Current Table of Contents

• Photoemission kinks and phonons in cuprates
  Arising from: F. Giustino, M. L. Cohen & S. G. Louie Nature452, 975–978 (2008)One of the possible mechanisms of high transition temperature (Tc) superconductivity is Cooper pairing with the help of bosons, which change the slope of the electronic dispersion as observed by photoemission. Giustino et al. calculated that in the high temperature superconductor La1.85Sr0.15CuO4 crystal lattice vibrations (phonons) should have a negligible effect on photoemission spectra and concluded that phonons do not have an important role. Here we show that the calculations used by Giustino et al. do not reproduce the huge influence of electron–phonon coupling on important phonons observed in experiments. Thus, we would similarly expect that these calculations do not explain the role of electron–phonon coupling for the electronic dispersion.
• Making the paper: Gerard Evan
  Protein inhibition that puts normal cells on hold but kills cancerous ones.
• Abstractions
  Last authorMagnetic resonance imaging is an indispensable medical tool, and produces images of matter by scanning the magnetic fields of a sample's atomic nuclei or electrons. Imaging at the single-molecule level is an unachieved goal that could have new applications such as quantum computing.
• From the blogosphere
  Can wiki encyclopaedias work better with the guidance of scientists? Citizendium, a next-generation wiki encyclopaedia, hosted Biology Week last week (22–28 September) — an online open house for biologists and biology students to explore contributing to this 'citizens' compendium' (see http://tinyurl.com/4bfwml).During the week,
• A question of balance
  The turmoil in the financial markets could lead to severe cost-cutting by governments, but US politicians would do well to note the benefits of continued support for clean energy and climate policies.
• Life after Zerhouni
  The next NIH director must juggle stagnant budgets, unhappy grantees and investigative lawmakers.
• An end to secrecy
  China's continuing openness on HIV is a welcome development and a model for other nations.
• Evolution: Vampire genes
  Naturwissenschaften doi:10.1007/s00114-008-0446-0 (2008)The evolution of the common vampire bat, Desmodus rotundus, included three rounds of duplication of a gene that encodes a salivary enzyme involved in breaking down blood clots. Desmodus laps the blood of mammals. The
• Geosciences: Carbon crunch
  Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0805382105 (2008)India's smashing into Asia around 50 million years ago brought changes far beyond the creation of the world's highest mountain range: the continental collision is widely thought to have altered global climate.Dennis
• Ecology: Diatoms downsize
  Proc. R. Soc. B doi:10.1098/rspb.2008.1200 (2008)Global warming is predicted to be bad for diatoms. Hungry and heavy as plankton go, they are expected to find themselves with fewer nutrients and sink more quickly as temperature gradients, and thus density
• Cancer biology: Ensuring a welcome
  Nature Cell Biol. doi:10.1038/ncb1794 (2008)Before travelling to new organs — or metastasizing — some cancers send chemical signals to prepare the target organ for their arrival.Yoshiro Maru and his colleagues at the Tokyo Women's Medical University in Japan
• Geology: Primitive petrous
  Science321, 1828–183110.1126/science.1161925 (2008)A beige outcrop in northern Quebec may be Earth's oldest known crustal rock. Jonathan O'Neil of McGill University in Montreal, Canada, and his colleagues have dated parts of the stone using ratios of neodymium
• Mechanics: Slippery when clean
  Phys. Rev. Lett.101, 125505 (2008)Friction is a familiar force in everyday life, but its nanometre-scale details are obscure. This is because the fundamental mechanisms are subtle and sensitive to contamination, say André Schirmeisen of the University of Münster, Germany, and his colleagues.
