Nature

Identification of a quality-control mechanism for mRNA 5'-end capping.

Publication Date: 2010 Aug 29 PMID: 20802481
Authors: Jiao, X. - Xiang, S. - Oh, C. - Martin, C. E. - Tong, L. - Kiledjian, M.
Journal: Nature

The 7-methylguanosine cap structure at the 5' end of eukaryotic messenger RNAs is a critical determinant of their stability and translational efficiency. It is generally believed that 5'-end capping is a constitutive process that occurs during mRNA maturation and lacks the need for a quality-control mechanism to ensure its fidelity. We recently reported that the yeast Rai1 protein has pyrophosphohydrolase activity towards mRNAs lacking a 5'-end cap. Here we show that, in vitro as well as in yeast cells, Rai1 possesses a novel decapping endonuclease activity that can also remove the entire cap structure dinucleotide from an mRNA. This activity is targeted preferentially towards mRNAs with unmethylated caps in contrast to the canonical decapping enzyme, Dcp2, which targets mRNAs with a methylated cap. Capped but unmethylated mRNAs generated in yeast cells with a defect in the methyltransferase gene are more stable in a rai1-gene-disrupted background. Moreover, rai1Delta yeast cells with wild-type capping enzymes show significant accumulation of mRNAs with 5'-end capping defects under nutritional stress conditions of glucose starvation or amino acid starvation. These findings provide evidence that 5'-end capping is not a constitutive process that necessarily always proceeds to completion and demonstrates that Rai1 has an essential role in clearing mRNAs with aberrant 5'-end caps. We propose that Rai1 is involved in an as yet uncharacterized quality control process that ensures mRNA 5'-end integrity by an aberrant-cap-mediated mRNA decay mechanism.

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Cellular imaging: A software spot.

Publication Date: 2010 Aug 26 PMID: 20740020
Authors:
Journal: Nature

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Cellular imaging: A long-term live-cell commitment.

Publication Date: 2010 Aug 26 PMID: 20740019
Authors:
Journal: Nature

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Cellular imaging: Taking a long, hard look.

Publication Date: 2010 Aug 26 PMID: 20740018
Authors: Baker, M.
Journal: Nature

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IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response.

Publication Date: 2010 Aug 26 PMID: 20740013
Authors: Rao, P. - Hayden, M. S. - Long, M. - Scott, M. L. - West, A. P. - Zhang, D. - Oeckinghaus, A. - Lynch, C. - Hoffmann, A. - Baltimore, D. - Ghosh, S.
Journal: Nature

The activation of pro-inflammatory gene programs by nuclear factor-kappaB (NF-kappaB) is primarily regulated through cytoplasmic sequestration of NF-kappaB by the inhibitor of kappaB (IkappaB) family of proteins. IkappaBbeta, a major isoform of IkappaB, can sequester NF-kappaB in the cytoplasm, although its biological role remains unclear. Although cells lacking IkappaBbeta have been reported, in vivo studies have been limited and suggested redundancy between IkappaBalpha and IkappaBbeta. Like IkappaBalpha, IkappaBbeta is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus. The crystal structure of IkappaBbeta bound to p65 suggested this complex might bind DNA. In vitro, hypophosphorylated IkappaBbeta can bind DNA with p65 and c-Rel, and the DNA-bound NF-kappaB:IkappaBbeta complexes are resistant to IkappaBalpha, suggesting hypophosphorylated, nuclear IkappaBbeta may prolong the expression of certain genes. Here we report that in vivo IkappaBbeta serves both to inhibit and facilitate the inflammatory response. IkappaBbeta degradation releases NF-kappaB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-alpha (TNF-alpha). Surprisingly, absence of IkappaBbeta results in a dramatic reduction of TNF-alpha in response to LPS even though activation of NF-kappaB is normal. The inhibition of TNF-alpha messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IkappaBbeta bound to p65:c-Rel heterodimers at a specific kappaB site on the TNF-alpha promoter. Therefore IkappaBbeta acts through p65:c-Rel dimers to maintain prolonged expression of TNF-alpha. As a result, IkappaBbeta(-/-) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IkappaBbeta might be a promising new strategy for selectively inhibiting the chronic phase of TNF-alpha production during the inflammatory response.

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Upper-ocean-to-atmosphere radiocarbon offsets imply fast deglacial carbon dioxide release.

Publication Date: 2010 Aug 26 PMID: 20740012
Authors: Rose, K. A. - Sikes, E. L. - Guilderson, T. P. - Shane, P. - Hill, T. M. - Zahn, R. - Spero, H. J.
Journal: Nature

Radiocarbon in the atmosphere is regulated largely by ocean circulation, which controls the sequestration of carbon dioxide (CO(2)) in the deep sea through atmosphere-ocean carbon exchange. During the last glaciation, lower atmospheric CO(2) levels were accompanied by increased atmospheric radiocarbon concentrations that have been attributed to greater storage of CO(2) in a poorly ventilated abyssal ocean. The end of the ice age was marked by a rapid increase in atmospheric CO(2) concentrations that coincided with reduced (14)C/(12)C ratios (Delta(14)C) in the atmosphere, suggesting the release of very 'old' ((14)C-depleted) CO(2) from the deep ocean to the atmosphere. Here we present radiocarbon records of surface and intermediate-depth waters from two sediment cores in the southwest Pacific and Southern oceans. We find a steady 170 per mil decrease in Delta(14)C that precedes and roughly equals in magnitude the decrease in the atmospheric radiocarbon signal during the early stages of the glacial-interglacial climatic transition. The atmospheric decrease in the radiocarbon signal coincides with regionally intensified upwelling and marine biological productivity, suggesting that CO(2) released by means of deep water upwelling in the Southern Ocean lost most of its original depleted-(14)C imprint as a result of exchange and isotopic equilibration with the atmosphere. Our data imply that the deglacial (14)C depletion previously identified in the eastern tropical North Pacific must have involved contributions from sources other than the previously suggested carbon release by way of a deep Southern Ocean pathway, and may reflect the expanded influence of the (14)C-depleted North Pacific carbon reservoir across this interval. Accordingly, shallow water masses advecting north across the South Pacific in the early deglaciation had little or no residual (14)C-depleted signals owing to degassing of CO(2) and biological uptake in the Southern Ocean.

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Coherent measurements of high-order electronic correlations in quantum wells.

Publication Date: 2010 Aug 26 PMID: 20740011
Authors: Turner, D. B. - Nelson, K. A.
Journal: Nature

Strong, long-range Coulomb interactions can lead to correlated motions of multiple charged particles, which can induce important many-body effects in semiconductors. The exciton states formed from correlated electron-hole pairs have been studied extensively, but basic properties of multiple-exciton correlations-such as coherence times, population lifetimes, binding energies and the number of particles that can be correlated-are largely unknown because they are not spectroscopically accessible from the ground state. Here we present direct observations of high-order coherences in gallium arsenide quantum wells, achieved using two-dimensional multiple-quantum spectroscopy methods in which up to seven successive light fields were used. The measurements were made possible by the combination of a reconfigurable spatial beam-shaper that formed multiple beams in specified geometries and a spatiotemporal pulse-shaper that controlled the relative optical phases and temporal delays among pulses in all the beams. The results reveal triexciton coherences (correlations of three excitons or six particles), whose existence was not obvious because the third exciton spin is unpaired, and the values of their coherence times and binding energies. Rephasing of biexcitons, triexcitons and unbound two-exciton coherences was demonstrated. We also determined that there are no significant unbound correlations of three excitons and no bound or unbound four-exciton (eight-particle) correlations. Thus, the limits, as well as the properties, of many-body correlations in this system were revealed. The measurement methods open a new window into high-order many-body interactions in materials and molecules, and the present results should guide ongoing work on first-principles calculations of electronic interactions in semiconductor nanostructures.

