors, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2, also known as LRP8). Loss of Reelin function in humans results in the severe developmental disorder lissencephaly and it has also been associated with other neurological disorders such as epilepsy, schizophrenia and Alzheimer’s disease. The molecular mechanisms by which Reelin activates its receptors and controls cellular functions are largely unknown. Here we show that the neuronal guidance cues ephrin B proteins are essential for Reelin signalling during the development of laminated structures in the brain. We show that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln+/−; Efnb3−/− or Reln+/−; Efnb2−/−) and triple ephrin B1, B2, B3 knockouts show neuronal migration defects that recapitulate the ones observed in the neocortex, hippocampus and cerebellum of the reeler mouse. Mechanistically, we show that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1 which is necessary for Reelin signalling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Together, our results identify ephrin Bs as essential components of the Reelin receptor/signalling pathway to control neuronal migration during the development of the nervous system.

TRIM5 is an innate immune sensor for the retrovirus capsid lattice - TRIM5 is a RING domain-E3 ubiquitin ligase that restricts infection by human immunodeficiency virus (HIV)-1 and other retroviruses immediately following virus invasion of the target cell cytoplasm. Antiviral potency correlates with TRIM5 avidity for the retrovirion capsid lattice and several reports indicate that TRIM5 has a role in signal transduction, but the precise mechanism of restriction is unknown. Here we demonstrate that TRIM5 promotes innate immune signalling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric, ubiquitin-conjugating enzyme UBC13–UEV1A (also known as UBE2N–UBE2V1), TRIM5 catalyses the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (also known as MAP3K7) kinase complex and stimulate AP-1 and NFκB signalling. Interaction with the HIV-1 capsid lattice greatly enhances the UBC13–UEV1A-dependent E3 activity of TRIM5 and challenge with retroviruses induces the transcription of AP-1 and NF-κB-dependent factors with a magnitude that tracks with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13–UEV1A contribute to capsid-specific restriction by TRIM5. Thus, the retroviral restriction factor TRIM5 has two additional activities that are linked to restriction: it constitutively promotes innate immune signalling and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.

A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK - In metazoans, the Ras–Raf–MEK (mitogen-activated protein-kinase kinase)–ERK (extracellular signal-regulated kinase) signalling pathway relays extracellular stimuli to elicit changes in cellular function and gene expression. Aberrant activation of this pathway through oncogenic mutations is responsible for a large proportion of human cancer. Kinase suppressor of Ras (KSR) functions as an essential scaffolding protein to coordinate the assembly of Raf–MEK–ERK complexes. Here we integrate structural and biochemical studies to understand how KSR promotes stimulatory Raf phosphorylation of MEK (refs 6, 7). We show, from the crystal structure of the kinase domain of human KSR2 (KSR2(KD)) in complex with rabbit MEK1, that interactions between KSR2(KD) and MEK1 are mediated by their respective activation segments and C-lobe αG helices. Analogous to BRAF (refs 8, 9), KSR2 self-associates through a side-to-side interface involving Arg 718, a residue identified in a genetic screen as a suppressor of Ras signalling. ATP is bound to the KSR2(KD) catalytic site, and we demonstrate KSR2 kinase activity towards MEK1 by in vitro assays and chemical genetics. In the KSR2(KD)–MEK1 complex, the activation segments of both kinases are mutually constrained, and KSR2 adopts an inactive conformation. BRAF allosterically stimulates the kinase activity of KSR2, which is dependent on formation of a side-to-side KSR2–BRAF heterodimer. Furthermore, KSR2–BRAF heterodimerization results in an increase of BRAF-induced MEK phosphorylation via the KSR2-mediated relay of a signal from BRAF to release the activation segment of MEK for phosphorylation. We propose that KSR interacts with a regulatory Raf molecule in cis to induce a conformational switch of MEK, facilitating MEK’s phosphorylation by a separate catalytic Raf molecule in trans.

Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development - X-chromosome inactivation (XCI) in female mammals allows dosage compensation for X-linked gene products between the sexes. The developmental regulation of this process has been extensively investigated in mice, where the X chromosome of paternal origin (Xp) is silenced during early embryogenesis owing to imprinted expression of the regulatory RNA, Xist (X-inactive specific transcript). Paternal XCI is reversed in the inner cell mass of the blastocyst and random XCI subsequently occurs in epiblast cells. Here we show that other eutherian mammals have very different strategies for initiating XCI. In rabbits and humans, the Xist homologue is not subject to imprinting and XCI begins later than in mice. Furthermore, Xist is upregulated on both X chromosomes in a high proportion of rabbit and human embryo cells, even in the inner cell mass. In rabbits, this triggers XCI on both X chromosomes in some cells. In humans, chromosome-wide XCI has not initiated even by the blastocyst stage, despite the upregulation of XIST. The choice of which X chromosome will finally become inactive thus occurs downstream of Xist upregulation in both rabbits and humans, unlike in mice. Our study demonstrates the remarkable diversity in XCI regulation and highlights differences between mammals in their requirement for dosage compensation during early embryogenesis.

Genome-wide analysis reveals novel molecular features of mouse recombination hotspots - Meiotic recombination predominantly occurs at discrete genomic loci called recombination hotspots, but the features defining these areas are still largely unknown (reviewed in refs 1–5). To allow a comprehensive analysis of hotspot-associated DNA and chromatin characteristics, we developed a direct molecular approach for mapping meiotic DNA double-strand breaks that initiate recombination. Here we present the genome-wide distribution of recombination initiation sites in the mouse genome. Hotspot centres are mapped with approximately 200-nucleotide precision, which allows analysis of the fine structural details of the preferred recombination sites. We determine that hotspots share a centrally distributed consensus motif, possess a nucleotide skew that changes polarity at the centres of hotspots and have an intrinsic preference to be occupied by a nucleosome. Furthermore, we find that the vast majority of recombination initiation sites in mouse males are associated with testis-specific trimethylation of lysine 4 on histone H3 that is distinct from histone H3 lysine 4 trimethylation marks associated with transcription. The recombination map presented here has been derived from a homogeneous mouse population with a defined genetic background and therefore lends itself to extensive future experimental exploration. We note that the mapping technique developed here does not depend on the availability of genetic markers and hence can be easily adapted to other species with complex genomes. Our findings uncover several fundamental features of mammalian recombination hotspots and underline the power of the new recombination map for future studies of genetic recombination, genome stability and evolution.