• Planetary science: Mars lander
  Icarus197, 452–45710.1016/j.icarus.2008.06.001 (2008)A curious elongated crater in the northern lowlands of Mars may mark the final resting place of a lost moonlet. A related crater a short distance away and 'butterfly wings' of ejecta to either
• Atmospheric chemistry: A chemical equator
  J. Geophys. Res. doi:10.1029/2008JD009940 (2008)A narrow atmospheric boundary in the Western Pacific keeps apart the more polluted air of the Northern Hemisphere from the cleaner air of the south. This newfound divide is markedly farther north than the Intertropical
• Theoretical physics: Computing with rainbows
  Phys. Res. Lett.101, 13050110.1103/PhysRevLett.101.130501 (2008)Schemes for quantum computing abound, but most intend to carry out computations on objects such as atoms. Now Nicolas Menicucci at Princeton University in New Jersey and his colleagues propose a method that uses
• Chemistry: Biofuel acid test
  Angew. Chem. Int. Edn doi: 10.1002/anie.200802879 (2008)Tough, chewy parts of plants and even wood can be tapped for their fuel by dissolving them in an ionic liquid and then passing them over a solid acid catalyst, report Ferdi Schüth and
• Journal club
  An astrobiologist considers the implications of microbes' mining abilities.Microbes have been boring ever since life began on Earth: boring into rocks, that is. But why? Perhaps to avoid competitors or predators, to escape from environmental extremes or simply to secure a site safe from
• Don't release other people's data without their consent
  SirI am astounded by the audacity of someone photographing the presentation of another researcher and then publishing their data without the presenter's permission ('Physicists aflutter about data photographed at conference' Nature455, 7; 2008). In what scientific forum, other than apparently the
• Further reflections on how we interpret the actions of others
  SirIn their Essay 'Behind the looking-glass' (Nature454, 167–168; 2008), Antonio Damasio and Kaspar Meyer suggest how mirror neurons might work. But they need to reflect on other aspects of the mirror phenomenon to complete the picture.Mirror
• Austria: Academy of Sciences states its case
  SirAs president and secretary-general of the Austrian Academy of Sciences, we wish to clarify the academy's position in the investigation into the alleged scientific misconduct associated with the urological clinical trial that you discuss in your Editorial 'Scandalous behaviour' (Nature454, 917
• Science journals have been slow to make themselves audible
  SirPodcasting has become very popular, mainly as a medium for entertainment. But it also holds huge potential for the visually impaired and others, such as dyslexics, who have reading difficulties. Simultaneously reading and listening to read-aloud news articles and scientific papers, for example, could
• Don't forget people and specimens that make the database
  SirFurther to points raised in your Feature 'The future of biocuration' (Nature455, 47–50; 2008), an example of the inadequate state of biocuration is to be found in the large number of entries in GenBank listed as “unpublished”.
• Religion and science: a guide for the 'perplexed'
  SirThere is no need for Matthew Cobb and Jerry Coyne (Nature454, 1049; 10.1038/4541049d2008) to be “perplexed” by your Editorial concerning the funding of science and religion ('Templeton's legacy' Nature454, 253–254; 10.1038/454253b2008).
• Religion and science: separated by an unbridgeable chasm
  SirIn his Correspondence 'Religion: science is partially based on faith' (Nature455, 26–27; 10.1038/455026d2008), Jonathan Cowie argues that science and religion are more similar than often thought, suggesting that experimental application of the scientific method involves faith.
• HIV immunology needs a new direction
  Researchers need to get past the standard model of vaccine development and focus on how immune responses are specifically tailored to retroviruses, argue Ruslan Medzhitov and Dan Littman.
• UK physics gets a health check
  The field is healthy, says Bill Wakeham, but scientists need to reclaim the intellectual ownership of research at the margins of the discipline such as medical or atmospheric physics.
• A fluid approach to HIV
  “Abstain,” said our hostess as we got off the bus to spend a week in Zwelethemba, a township in Western Cape, South Africa. She added that for her grown-up children, her message is different: “Be wise, condomize.” A few days later, our group of students
• Injecting trust into vaccines
  Paul Offit's distinguished academic credentials and long-standing advocacy for vaccines in the United States provide the weight behind this forceful book. Autism's False Prophets focuses on the people and events in that country that were central to the claimed link between vaccination and autism.
• Q&A: Creations from the cosmos
  Artist Karel Nel works with astronomers from COSMOS, the global Cosmic Evolution Survey that is mapping galaxies and dark matter. Now exhibiting his work in London, he tells Nature how his view of the Universe has changed.
• Enhance your life with Nature debates
  Nature has picked two panels of experts in science, policy and ethics to debate research that is improving mental and physical abilities.
• Beyond the greenhouse
  Botanic gardens are using good garden design to attract and educate the public. Mike Maunder explains how they can thrive both as businesses and as institutions of learning.