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Formation of asteroid pairs by rotational fission.

Publication Date: 2010 Aug 26 PMID: 20740010
Authors: Pravec, P. - Vokrouhlicky, D. - Polishook, D. - Scheeres, D. J. - Harris, A. W. - Galad, A. - Vaduvescu, O. - Pozo, F. - Barr, A. - Longa, P. - Vachier, F. - Colas, F. - Pray, D. P. - Pollock, J. - Reichart, D. - Ivarsen, K. - Haislip, J. - Lacluyze, A. - Kusnirak, P. - Henych, T. - Marchis, F. - Macomber, B. - Jacobson, S. A. - Krugly, Y. N. - Sergeev, A. V. - Leroy, A.
Journal: Nature

Pairs of asteroids sharing similar heliocentric orbits, but not bound together, were found recently. Backward integrations of their orbits indicated that they separated gently with low relative velocities, but did not provide additional insight into their formation mechanism. A previously hypothesized rotational fission process may explain their formation-critical predictions are that the mass ratios are less than about 0.2 and, as the mass ratio approaches this upper limit, the spin period of the larger body becomes long. Here we report photometric observations of a sample of asteroid pairs, revealing that the primaries of pairs with mass ratios much less than 0.2 rotate rapidly, near their critical fission frequency. As the mass ratio approaches 0.2, the primary period grows long. This occurs as the total energy of the system approaches zero, requiring the asteroid pair to extract an increasing fraction of energy from the primary's spin in order to escape. We do not find asteroid pairs with mass ratios larger than 0.2. Rotationally fissioned systems beyond this limit have insufficient energy to disrupt. We conclude that asteroid pairs are formed by the rotational fission of a parent asteroid into a proto-binary system, which subsequently disrupts under its own internal system dynamics soon after formation.

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Direct formation of supermassive black holes via multi-scale gas inflows in galaxy mergers.

Publication Date: 2010 Aug 26 PMID: 20740009
Authors: Mayer, L. - Kazantzidis, S. - Escala, A. - Callegari, S.
Journal: Nature

Observations of distant quasars indicate that supermassive black holes of billions of solar masses already existed less than a billion years after the Big Bang. Models in which the 'seeds' of such black holes form by the collapse of primordial metal-free stars cannot explain the rapid appearance of these supermassive black holes because gas accretion is not sufficiently efficient. Alternatively, these black holes may form by direct collapse of gas within isolated protogalaxies, but current models require idealized conditions, such as metal-free gas, to prevent cooling and star formation from consuming the gas reservoir. Here we report simulations showing that mergers between massive protogalaxies naturally produce the conditions for direct collapse into a supermassive black hole with no need to suppress cooling and star formation. Merger-driven gas inflows give rise to an unstable, massive nuclear gas disk of a few billion solar masses, which funnels more than 10(8) solar masses of gas to a sub-parsec-scale gas cloud in only 100,000 years. The cloud undergoes gravitational collapse, which eventually leads to the formation of a massive black hole. The black hole can subsequently grow to a billion solar masses on timescales of about 10(8) years by accreting gas from the surrounding disk.

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Heterochromatin silencing of p53 target genes by a small viral protein.

Publication Date: 2010 Aug 26 PMID: 20740008
Authors: Soria, C. - Estermann, F. E. - Espantman, K. C. - O'Shea, C. C.
Journal: Nature

The transcription factor p53 (also known as TP53) guards against tumour and virus replication and is inactivated in almost all cancers. p53-activated transcription of target genes is thought to be synonymous with the stabilization of p53 in response to oncogenes and DNA damage. During adenovirus replication, the degradation of p53 by E1B-55k is considered essential for p53 inactivation, and is the basis for p53-selective viral cancer therapies. Here we reveal a dominant epigenetic mechanism that silences p53-activated transcription, irrespective of p53 phosphorylation and stabilization. We show that another adenoviral protein, E4-ORF3, inactivates p53 independently of E1B-55k by forming a nuclear structure that induces de novo H3K9me3 heterochromatin formation at p53 target promoters, preventing p53-DNA binding. This suppressive nuclear web is highly selective in silencing p53 promoters and operates in the backdrop of global transcriptional changes that drive oncogenic replication. These findings are important for understanding how high levels of wild-type p53 might also be inactivated in cancer as well as the mechanisms that induce aberrant epigenetic silencing of tumour-suppressor loci. Our study changes the longstanding definition of how p53 is inactivated in adenovirus infection and provides key insights that could enable the development of true p53-selective oncolytic viral therapies.

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Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.

Publication Date: 2010 Aug 26 PMID: 20740007
Authors: Elden, A. C. - Kim, H. J. - Hart, M. P. - Chen-Plotkin, A. S. - Johnson, B. S. - Fang, X. - Armakola, M. - Geser, F. - Greene, R. - Lu, M. M. - Padmanabhan, A. - Clay-Falcone, D. - McCluskey, L. - Elman, L. - Juhr, D. - Gruber, P. J. - Rub, U. - Auburger, G. - Trojanowski, J. Q. - Lee, V. M. - Van Deerlin, V. M. - Bonini, N. M. - Gitler, A. D.
Journal: Nature

The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.

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Lithospheric layering in the North American craton.

Publication Date: 2010 Aug 26 PMID: 20740006
Authors: Yuan, H. - Romanowicz, B.
Journal: Nature

How cratons-extremely stable continental areas of the Earth's crust-formed and remained largely unchanged for more than 2,500 million years is much debated. Recent studies of seismic-wave receiver function data have detected a structural boundary under continental cratons at depths too shallow to be consistent with the lithosphere-asthenosphere boundary, as inferred from seismic tomography and other geophysical studies. Here we show that changes in the direction of azimuthal anisotropy with depth reveal the presence of two distinct lithospheric layers throughout the stable part of the North American continent. The top layer is thick ( approximately 150 km) under the Archaean core and tapers out on the surrounding Palaeozoic borders. Its thickness variations follow those of a highly depleted layer inferred from thermo-barometric analysis of xenoliths. The lithosphere-asthenosphere boundary is relatively flat (ranging from 180 to 240 km in depth), in agreement with the presence of a thermal conductive root that subsequently formed around the depleted chemical layer. Our findings tie together seismological, geochemical and geodynamical studies of the cratonic lithosphere in North America. They also suggest that the horizon detected in receiver function studies probably corresponds to the sharp mid-lithospheric boundary rather than to the more gradual lithosphere-asthenosphere boundary.

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The evolution of eusociality.

Publication Date: 2010 Aug 26 PMID: 20740005
Authors: Nowak, M. A. - Tarnita, C. E. - Wilson, E. O.
Journal: Nature

Eusociality, in which some individuals reduce their own lifetime reproductive potential to raise the offspring of others, underlies the most advanced forms of social organization and the ecologically dominant role of social insects and humans. For the past four decades kin selection theory, based on the concept of inclusive fitness, has been the major theoretical attempt to explain the evolution of eusociality. Here we show the limitations of this approach. We argue that standard natural selection theory in the context of precise models of population structure represents a simpler and superior approach, allows the evaluation of multiple competing hypotheses, and provides an exact framework for interpreting empirical observations.

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Cancer: Viruses' backup plan.

Publication Date: 2010 Aug 26 PMID: 20740004
Authors: Ryan, K. M.
Journal: Nature

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Quantum mechanics: The usefulness of uselessness.

Publication Date: 2010 Aug 26 PMID: 20740003
Authors: Winter, A.
Journal: Nature

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Neurodegeneration: An expansion in ALS genetics.

Publication Date: 2010 Aug 26 PMID: 20740002
Authors: Lagier-Tourenne, C. - Cleveland, D. W.
Journal: Nature

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Cell cycle: Retinoblastoma, a trip organizer.