• Beijing 1987: China's coming-out party
  Two decades ago, Deng Xiaoping welcomed nations to an international meeting in Beijing. Mohamed Hassan recalls how China's leaders set out their plans for the nation to rejoin the world's scientific elite.
• Sensory ecology: In sight of speciation
  Adaptation of a fish's eyes to its visual environment can bias females to mate with different males according to their coloration. This sensory preference can contribute to the formation of new species.
• Climate change: When did the icehouse cometh?
  The concentration of atmospheric carbon dioxide decreased between 45 million and 25 million years ago, a trend accompanied by glaciation at the poles. Modelling results suggest when and where the ice closed in.
• Regenerative medicine: Short cut to cell replacement
  To make one differentiated cell type from another, a 'stopover' at an undifferentiated state is often required. An alternative method offering an efficient direct route could have implications for disease treatment.
• AIDS: Prehistory of HIV-1
  The origin of the current AIDS pandemic has been a subject of great interest and speculation. Viral archaeology sheds light on the geography and timescale of the early diversification of HIV-1 in humans.
• Applied physics: Virtues of diamond defects
  A general method for detecting nuclear magnetic resonance signals from a single molecule has so far been elusive. Magnetic sensors that exploit crystal imperfections in diamond might make such a method a reality.
• Neuroscience: Fragile dopamine
  Dopamine dysfunction, which is implicated in Parkinson's disease and drug addiction, seems an unlikely culprit in fragile X syndrome. A surprising set of findings means a rethink is required.
• The changing face of HIV in China
  HIV has advanced from high-risk groups such as intravenous drug users to some in the general population, according to comprehensive new data from the south of China. What needs to be done to halt its spread?
• Challenges in the development of an HIV-1 vaccine
  The development of a safe and effective human immunodeficiency virus (HIV)-1 vaccine is a critically important global health priority. Despite recent advances in our understanding of HIV-1 pathogenesis and immunology, however, major scientific obstacles remain. Prototype HIV-1 vaccine candidates aimed at eliciting humoral and cellular immune responses have so far failed to protect against HIV-1 infection or to reduce viral loads after infection in clinical efficacy studies. A renewed and coordinated commitment to basic discovery research, preclinical studies and clinical trials will therefore be required to overcome the hurdles currently facing the field. Here I review key challenges and future prospects in the quest to develop a prophylactic HIV-1 vaccine.
• Speciation through sensory drive in cichlid fish
  Theoretically, divergent selection on sensory systems can cause speciation through sensory drive. However, empirical evidence is rare and incomplete. Here we demonstrate sensory drive speciation within island populations of cichlid fish. We identify the ecological and molecular basis of divergent evolution in the cichlid visual
• In vivo reprogramming of adult pancreatic exocrine cells to β-cells
  One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a
• Structure of the Tribolium castaneum telomerase catalytic subunit TERT
  A common hallmark of human cancers is the overexpression of telomerase, a ribonucleoprotein complex that is responsible for maintaining the length and integrity of chromosome ends. Telomere length deregulation and telomerase activation is an early, and perhaps necessary, step in cancer cell evolution. Here we
• An 84-μG magnetic field in a galaxy at redshift z = 0.692
  The magnetic field pervading our Galaxy is a crucial constituent of the interstellar medium: it mediates the dynamics of interstellar clouds, the energy density of cosmic rays, and the formation of stars. The field associated with ionized interstellar gas has been determined through observations of pulsars in our Galaxy. Radio-frequency measurements of pulse dispersion and the rotation of the plane of linear polarization, that is, Faraday rotation, yield an average value for the magnetic field of B ≈ 3 μG (ref. 2). The possible detection of Faraday rotation of linearly polarized photons emitted by high-redshift quasars suggests similar magnetic fields are present in foreground galaxies with redshifts z > 1. As Faraday rotation alone, however, determines neither the magnitude nor the redshift of the magnetic field, the strength of galactic magnetic fields at redshifts z > 0 remains uncertain. Here we report a measurement of a magnetic field of B ≈ 84 μG in a galaxy at z = 0.692, using the same Zeeman-splitting technique that revealed an average value of B = 6 μG in the neutral interstellar gas of our Galaxy. This is unexpected, as the leading theory of magnetic field generation, the mean-field dynamo model, predicts large-scale magnetic fields to be weaker in the past rather than stronger.
• Clustered star formation as a natural explanation for the Hα cut-off in disk galaxies
  The rate of star formation in a galaxy is often determined by the observation of emission in the Hα line, which is related to the presence of short-lived massive stars. Disk galaxies show a strong cut-off in Hα radiation at a certain galactocentric distance, which has led to the conclusion that star formation is suppressed in the outer regions of disk galaxies. This is seemingly in contradiction to recent observations in the ultraviolet which imply that disk galaxies have star formation beyond the Hα cut-off, and that the star-formation-rate surface density is linearly related to the underlying gas surface density, which is a shallower relationship than that derived from Hα luminosities. In a galaxy-wide formulation, the clustered nature of star formation has recently led to the insight that the total galactic Hα luminosity is nonlinearly related to the galaxy-wide star formation rate. Here we show that a local formulation of the concept of clustered star formation naturally leads to a steeper radial decrease in the Hα surface luminosity than in the star-formation-rate surface density, in quantitative agreement with the observations, and that the observed Hα cut-off arises naturally.
• Nanoscale magnetic sensing with an individual electronic spin in diamond
  Detection of weak magnetic fields with nanoscale spatial resolution is an outstanding problem in the biological and physical sciences. For example, at a distance of 10 nm, the spin of a single electron produces a magnetic field of about 1 μT, and the corresponding field from a single proton is a few nanoteslas. A sensor able to detect such magnetic fields with nanometre spatial resolution would enable powerful applications, ranging from the detection of magnetic resonance signals from individual electron or nuclear spins in complex biological molecules to readout of classical or quantum bits of information encoded in an electron or nuclear spin memory. Here we experimentally demonstrate an approach to such nanoscale magnetic sensing, using coherent manipulation of an individual electronic spin qubit associated with a nitrogen-vacancy impurity in diamond at room temperature. Using an ultra-pure diamond sample, we achieve detection of 3 nT magnetic fields at kilohertz frequencies after 100 s of averaging. In addition, we demonstrate a sensitivity of 0.5 μT Hz-1/2 for a diamond nanocrystal with a diameter of 30 nm.
• Nanoscale imaging magnetometry with diamond spins under ambient conditions
  Magnetic resonance imaging and optical microscopy are key technologies in the life sciences. For microbiological studies, especially of the inner workings of single cells, optical microscopy is normally used because it easily achieves resolution close to the optical wavelength. But in conventional microscopy, diffraction limits the resolution to about half the wavelength. Recently, it was shown that this limit can be partly overcome by nonlinear imaging techniques, but there is still a barrier to reaching the molecular scale. In contrast, in magnetic resonance imaging the spatial resolution is not determined by diffraction; rather, it is limited by magnetic field sensitivity, and so can in principle go well below the optical wavelength. The sensitivity of magnetic resonance imaging has recently been improved enough to image single cells, and magnetic resonance force microscopy has succeeded in detecting single electrons and small nuclear spin ensembles. However, this technique currently requires cryogenic temperatures, which limit most potential biological applications. Alternatively, single-electron spin states can be detected optically, even at room temperature in some systems. Here we show how magneto-optical spin detection can be used to determine the location of a spin associated with a single nitrogen-vacancy centre in diamond with nanometre resolution under ambient conditions. By placing these nitrogen-vacancy spins in functionalized diamond nanocrystals, biologically specific magnetofluorescent spin markers can be produced. Significantly, we show that this nanometre-scale resolution can be achieved without any probes located closer than typical cell dimensions. Furthermore, we demonstrate the use of a single diamond spin as a scanning probe magnetometer to map nanoscale magnetic field variations. The potential impact of single-spin imaging at room temperature is far-reaching. It could lead to the capability to probe biologically relevant spins in living cells.