Publication Date: 2010 Aug 26 PMID: 20740001
Authors: Bosco, G.
Journal: Nature

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Astrophysics: Making black holes from scratch.

Publication Date: 2010 Aug 26 PMID: 20739999
Authors: Volonteri, M.
Journal: Nature

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Structural biology: Conservation in vesicle coats.

Publication Date: 2010 Aug 26 PMID: 20739998
Authors: Harrison, S. C. - Kirchhausen, T.
Journal: Nature

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Condensed-matter physics: The dance of electrons and holes.

Publication Date: 2010 Aug 26 PMID: 20739997
Authors: Scholes, G. D.
Journal: Nature

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Save your census.

Publication Date: 2010 Aug 26 PMID: 20739993
Authors: Fienberg, S. E. - Prewitt, K.
Journal: Nature

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Disasters widen the rich-poor gap.

Publication Date: 2010 Aug 26 PMID: 20739992
Authors: Mutter, J.
Journal: Nature

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Mosquitoes: schemes to render them extinct are impracticable.

Publication Date: 2010 Aug 26 PMID: 20739991
Authors: Smith, S. M.
Journal: Nature

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Mosquitoes: first evaluate impacts of eradicating them.

Publication Date: 2010 Aug 26 PMID: 20739990
Authors: Hoekstra, J. D.
Journal: Nature

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Mosquitoes: retain an ex situ population for ecological insurance.

Publication Date: 2010 Aug 26 PMID: 20739989
Authors: Phalan, B.
Journal: Nature

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Mosquitoes: just how much biodiversity does humanity need?

Publication Date: 2010 Aug 26 PMID: 20739988
Authors: Wickson, F.
Journal: Nature

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Consumers have a right to affordable genetic testing.

Publication Date: 2010 Aug 26 PMID: 20739987
Authors: Kanan, C.
Journal: Nature

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Misconduct: don't assume science is self-correcting.

Publication Date: 2010 Aug 26 PMID: 20739986
Authors: Hettinger, T. P.
Journal: Nature

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Misconduct: don't penalize the honest majority of scientists.

Publication Date: 2010 Aug 26 PMID: 20739985
Authors: Moore, J. P.
Journal: Nature

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Clarifying knowledge ownership in Europe's medicines initiative.

Publication Date: 2010 Aug 26 PMID: 20739984
Authors: De Rijck, K. - Goldman, M.
Journal: Nature

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Proposals for surface-temperature databank now open for scrutiny.

Publication Date: 2010 Aug 26 PMID: 20739983
Authors: Stott, P. - Thorne, P.
Journal: Nature

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Genetics: Pet project.

Publication Date: 2010 Aug 26 PMID: 20739982
Authors: Cyranoski, D.
Journal: Nature

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Nuclear theory nudged.

Publication Date: 2010 Aug 26 PMID: 20739981
Authors: Reich, E. S.
Journal: Nature

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Battle to degas deadly lakes continues.

Publication Date: 2010 Aug 26 PMID: 20739980
Authors: Jones, N.
Journal: Nature

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Key Alzheimer's findings questioned.

Publication Date: 2010 Aug 26 PMID: 20739979
Authors: Ledford, H.
Journal: Nature

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G-whizzes disagree over gravity.

Publication Date: 2010 Aug 26 PMID: 20739978
Authors: Reich, E. S.
Journal: Nature

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Sugar synthesis speeds up.

Publication Date: 2010 Aug 26 PMID: 20739977
Authors: Van Noorden, R.
Journal: Nature

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Big science feels the pinch in Europe.

Publication Date: 2010 Aug 26 PMID: 20739976
Authors: Brumfiel, G.
Journal: Nature

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Journal club. A physicist and biogeochemist gets a kick out of the problem of Brownian motion and diffusion.

Publication Date: 2010 Aug 26 PMID: 20739970
Authors: Zeebe, R. E.
Journal: Nature

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Collateral damage.

Publication Date: 2010 Aug 26 PMID: 20739963
Authors:
Journal: Nature

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Australia's mixed climate.

Publication Date: 2010 Aug 26 PMID: 20739962
Authors:
Journal: Nature

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Evidence for male allocation in pipefish?

Publication Date: 2010 Aug 26 PMID: 20739960
Authors: Gwynne, D. T. - Judge, K. A. - Kelly, C. D.
Journal: Nature

Sexual differences in the extent and type of parental care lie at the heart of sexual selection theory, and evolution resulting from parental conflict has produced some striking behavioural and morphological adaptations. In a study of male pregnancy in Gulf pipefish, Paczolt and Jones showed that more eggs were transferred to the male's brood pouch and more offspring survived following mating with large females (preferred by males) than with small (less preferred) females. Although the authors conclude that the lower survival of embryos from small females is most consistent with males actively removing resources from these offspring, no data are presented to directly support this hypothesis (ref. 2, and Supplementary Information therein) and the data do not refute the alternative explanation that differential egg survival is caused by female effects mediated by variation in fecundity and egg size or quality. We argue that only by experimentally manipulating female attractiveness separately from the quality of eggs deposited in the brood pouch can the extent of sexual conflict in this role-reversed system be assessed.

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Structure of RCC1 chromatin factor bound to the nucleosome core particle.

Publication Date: 2010 Aug 25 PMID: 20739938
Authors: Makde, R. D. - England, J. R. - Yennawar, H. P. - Tan, S.
Journal: Nature

The small GTPase Ran enzyme regulates critical eukaryotic cellular functions including nuclear transport and mitosis through the creation of a RanGTP gradient around the chromosomes. This concentration gradient is created by the chromatin-bound RCC1 (regulator of chromosome condensation) protein, which recruits Ran to nucleosomes and activates Ran's nucleotide exchange activity. Although RCC1 has been shown to bind directly with the nucleosome, the molecular details of this interaction were not known. Here we determine the crystal structure of a complex of Drosophila RCC1 and the nucleosome core particle at 2.9 A resolution, providing an atomic view of how a chromatin protein interacts with the histone and DNA components of the nucleosome. Our structure also suggests that the Widom 601 DNA positioning sequence present in the nucleosomes forms a 145-base-pair nucleosome core particle, not the expected canonical 147-base-pair particle.

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The structure of (CENP-A-H4)(2) reveals physical features that mark centromeres.

Publication Date: 2010 Aug 25 PMID: 20739937
Authors: Sekulic, N. - Bassett, E. A. - Rogers, D. J. - Black, B. E.
Journal: Nature

Centromeres are specified epigenetically, and the histone H3 variant CENP-A is assembled into the chromatin of all active centromeres. Divergence from H3 raises the possibility that CENP-A generates unique chromatin features to mark physically centromere location. Here we report the crystal structure of a subnucleosomal heterotetramer, human (CENP-A-H4)(2), that reveals three distinguishing properties encoded by the residues that comprise the CENP-A targeting domain (CATD; ref. 2): (1) a CENP-A-CENP-A interface that is substantially rotated relative to the H3-H3 interface; (2) a protruding loop L1 of the opposite charge as that on H3; and (3) strong hydrophobic contacts that rigidify the CENP-A-H4 interface. Residues involved in the CENP-A-CENP-A rotation are required for efficient incorporation into centromeric chromatin, indicating specificity for an unconventional nucleosome shape. DNA topological analysis indicates that CENP-A-containing nucleosomes are octameric with conventional left-handed DNA wrapping, in contrast to other recent proposals. Our results indicate that CENP-A marks centromere location by restructuring the nucleosome from within its folded histone core.

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Phosphorylation of the CPC by Cdk1 promotes chromosome bi-orientation.

Publication Date: 2010 Aug 25 PMID: 20739936
Authors: Tsukahara, T. - Tanno, Y. - Watanabe, Y.
Journal: Nature

Successful partition of replicated genomes at cell division requires chromosome attachment to opposite poles of mitotic spindle (bi-orientation). Any defects in this regulation bring about chromosomal instability, which may accelerate tumour progression in humans. To achieve chromosome bi-orientation at prometaphase, the chromosomal passenger complex (CPC), composed of catalytic kinase Aurora B and regulatory components (INCENP, Survivin and Borealin), must be localized to centromeres to phosphorylate kinetochore substrates. Although the CPC dynamically changes the subcellular localization, the regulation of centromere targeting is largely unknown. Here we isolated a fission yeast cyclin B mutant defective specifically in chromosome bi-orientation. Accordingly, we identified Cdk1 (also known as Cdc2)-cyclin-B-dependent phosphorylation of Survivin. Preventing Survivin phosphorylation impairs centromere CPC targeting as well as chromosome bi-orientation, whereas phosphomimetic Survivin suppresses the bi-orientation defect in the cyclin B mutant. Survivin phosphorylation promotes direct binding with shugoshin, which we now define as a conserved centromeric adaptor of the CPC. In human cells, the phosphorylation of Borealin has a comparable role. Thus, our study resolves the conserved mechanisms of CPC targeting to centromeres, highlighting a key role of Cdk1-cyclin B in chromosome bi-orientation.

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Parkinson's disease: a model dilemma.

Publication Date: 2010 Aug 26 PMID: 20739935
Authors: Beal, M. F.
Journal: Nature

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Levodopa: the story so far.

Publication Date: 2010 Aug 26 PMID: 20739934
Authors: Abbott, A.
Journal: Nature

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Secrets of the shaking palsy.

Publication Date: 2010 Aug 26 PMID: 20739933
Authors: Schnabel, J.
Journal: Nature

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Treatment frontiers.

Publication Date: 2010 Aug 26 PMID: 20739932
Authors: Smith, K.
Journal: Nature

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Slowing the decline.

Publication Date: 2010 Aug 26 PMID: 20739931
Authors: Williams, R.
Journal: Nature

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Biomarkers: casting the net wide.

Publication Date: 2010 Aug 26 PMID: 20739930
Authors: Jones, R.
Journal: Nature

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Parkinson's disease.

Publication Date: 2010 Aug 26 PMID: 20739929
Authors: Grayson, M.
Journal: Nature

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Purified human BRCA2 stimulates RAD51-mediated recombination.

Publication Date: 2010 Aug 22 PMID: 20729832
Authors: Jensen, R. B. - Carreira, A. - Kowalczykowski, S. C.
Journal: Nature

Mutation of the breast cancer susceptibility gene, BRCA2, leads to breast and ovarian cancers. Mechanistic insight into the functions of human BRCA2 has been limited by the difficulty of isolating this large protein (3,418 amino acids). Here we report the purification of full-length BRCA2 and show that it both binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). BRCA2 acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. BRCA2 does not anneal ssDNA complexed with RPA, implying it does not directly function in repair processes that involve ssDNA annealing. Our findings show that BRCA2 is a key mediator of homologous recombination, and they provide a molecular basis for understanding how this DNA repair process is disrupted by BRCA2 mutations, which lead to chromosomal instability and cancer.

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Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.

Publication Date: 2010 Aug 22 PMID: 20729831
Authors: Bilguvar, K. - Ozturk, A. K. - Louvi, A. - Kwan, K. Y. - Choi, M. - Tatli, B. - Yalnizoglu, D. - Tuysuz, B. - Caglayan, A. O. - Gokben, S. - Kaymakcalan, H. - Barak, T. - Bakircioglu, M. - Yasuno, K. - Ho, W. - Sanders, S. - Zhu, Y. - Yilmaz, S. - Dincer, A. - Johnson, M. H. - Bronen, R. A. - Kocer, N. - Per, H. - Mane, S. - Pamir, M. N. - Yalcinkaya, C. - Kumandas, S. - Topcu, M. - Ozmen, M. - Sestan, N. - Lifton, R. P. - State, M. W. - Gunel, M.
Journal: Nature

The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

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Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase.

Publication Date: 2010 Aug 19 PMID: 20725044
Authors: Huang, C. S. - Sadre-Bazzaz, K. - Shen, Y. - Deng, B. - Zhou, Z. H. - Tong, L.
Journal: Nature

Propionyl-coenzyme A carboxylase (PCC), a mitochondrial biotin-dependent enzyme, is essential for the catabolism of the amino acids Thr, Val, Ile and Met, cholesterol and fatty acids with an odd number of carbon atoms. Deficiencies in PCC activity in humans are linked to the disease propionic acidaemia, an autosomal recessive disorder that can be fatal in infants. The holoenzyme of PCC is an alpha(6)beta(6) dodecamer, with a molecular mass of 750 kDa. The alpha-subunit contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, whereas the beta-subunit supplies the carboxyltransferase (CT) activity. Here we report the crystal structure at 3.2-A resolution of a bacterial PCC alpha(6)beta(6) holoenzyme as well as cryo-electron microscopy (cryo-EM) reconstruction at 15-A resolution demonstrating a similar structure for human PCC. The structure defines the overall architecture of PCC and reveals unexpectedly that the alpha-subunits are arranged as monomers in the holoenzyme, decorating a central beta(6) hexamer. A hitherto unrecognized domain in the alpha-subunit, formed by residues between the BC and BCCP domains, is crucial for interactions with the beta-subunit. We have named it the BT domain. The structure reveals for the first time the relative positions of the BC and CT active sites in the holoenzyme. They are separated by approximately 55 A, indicating that the entire BCCP domain must translocate during catalysis. The BCCP domain is located in the active site of the beta-subunit in the current structure, providing insight for its involvement in the CT reaction. The structural information establishes a molecular basis for understanding the large collection of disease-causing mutations in PCC and is relevant for the holoenzymes of other biotin-dependent carboxylases, including 3-methylcrotonyl-CoA carboxylase (MCC) and eukaryotic acetyl-CoA carboxylase (ACC).

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A mechanically stabilized receptor-ligand flex-bond important in the vasculature.

Publication Date: 2010 Aug 19 PMID: 20725043
Authors: Kim, J. - Zhang, C. Z. - Zhang, X. - Springer, T. A.
Journal: Nature

Haemostasis in the arteriolar circulation mediated by von Willebrand factor (VWF) binding to platelets is an example of an adhesive interaction that must withstand strong hydrodynamic forces acting on cells. VWF is a concatenated, multifunctional protein that has binding sites for platelets as well as subendothelial collagen. Binding of the A1 domain in VWF to the glycoprotein Ib alpha subunit (GPIbalpha) on the surface of platelets mediates crosslinking of platelets to one another and the formation of a platelet plug for arterioles. The importance of VWF is illustrated by its mutation in von Willebrand disease, a bleeding diathesis. Here, we describe a novel mechanochemical specialization of the A1-GPIbalpha bond for force-resistance. We have developed a method that enables, for the first time, repeated measurements of the binding and unbinding of a receptor and ligand in a single molecule (ReaLiSM). We demonstrate two states of the receptor-ligand bond, that is, a flex-bond. One state is seen at low force; a second state begins to engage at 10 pN with a approximately 20-fold longer lifetime and greater force resistance. The lifetimes of the two states, how force exponentiates lifetime, and the kinetics of switching between the two states are all measured. For the first time, single-molecule measurements on this system are in agreement with bulk phase measurements. The results have important implications not only for how platelets bound to VWF are able to resist force to plug arterioles, but also how increased flow activates platelet plug formation.

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Trans-acting small RNA determines dominance relationships in Brassica self-incompatibility.