• Thresholds for Cenozoic bipolar glaciation
  The long-standing view of Earth’s Cenozoic glacial history calls for the first continental-scale glaciation of Antarctica in the earliest Oligocene epoch (∼33.6 million years ago), followed by the onset of northern-hemispheric glacial cycles in the late Pliocene epoch, about 31 million years later. The pivotal early Oligocene event is characterized by a rapid shift of 1.5 parts per thousand in deep-sea benthic oxygen-isotope values (Oi-1) within a few hundred thousand years, reflecting a combination of terrestrial ice growth and deep-sea cooling. The apparent absence of contemporaneous cooling in deep-sea Mg/Ca records, however, has been argued to reflect the growth of more ice than can be accommodated on Antarctica; this, combined with new evidence of continental cooling and ice-rafted debris in the Northern Hemisphere during this period, raises the possibility that Oi-1 represents a precursory bipolar glaciation. Here we test this hypothesis using an isotope-capable global climate/ice-sheet model that accommodates both the long-term decline of Cenozoic atmospheric CO2 levels and the effects of orbital forcing. We show that the CO2 threshold below which glaciation occurs in the Northern Hemisphere (∼280 p.p.m.v.) is much lower than that for Antarctica (∼750 p.p.m.v.). Therefore, the growth of ice sheets in the Northern Hemisphere immediately following Antarctic glaciation would have required rapid CO2 drawdown within the Oi-1 timeframe, to levels lower than those estimated by geochemical proxies and carbon-cycle models. Instead of bipolar glaciation, we find that Oi-1 is best explained by Antarctic glaciation alone, combined with deep-sea cooling of up to 4 °C and Antarctic ice that is less isotopically depleted (-30 to -35‰) than previously suggested. Proxy CO2 estimates remain above our model’s northern-hemispheric glaciation threshold of ∼280 p.p.m.v. until ∼25 Myr ago, but have been near or below that level ever since. This implies that episodic northern-hemispheric ice sheets have been possible some 20 million years earlier than currently assumed (although still much later than Oi-1) and could explain some of the variability in Miocene sea-level records.
• Crystallographic preferred orientation of akimotoite and seismic anisotropy of Tonga slab
  The mineral akimotoite, ilmenite-structured MgSiO3, exists at the bottom of the Earth’s mantle transition zone and within the uppermost lower mantle, especially under low-temperature conditions. Akimotoite is thought to be a major constituent of the harzburgite layer of subducting slabs, and the most anisotropic mineral in the mantle transition zone. It has been predicted that if akimotoite crystals are preferentially oriented by plastic deformation, a cold subducted slab would be extremely anisotropic. However, there have been no studies of crystallographic preferred orientations and very few reports of plastic deformation experiments for MgSiO3 ilmenite. Here we present plastic deformation experiments on polycrystalline akimotoite, which were conducted at confining pressures of 20–22 GPa and temperatures of 1,000–1,300 °C. We found a change in crystallographic preferred orientation pattern of akimotoite with temperature, where the c-axis maximum parallel to the compression direction develops at high temperature, whereas the c axes are preferentially oriented parallel to the shear direction or perpendicular to the compression direction at lower temperature. The previously reported difference in compressional-wave seismic anisotropy between the northern and southern segments of the Tonga slab at depths of the mantle transition zone can conceivably be attributed to the difference in the crystallographic preferred orientation pattern of akimotoite at varying temperature within the slab.
• Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960
  Human immunodeficiency virus type 1 (HIV-1) sequences that pre-date the recognition of AIDS are critical to defining the time of origin and the timescale of virus evolution. A viral sequence from 1959 (ZR59) is the oldest known HIV-1 infection. Other historically documented sequences, important calibration points to convert evolutionary distance into time, are lacking, however; ZR59 is the only one sampled before 1976. Here we report the amplification and characterization of viral sequences from a Bouin’s-fixed paraffin-embedded lymph node biopsy specimen obtained in 1960 from an adult female in Léopoldville, Belgian Congo (now Kinshasa, Democratic Republic of the Congo (DRC)), and we use them to conduct the first comparative evolutionary genetic study of early pre-AIDS epidemic HIV-1 group M viruses. Phylogenetic analyses position this viral sequence (DRC60) closest to the ancestral node of subtype A (excluding A2). Relaxed molecular clock analyses incorporating DRC60 and ZR59 date the most recent common ancestor of the M group to near the beginning of the twentieth century. The sizeable genetic distance between DRC60 and ZR59 directly demonstrates that diversification of HIV-1 in west-central Africa occurred long before the recognized AIDS pandemic. The recovery of viral gene sequences from decades-old paraffin-embedded tissues opens the door to a detailed palaeovirological investigation of the evolutionary history of HIV-1 that is not accessible by other methods.