Publication Date: 2010 Aug 19 PMID: 20725042
Authors: Tarutani, Y. - Shiba, H. - Iwano, M. - Kakizaki, T. - Suzuki, G. - Watanabe, M. - Isogai, A. - Takayama, S.
Journal: Nature

A diploid organism has two copies of each gene, one inherited from each parent. The expression of two inherited alleles is sometimes biased by the effects known as dominant/recessive relationships, which determine the final phenotype of the organism. To explore the mechanisms underlying these relationships, we have examined the monoallelic expression of S-locus protein 11 genes (SP11), which encode the male determinants of self-incompatibility in Brassica. We previously reported that SP11 expression was monoallelic in some S heterozygotes, and that the promoter regions of recessive SP11 alleles were specifically methylated in the anther tapetum. Here we show that this methylation is controlled by trans-acting small non-coding RNA (sRNA). We identified inverted genomic sequences that were similar to the recessive SP11 promoters in the flanking regions of dominant SP11 alleles. These sequences were specifically expressed in the anther tapetum and processed into 24-nucleotide sRNA, named SP11 methylation inducer (Smi). Introduction of the Smi genomic region into the recessive S homozygotes triggered the methylation of the promoter of recessive SP11 alleles and repressed their transcription. This is an example showing sRNA encoded in the flanking region of a dominant allele acts in trans to induce transcriptional silencing of the recessive allele. Our finding may provide new insights into the widespread monoallelic gene expression systems.

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Microenvironmental reprogramming of thymic epithelial cells to skin multipotent stem cells.

Publication Date: 2010 Aug 19 PMID: 20725041
Authors: Bonfanti, P. - Claudinot, S. - Amici, A. W. - Farley, A. - Blackburn, C. C. - Barrandon, Y.
Journal: Nature

The thymus develops from the third pharyngeal pouch of the anterior gut and provides the necessary environment for thymopoiesis (the process by which thymocytes differentiate into mature T lymphocytes) and the establishment and maintenance of self-tolerance. It contains thymic epithelial cells (TECs) that form a complex three-dimensional network organized in cortical and medullary compartments, the organization of which is notably different from simple or stratified epithelia. TECs have an essential role in the generation of self-tolerant thymocytes through expression of the autoimmune regulator Aire, but the mechanisms involved in the specification and maintenance of TECs remain unclear. Despite the different embryological origins of thymus and skin (endodermal and ectodermal, respectively), some cells of the thymic medulla express stratified-epithelium markers, interpreted as promiscuous gene expression. Here we show that the thymus of the rat contains a population of clonogenic TECs that can be extensively cultured while conserving the capacity to integrate in a thymic epithelial network and to express major histocompatibility complex class II (MHC II) molecules and Aire. These cells can irreversibly adopt the fate of hair follicle multipotent stem cells when exposed to an inductive skin microenvironment; this change in fate is correlated with robust changes in gene expression. Hence, microenvironmental cues are sufficient here to re-direct epithelial cell fate, allowing crossing of primitive germ layer boundaries and an increase in potency.

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An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.

Publication Date: 2010 Aug 19 PMID: 20725040
Authors: Berry, M. P. - Graham, C. M. - McNab, F. W. - Xu, Z. - Bloch, S. A. - Oni, T. - Wilkinson, K. A. - Banchereau, R. - Skinner, J. - Wilkinson, R. J. - Quinn, C. - Blankenship, D. - Dhawan, R. - Cush, J. J. - Mejias, A. - Ramilo, O. - Kon, O. M. - Pascual, V. - Banchereau, J. - Chaussabel, D. - O'Garra, A.
Journal: Nature

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-gamma and type I IFN-alphabeta signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-alphabeta signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.

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Promiscuity and the evolutionary transition to complex societies.

Publication Date: 2010 Aug 19 PMID: 20725039
Authors: Cornwallis, C. K. - West, S. A. - Davis, K. E. - Griffin, A. S.
Journal: Nature

Theory predicts that the evolution of cooperative behaviour is favoured by low levels of promiscuity leading to high within-group relatedness. However, in vertebrates, cooperation often occurs between non-relatives and promiscuity rates are among the highest recorded. Here we resolve this apparent inconsistency with a phylogenetic analysis of 267 bird species, demonstrating that cooperative breeding is associated with low promiscuity; that in cooperative species, helping is more common when promiscuity is low; and that intermediate levels of promiscuity favour kin discrimination. Overall, these results suggest that promiscuity is a unifying feature across taxa in explaining transitions to and from cooperative societies.

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The 2009 Samoa-Tonga great earthquake triggered doublet.

Publication Date: 2010 Aug 19 PMID: 20725038
Authors: Lay, T. - Ammon, C. J. - Kanamori, H. - Rivera, L. - Koper, K. D. - Hutko, A. R.
Journal: Nature

Great earthquakes (having seismic magnitudes of at least 8) usually involve abrupt sliding of rock masses at a boundary between tectonic plates. Such interplate ruptures produce dynamic and static stress changes that can activate nearby intraplate aftershocks, as is commonly observed in the trench-slope region seaward of a great subduction zone thrust event. The earthquake sequence addressed here involves a rare instance in which a great trench-slope intraplate earthquake triggered extensive interplate faulting, reversing the typical pattern and broadly expanding the seismic and tsunami hazard. On 29 September 2009, within two minutes of the initiation of a normal faulting event with moment magnitude 8.1 in the outer trench-slope at the northern end of the Tonga subduction zone, two major interplate underthrusting subevents (both with moment magnitude 7.8), with total moment equal to a second great earthquake of moment magnitude 8.0, ruptured the nearby subduction zone megathrust. The collective faulting produced tsunami waves with localized regions of about 12 metres run-up that claimed 192 lives in Samoa, American Samoa and Tonga. Overlap of the seismic signals obscured the fact that distinct faults separated by more than 50 km had ruptured with different geometries, with the triggered thrust faulting only being revealed by detailed seismic wave analyses. Extensive interplate and intraplate aftershock activity was activated over a large region of the northern Tonga subduction zone.

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Near-simultaneous great earthquakes at Tongan megathrust and outer rise in September 2009.

Publication Date: 2010 Aug 19 PMID: 20725037
Authors: Beavan, J. - Wang, X. - Holden, C. - Wilson, K. - Power, W. - Prasetya, G. - Bevis, M. - Kautoke, R.
Journal: Nature

The Earth's largest earthquakes and tsunamis are usually caused by thrust-faulting earthquakes on the shallow part of the subduction interface between two tectonic plates, where stored elastic energy due to convergence between the plates is rapidly released. The tsunami that devastated the Samoan and northern Tongan islands on 29 September 2009 was preceded by a globally recorded magnitude-8 normal-faulting earthquake in the outer-rise region, where the Pacific plate bends before entering the subduction zone. Preliminary interpretation suggested that this earthquake was the source of the tsunami. Here we show that the outer-rise earthquake was accompanied by a nearly simultaneous rupture of the shallow subduction interface, equivalent to a magnitude-8 earthquake, that also contributed significantly to the tsunami. The subduction interface event was probably a slow earthquake with a rise time of several minutes that triggered the outer-rise event several minutes later. However, we cannot rule out the possibility that the normal fault ruptured first and dynamically triggered the subduction interface event. Our evidence comes from displacements of Global Positioning System stations and modelling of tsunami waves recorded by ocean-bottom pressure sensors, with support from seismic data and tsunami field observations. Evidence of the subduction earthquake in global seismic data is largely hidden because of the earthquake's slow rise time or because its ground motion is disguised by that of the normal-faulting event. Earthquake doublets where subduction interface events trigger large outer-rise earthquakes have been recorded previously, but this is the first well-documented example where the two events occur so closely in time and the triggering event might be a slow earthquake. As well as providing information on strain release mechanisms at subduction zones, earthquakes such as this provide a possible mechanism for the occasional large tsunamis generated at the Tonga subduction zone, where slip between the plates is predominantly aseismic.

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A strong ferroelectric ferromagnet created by means of spin-lattice coupling.

Publication Date: 2010 Aug 19 PMID: 20725036
Authors: Lee, J. H. - Fang, L. - Vlahos, E. - Ke, X. - Jung, Y. W. - Kourkoutis, L. F. - Kim, J. W. - Ryan, P. J. - Heeg, T. - Roeckerath, M. - Goian, V. - Bernhagen, M. - Uecker, R. - Hammel, P. C. - Rabe, K. M. - Kamba, S. - Schubert, J. - Freeland, J. W. - Muller, D. A. - Fennie, C. J. - Schiffer, P. - Gopalan, V. - Johnston-Halperin, E. - Schlom, D. G.
Journal: Nature

Ferroelectric ferromagnets are exceedingly rare, fundamentally interesting multiferroic materials that could give rise to new technologies in which the low power and high speed of field-effect electronics are combined with the permanence and routability of voltage-controlled ferromagnetism. Furthermore, the properties of the few compounds that simultaneously exhibit these phenomena are insignificant in comparison with those of useful ferroelectrics or ferromagnets: their spontaneous polarizations or magnetizations are smaller by a factor of 1,000 or more. The same holds for magnetic- or electric-field-induced multiferroics. Owing to the weak properties of single-phase multiferroics, composite and multilayer approaches involving strain-coupled piezoelectric and magnetostrictive components are the closest to application today. Recently, however, a new route to ferroelectric ferromagnets was proposed by which magnetically ordered insulators that are neither ferroelectric nor ferromagnetic are transformed into ferroelectric ferromagnets using a single control parameter, strain. The system targeted, EuTiO(3), was predicted to exhibit strong ferromagnetism (spontaneous magnetization, approximately 7 Bohr magnetons per Eu) and strong ferroelectricity (spontaneous polarization, approximately 10 microC cm(-2)) simultaneously under large biaxial compressive strain. These values are orders of magnitude higher than those of any known ferroelectric ferromagnet and rival the best materials that are solely ferroelectric or ferromagnetic. Hindered by the absence of an appropriate substrate to provide the desired compression we turned to tensile strain. Here we show both experimentally and theoretically the emergence of a multiferroic state under biaxial tension with the unexpected benefit that even lower strains are required, thereby allowing thicker high-quality crystalline films. This realization of a strong ferromagnetic ferroelectric points the way to high-temperature manifestations of this spin-lattice coupling mechanism. Our work demonstrates that a single experimental parameter, strain, simultaneously controls multiple order parameters and is a viable alternative tuning parameter to composition for creating multiferroics.

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Enhancement of superconductivity by pressure-driven competition in electronic order.

Publication Date: 2010 Aug 19 PMID: 20725035
Authors: Chen, X. J. - Struzhkin, V. V. - Yu, Y. - Goncharov, A. F. - Lin, C. T. - Mao, H. K. - Hemley, R. J.
Journal: Nature

Finding ways to achieve higher values of the transition temperature, T(c), in superconductors remains a great challenge. The superconducting phase is often one of several competing types of electronic order, including antiferromagnetism and charge density waves. An emerging trend documented in heavy-fermion and organic conductors is that the maximum T(c) for superconductivity occurs under external conditions that cause the critical temperature for a competing order to go to zero. Recently, such competition has been found in multilayer copper oxide high-temperature superconductors (HTSCs) that possess two crystallographically inequivalent CuO(2) planes in the unit cell. However, whether the competing electronic state can be suppressed to enhance T(c) in HTSCs remains an open question. Here we show that pressure-driven phase competition leads to an unusual two-step enhancement of T(c) in optimally doped trilayer Bi(2)Sr(2)Ca(2)Cu(3)O(10+delta) (Bi2223). We find that T(c) first increases with pressure and then decreases after passing through a maximum. Unexpectedly, T(c) increases again when the pressure is further raised above a critical value of around 24 GPa, surpassing the first maximum. The presence of this critical pressure is a manifestation of the crossover from the competing order to superconductivity in the inner of the three CuO(2) planes. We suggest that the increase at higher pressures occurs as a result of competition between pairing and phase ordering in different CuO(2) planes.

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Waves on the surface of the Orion molecular cloud.

Publication Date: 2010 Aug 19 PMID: 20725034
Authors: Berne, O. - Marcelino, N. - Cernicharo, J.
Journal: Nature

Massive stars influence their parental molecular cloud, and it has long been suspected that the development of hydrodynamical instabilities can compress or fragment the cloud. Identifying such instabilities has proved difficult. It has been suggested that elongated structures (such as the 'pillars of creation') and other shapes arise because of instabilities, but alternative explanations are available. One key signature of an instability is a wave-like structure in the gas, which has hitherto not been seen. Here we report the presence of 'waves' at the surface of the Orion molecular cloud near where massive stars are forming. The waves seem to be a Kelvin-Helmholtz instability that arises during the expansion of the nebula as gas heated and ionized by massive stars is blown over pre-existing molecular gas.

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Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1.

Publication Date: 2010 Aug 19 PMID: 20725033
Authors: Nakada, S. - Tai, I. - Panier, S. - Al-Hakim, A. - Iemura, S. - Juang, Y. C. - O'Donnell, L. - Kumakubo, A. - Munro, M. - Sicheri, F. - Gingras, A. C. - Natsume, T. - Suda, T. - Durocher, D.
Journal: Nature

DNA double-strand breaks (DSBs) pose a potent threat to genome integrity. These lesions also contribute to the efficacy of radiotherapy and many cancer chemotherapeutics. DSBs elicit a signalling cascade that modifies the chromatin surrounding the break, first by ATM-dependent phosphorylation and then by RNF8-, RNF168- and BRCA1-dependent regulatory ubiquitination. Here we report that OTUB1, a deubiquitinating enzyme, is an inhibitor of DSB-induced chromatin ubiquitination. Surprisingly, we found that OTUB1 suppresses RNF168-dependent poly-ubiquitination independently of its catalytic activity. OTUB1 does so by binding to and inhibiting UBC13 (also known as UBE2N), the cognate E2 enzyme for RNF168. This unusual mode of regulation is unlikely to be limited to UBC13 because analysis of OTUB1-associated proteins revealed that OTUB1 binds to E2s of the UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigates the DSB repair defect associated with defective ATM signalling, indicating that pharmacological targeting of the OTUB1-UBC13 interaction might enhance the DNA damage response.

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Obituary: Stephen Henry Schneider (1945-2010).

Publication Date: 2010 Aug 19 PMID: 20725032
Authors: Mastrandrea, M. D.
Journal: Nature

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Earthquakes: Double trouble at Tonga.

Publication Date: 2010 Aug 19 PMID: 20725031
Authors: Satake, K.
Journal: Nature

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Evolutionary biology: Oh sibling, who art thou?

Publication Date: 2010 Aug 19 PMID: 20725030
Authors: Cockburn, A.
Journal: Nature

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DNA repair: Blocking ubiquitin transfer.

Publication Date: 2010 Aug 19 PMID: 20725029
Authors: Rose, A. - Schlieker, C.
Journal: Nature

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Astrophysics: Waves on Orion's shores.

Publication Date: 2010 Aug 19 PMID: 20725028
Authors: Bally, J.
Journal: Nature

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Gene expression: How plants avoid incest.

Publication Date: 2010 Aug 19 PMID: 20725026
Authors: Goring, D. - Indriolo, E.
Journal: Nature

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Atmospheric chemistry: A missing sink for radicals.

Publication Date: 2010 Aug 19 PMID: 20725025
Authors: Lelieveld, J.
Journal: Nature

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Culturing practices can make roots more robust too.