• Individual differences in non-verbal number acuity correlate with maths achievement
  Human mathematical competence emerges from two representational systems. Competence in some domains of mathematics, such as calculus, relies on symbolic representations that are unique to humans who have undergone explicit teaching. More basic numerical intuitions are supported by an evolutionarily ancient approximate number system that is shared by adults, infants and non-human animals—these groups can all represent the approximate number of items in visual or auditory arrays without verbally counting, and use this capacity to guide everyday behaviour such as foraging. Despite the widespread nature of the approximate number system both across species and across development, it is not known whether some individuals have a more precise non-verbal ‘number sense’ than others. Furthermore, the extent to which this system interfaces with the formal, symbolic maths abilities that humans acquire by explicit instruction remains unknown. Here we show that there are large individual differences in the non-verbal approximation abilities of 14-year-old children, and that these individual differences in the present correlate with children’s past scores on standardized maths achievement tests, extending all the way back to kindergarten. Moreover, this correlation remains significant when controlling for individual differences in other cognitive and performance factors. Our results show that individual differences in achievement in school mathematics are related to individual differences in the acuity of an evolutionarily ancient, unlearned approximate number sense. Further research will determine whether early differences in number sense acuity affect later maths learning, whether maths education enhances number sense acuity, and the extent to which tertiary factors can affect both.
• UNC-6/netrin and its receptor UNC-5 locally exclude presynaptic components from dendrites
  Polarity is an essential feature of many cell types, including neurons that receive information from local inputs within their dendrites and propagate nerve impulses to distant targets through a single axon. It is generally believed that intrinsic structural differences between axons and dendrites dictate the polarized localization of axonal and dendritic proteins. However, whether extracellular cues also instruct this process in vivo has not been explored. Here we show that the axon guidance cue UNC-6/netrin and its receptor UNC-5 act throughout development to exclude synaptic vesicle and active zone proteins from the dendrite of the Caenorhabditis elegans motor neuron DA9, which is proximal to a source of UNC-6/netrin. In unc-6/netrin and unc-5 loss-of-function mutants, presynaptic components mislocalize to the DA9 dendrite. In addition, ectopically expressed UNC-6/netrin, acting through UNC-5, is sufficient to exclude endogenous synapses from adjacent subcellular domains within the DA9 axon. Furthermore, this anti-synaptogenic activity is interchangeable with that of LIN-44/Wnt despite being transduced through different receptors, suggesting that extracellular cues such as netrin and Wnts not only guide axon navigation but also regulate the polarized accumulation of presynaptic components through local exclusion.
• STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling
  The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response—following infection with DNA and RNA viruses, for example—remain to be identified. Here we report the identification, following expression cloning, of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes. It comprises five putative transmembrane regions, predominantly resides in the endoplasmic reticulum and is able to activate both NF-κB and IRF3 transcription pathways to induce expression of type I interferon (IFN-α and IFN-β ) and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpesvirus family, to induce IFN-β, but did not significantly affect the Toll-like receptor (TLR) pathway. Yeast two-hybrid and co-immunoprecipitation studies indicated that STING interacts with RIG-I and with SSR2 (also known as TRAPβ), which is a member of the translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation. Ablation by RNA interference of both TRAPβ and translocon adaptor SEC61β was subsequently found to inhibit STING’s ability to stimulate expression of IFN-β. Thus, as well as identifying a regulator of innate immune signalling, our results imply a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.
• Modelling Myc inhibition as a cancer therapy
  Myc is a pleiotropic basic helix–loop–helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.
• Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation
  Cell growth and proliferation require coordinated ribosomal biogenesis and translation. Eukaryotic initiation factors (eIFs) control translation at the rate-limiting step of initiation. So far, only two eIFs connect extracellular stimuli to global translation rates: eIF4E acts in the eIF4F complex and regulates binding of capped messenger RNA to 40S subunits, downstream of growth factors, and eIF2 controls loading of the ternary complex on the 40S subunit and is inhibited on stress stimuli. No eIFs have been found to link extracellular stimuli to the activity of the large 60S ribosomal subunit. eIF6 binds 60S ribosomes precluding ribosome joining in vitro. However, studies in yeasts showed that eIF6 is required for ribosome biogenesis rather than translation. Here we show that mammalian eIF6 is required for efficient initiation of translation, in vivo. eIF6 null embryos are lethal at preimplantation. Heterozygous mice have 50% reduction of eIF6 levels in all tissues, and show reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6+/- cells retain sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6+/- mice displays an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes have impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts recapitulate the organism phenotype and have normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIF6+/- cells are resistant to oncogene-induced transformation. Thus, eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals.
• CDK targets Sae2 to control DNA-end resection and homologous recombination
  DNA double-strand breaks (DSBs) are repaired by two principal mechanisms: non-homologous end-joining (NHEJ) and homologous recombination (HR). HR is the most accurate DSB repair mechanism but is generally restricted to the S and G2 phases of the cell cycle, when DNA has been replicated and a sister chromatid is available as a repair template. By contrast, NHEJ operates throughout the cell cycle but assumes most importance in G1 (refs 4, 6). The choice between repair pathways is governed by cyclin-dependent protein kinases (CDKs), with a major site of control being at the level of DSB resection, an event that is necessary for HR but not NHEJ, and which takes place most effectively in S and G2 (refs 2, 5). Here we establish that cell-cycle control of DSB resection in Saccharomyces cerevisiae results from the phosphorylation by CDK of an evolutionarily conserved motif in the Sae2 protein. We show that mutating Ser 267 of Sae2 to a non-phosphorylatable residue causes phenotypes comparable to those of a sae2Δ null mutant, including hypersensitivity to camptothecin, defective sporulation, reduced hairpin-induced recombination, severely impaired DNA-end processing and faulty assembly and disassembly of HR factors. Furthermore, a Sae2 mutation that mimics constitutive Ser 267 phosphorylation complements these phenotypes and overcomes the necessity of CDK activity for DSB resection. The Sae2 mutations also cause cell-cycle-stage specific hypersensitivity to DNA damage and affect the balance between HR and NHEJ. These findings therefore provide a mechanistic basis for cell-cycle control of DSB repair and highlight the importance of regulating DSB resection.
• Visualizing transient events in amino-terminal autoprocessing of HIV-1 protease
  HIV-1 protease processes the Gag and Gag-Pol polyproteins into mature structural and functional proteins, including itself, and is therefore indispensable for viral maturation. The mature protease is active only as a dimer with each subunit contributing catalytic residues. The full-length transframe region protease precursor appears to be monomeric yet undergoes maturation via intramolecular cleavage of a putative precursor dimer, concomitant with the appearance of mature-like catalytic activity. How such intramolecular cleavage can occur when the amino and carboxy termini of the mature protease are part of an intersubunit β-sheet located distal from the active site is unclear. Here we visualize the early events in N-terminal autoprocessing using an inactive mini-precursor with a four-residue N-terminal extension that mimics the transframe region protease precursor. Using paramagnetic relaxation enhancement, a technique that is exquisitely sensitive to the presence of minor species, we show that the mini-precursor forms highly transient, lowly populated (3–5%) dimeric encounter complexes that involve the mature dimer interface but occupy a wide range of subunit orientations relative to the mature dimer. Furthermore, the occupancy of the mature dimer configuration constitutes a very small fraction of the self-associated species (accounting for the very low enzymatic activity of the protease precursor), and the N-terminal extension makes transient intra- and intersubunit contacts with the substrate binding site and is therefore available for autocleavage when the correct dimer orientation is sampled within the encounter complex ensemble.
• Metabolomics: Biochemistry's new look
  Until now, metabolomics researchers have had to adapt technology developed mainly for proteomics. But there are now solutions designed with them in mind. Nathan Blow reports.
• Metabolomics: Dark matter
  “There are a lot of small molecules that we do not even know about yet,” says Arthur Castle, programme director for the Roadmap Metabolomics Technology development programme at the US National Institutes of Health in Bethesda, Maryland. Metabolomics has a good handle on analysing human
• Metabolomics: Wine-omics
  For Kirsten Skogerson at the University of California, Davis, wondering about how chemical composition affects the flavour and body of a wine took her from a degree in viticulture and enology into metabolomics research. When Skogerson arrived in Oliver Fiehn's lab as a postgrad she
• Metabolomics: Table of suppliers
  Table 1
• Mars is the wrong colour
  No longer seeing red.