Publication Date: 2010 Aug 19 PMID: 20725021
Authors: Uphoff, N.
Journal: Nature

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Reduce soil damage for more sustainable crop production.

Publication Date: 2010 Aug 19 PMID: 20725020
Authors: Tullberg, J.
Journal: Nature

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Mitigate food loss to feed more people right now.

Publication Date: 2010 Aug 19 PMID: 20725019
Authors: Nicholls, T.
Journal: Nature

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Track social and economic impacts of food production.

Publication Date: 2010 Aug 19 PMID: 20725018
Authors: Gunasekera, D. - Finnigan, J.
Journal: Nature

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Monitoring systems outdated and protectionist.

Publication Date: 2010 Aug 19 PMID: 20725017
Authors: Bawa, K. S.
Journal: Nature

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World view: Leaders wanted.

Publication Date: 2010 Aug 19 PMID: 20725016
Authors: Macilwain, C.
Journal: Nature

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Biotechnology: Crossing the barrier.

Publication Date: 2010 Aug 19 PMID: 20725015
Authors: Vastag, B.
Journal: Nature

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Physiology: The bones of contention.

Publication Date: 2010 Aug 19 PMID: 20725014
Authors: Katsnelson, A.
Journal: Nature

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E-mails spark ethics row.

Publication Date: 2010 Aug 19 PMID: 20725013
Authors: Dalton, R.
Journal: Nature

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Jet reveals atmosphere's secrets.

Publication Date: 2010 Aug 19 PMID: 20725012
Authors: Tollefson, J.
Journal: Nature

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Science panel gives hope in river-pollution dispute.

Publication Date: 2010 Aug 19 PMID: 20725011
Authors: Petherick, A.
Journal: Nature

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US survey sets cosmic priorities.

Publication Date: 2010 Aug 19 PMID: 20725010
Authors: Mann, A.
Journal: Nature

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FDA challenges stem-cell clinic.

Publication Date: 2010 Aug 19 PMID: 20725009
Authors: Cyranoski, D.
Journal: Nature

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Harvard probe kept under wraps.

Publication Date: 2010 Aug 19 PMID: 20725008
Authors: Ledford, H.
Journal: Nature

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Journal club. A cancer biologist weighs up p53, metabolism and cancer.

Publication Date: 2010 Aug 19 PMID: 20725003
Authors: Melino, G.
Journal: Nature

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Far-sighted vision.

Publication Date: 2010 Aug 19 PMID: 20724996
Authors:
Journal: Nature

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After the pandemic.

Publication Date: 2010 Aug 19 PMID: 20724995
Authors:
Journal: Nature

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Inferring echolocation in ancient bats.

Publication Date: 2010 Aug 19 PMID: 20724993
Authors: Simmons, N. B. - Seymour, K. L. - Habersetzer, J. - Gunnell, G. F.
Journal: Nature

Laryngeal echolocation, used by most living bats to form images of their surroundings and to detect and capture flying prey, is considered to be a key innovation for the evolutionary success of bats, and palaeontologists have long sought osteological correlates of echolocation that can be used to infer the behaviour of fossil bats. Veselka et al. argued that the most reliable trait indicating echolocation capabilities in bats is an articulation between the stylohyal bone (part of the hyoid apparatus that supports the throat and larynx) and the tympanic bone, which forms the floor of the middle ear. They examined the oldest and most primitive known bat, Onychonycteris finneyi (early Eocene, USA), and argued that it showed evidence of this stylohyal-tympanic articulation, from which they concluded that O. finneyi may have been capable of echolocation. We disagree with their interpretation of key fossil data and instead argue that O. finneyi was probably not an echolocating bat.

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Laryngeally echolocating bats.

Publication Date: 2010 Aug 19 PMID: 20724991
Authors: Wittrock, U.
Journal: Nature

Echolocation of bats is a fascinating topic with an ongoing controversy regarding the signal processing that bats perform on the echo. Veselka et al. found that bats that use the larynx for producing the echolocating ultrasound have a stylohyal bone that connects the larynx to the auditory bulla. I propose that the stylohyal bone is used for heterodyne detection of Doppler-shifted echoes. This would allow very precise frequency resolution and phase-sensitive analysis of the returning echoes for determining the velocity of echolocated objects like insects.

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Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase.

Publication Date: 2010 Sep 2 PMID: 20720542
Authors: Poulsen, H. - Khandelia, H. - Morth, J. P. - Bublitz, M. - Mouritsen, O. G. - Egebjerg, J. - Nissen, P.
Journal: Nature

The Na(+)/K(+)-ATPase pumps three sodium ions out of and two potassium ions into the cell for each ATP molecule that is split, thereby generating the chemical and electrical gradients across the plasma membrane that are essential in, for example, signalling, secondary transport and volume regulation in animal cells. Crystal structures of the potassium-bound form of the pump revealed an intimate docking of the alpha-subunit carboxy terminus at the transmembrane domain. Here we show that this element is a key regulator of a previously unrecognized ion pathway. Current models of P-type ATPases operate with a single ion conduit through the pump, but our data suggest an additional pathway in the Na(+)/K(+)-ATPase between the ion-binding sites and the cytoplasm. The C-terminal pathway allows a cytoplasmic proton to enter and stabilize site III when empty in the potassium-bound state, and when potassium is released the proton will also return to the cytoplasm, thus allowing an overall asymmetric stoichiometry of the transported ions. The C terminus controls the gate to the pathway. Its structure is crucial for pump function, as demonstrated by at least eight mutations in the region that cause severe neurological diseases. This novel model for ion transport by the Na(+)/K(+)-ATPase is established by electrophysiological studies of C-terminal mutations in familial hemiplegic migraine 2 (FHM2) and is further substantiated by molecular dynamics simulations. A similar ion regulation is likely to apply to the H(+)/K(+)-ATPase and the Ca(2+)-ATPase.

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Comprehensive methylome map of lineage commitment from haematopoietic progenitors.

Publication Date: 2010 Aug 15 PMID: 20720541
Authors: Ji, H. - Ehrlich, L. I. - Seita, J. - Murakami, P. - Doi, A. - Lindau, P. - Lee, H. - Aryee, M. J. - Irizarry, R. A. - Kim, K. - Rossi, D. J. - Inlay, M. A. - Serwold, T. - Karsunky, H. - Ho, L. - Daley, G. Q. - Weissman, I. L. - Feinberg, A. P.
Journal: Nature

Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions.

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Single-atom-resolved fluorescence imaging of an atomic Mott insulator.

Publication Date: 2010 Sep 2 PMID: 20720540
Authors: Sherson, J. F. - Weitenberg, C. - Endres, M. - Cheneau, M. - Bloch, I. - Kuhr, S.
Journal: Nature

The reliable detection of single quantum particles has revolutionized the field of quantum optics and quantum information processing. For several years, researchers have aspired to extend such detection possibilities to larger-scale, strongly correlated quantum systems in order to record in situ images of a quantum fluid in which each underlying quantum particle is detected. Here we report fluorescence imaging of strongly interacting bosonic Mott insulators in an optical lattice with single-atom and single-site resolution. From our images, we fully reconstruct the atom distribution on the lattice and identify individual excitations with high fidelity. A comparison of the radial density and variance distributions with theory provides a precise in situ temperature and entropy measurement from single images. We observe Mott-insulating plateaus with near-zero entropy and clearly resolve the high-entropy rings separating them, even though their width is of the order of just a single lattice site. Furthermore, we show how a Mott insulator melts with increasing temperature, owing to a proliferation of local defects. The ability to resolve individual lattice sites directly opens up new avenues for the manipulation, analysis and applications of strongly interacting quantum gases on a lattice. For example, one could introduce local perturbations or access regions of high entropy, a crucial requirement for the implementation of novel cooling schemes.

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Mediator and cohesin connect gene expression and chromatin architecture.

Publication Date: 2010 Aug 18 PMID: 20720539
Authors: Kagey, M. H. - Newman, J. J. - Bilodeau, S. - Zhan, Y. - Orlando, D. A. - van Berkum, N. L. - Ebmeier, C. C. - Goossens, J. - Rahl, P. B. - Levine, S. S. - Taatjes, D. J. - Dekker, J. - Young, R. A.
Journal: Nature

Transcription factors control cell-specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. Here we report that mediator and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect two DNA segments. The cohesin-loading factor Nipbl is associated with mediator-cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell-type-specific DNA loops linked to the gene expression program of each cell.

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Graphene as a subnanometre trans-electrode membrane.

Publication Date: 2010 Aug 18 PMID: 20720538
Authors: Garaj, S. - Hubbard, W. - Reina, A. - Kong, J. - Branton, D. - Golovchenko, J. A.
Journal: Nature

Isolated, atomically thin conducting membranes of graphite, called graphene, have recently been the subject of intense research with the hope that practical applications in fields ranging from electronics to energy science will emerge. The atomic thinness, stability and electrical sensitivity of graphene motivated us to investigate the potential use of graphene membranes and graphene nanopores to characterize single molecules of DNA in ionic solution. Here we show that when immersed in an ionic solution, a layer of graphene becomes a new electrochemical structure that we call a trans-electrode. The trans-electrode's unique properties are the consequence of the atomic-scale proximity of its two opposing liquid-solid interfaces together with graphene's well known in-plane conductivity. We show that several trans-electrode properties are revealed by ionic conductance measurements on a graphene membrane that separates two aqueous ionic solutions. Although our membranes are only one to two atomic layers thick, we find they are remarkable ionic insulators with a very small stable conductance that depends on the ion species in solution. Electrical measurements on graphene membranes in which a single nanopore has been drilled show that the membrane's effective insulating thickness is less than one nanometre. This small effective thickness makes graphene an ideal substrate for very high resolution, high throughput nanopore-based single-molecule detectors. The sensitivity of graphene's in-plane electronic conductivity to its immediate surface environment and trans-membrane solution potentials will offer new insights into atomic surface processes and sensor development opportunities.

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Structure of the LexA-DNA complex and implications for SOS box measurement.

Publication Date: 2010 Aug 12 PMID: 20703307
Authors: Zhang, A. P. - Pigli, Y. Z. - Rice, P. A.
Journal: Nature

The eubacterial SOS system is a paradigm of cellular DNA damage and repair, and its activation can contribute to antibiotic resistance. Under normal conditions, LexA represses the transcription of many DNA repair proteins by binding to SOS 'boxes' in their operators. Under genotoxic stress, accumulating complexes of RecA, ATP and single-stranded DNA (ssDNA) activate LexA for autocleavage. To address how LexA recognizes its binding sites, we determined three crystal structures of Escherichia coli LexA in complex with SOS boxes. Here we report the structure of these LexA-DNA complexes. The DNA-binding domains of the LexA dimer interact with the DNA in the classical fashion of a winged helix-turn-helix motif. However, the wings of these two DNA-binding domains bind to the same minor groove of the DNA. These wing-wing contacts may explain why the spacing between the two half-sites of E. coli SOS boxes is invariant.

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Amygdalar and hippocampal substrates of anxious temperament differ in their heritability.

Publication Date: 2010 Aug 12 PMID: 20703306
Authors: Oler, J. A. - Fox, A. S. - Shelton, S. E. - Rogers, J. - Dyer, T. D. - Davidson, R. J. - Shelledy, W. - Oakes, T. R. - Blangero, J. - Kalin, N. H.
Journal: Nature

Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we studied a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution (18)F-labelled deoxyglucose positron-emission tomography (FDG-PET) was selected as the imaging modality because it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Here we demonstrate that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. We also show significant heritability of the AT phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, we reveal significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT is not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differ from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk of developing anxiety and depression.

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Evidence for stone-tool-assisted consumption of animal tissues before 3.39 million years ago at Dikika, Ethiopia.

Publication Date: 2010 Aug 12 PMID: 20703305
Authors: McPherron, S. P. - Alemseged, Z. - Marean, C. W. - Wynn, J. G. - Reed, D. - Geraads, D. - Bobe, R. - Bearat, H. A.
Journal: Nature

The oldest direct evidence of stone tool manufacture comes from Gona (Ethiopia) and dates to between 2.6 and 2.5 million years (Myr) ago. At the nearby Bouri site several cut-marked bones also show stone tool use approximately 2.5 Myr ago. Here we report stone-tool-inflicted marks on bones found during recent survey work in Dikika, Ethiopia, a research area close to Gona and Bouri. On the basis of low-power microscopic and environmental scanning electron microscope observations, these bones show unambiguous stone-tool cut marks for flesh removal and percussion marks for marrow access. The bones derive from the Sidi Hakoma Member of the Hadar Formation. Established (40)Ar-(39)Ar dates on the tuffs that bracket this member constrain the finds to between 3.42 and 3.24 Myr ago, and stratigraphic scaling between these units and other geological evidence indicate that they are older than 3.39 Myr ago. Our discovery extends by approximately 800,000 years the antiquity of stone tools and of stone-tool-assisted consumption of ungulates by hominins; furthermore, this behaviour can now be attributed to Australopithecus afarensis.

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Evidence for the survival of the oldest terrestrial mantle reservoir.

Publication Date: 2010 Aug 12 PMID: 20703304
Authors: Jackson, M. G. - Carlson, R. W. - Kurz, M. D. - Kempton, P. D. - Francis, D. - Blusztajn, J.
Journal: Nature

Helium is a powerful tracer of primitive material in Earth's mantle. Extremely high (3)He/(4)He ratios in some ocean-island basalts suggest the presence of relatively undegassed and undifferentiated material preserved in Earth's mantle. However, terrestrial lavas with high (3)He/(4)He ratios have never been observed to host the primitive lead-isotopic compositions that are required for an early (roughly 4.5 Gyr ago) formation age. Here we show that Cenozoic-era Baffin Island and West Greenland lavas, previously found to host the highest terrestrial-mantle (3)He/(4)He ratios, exhibit primitive lead-isotope ratios that are consistent with an ancient mantle source age of 4.55-4.45 Gyr. The Baffin Island and West Greenland lavas also exhibit (143)Nd/(144)Nd ratios similar to values recently proposed for an early-formed (roughly 4.5 Gyr ago) terrestrial mantle reservoir. The combined helium-, lead- and Nd-isotopic compositions in Baffin Island and West Greenland lavas therefore suggest that their source is the most ancient accessible reservoir in the Earth's mantle, and it may be parental to all mantle reservoirs that give rise to modern volcanism.

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Precipitation-generated oscillations in open cellular cloud fields.

Publication Date: 2010 Aug 12 PMID: 20703303
Authors: Feingold, G. - Koren, I. - Wang, H. - Xue, H. - Brewer, W. A.
Journal: Nature

Cloud fields adopt many different patterns that can have a profound effect on the amount of sunlight reflected back to space, with important implications for the Earth's climate. These cloud patterns can be observed in satellite images of the Earth and often exhibit distinct cell-like structures associated with organized convection at scales of tens of kilometres. Recent evidence has shown that atmospheric aerosol particles-through their influence on precipitation formation-help to determine whether cloud fields take on closed (more reflective) or open (less reflective) cellular patterns. The physical mechanisms controlling the formation and evolution of these cells, however, are still poorly understood, limiting our ability to simulate realistically the effects of clouds on global reflectance. Here we use satellite imagery and numerical models to show how precipitating clouds produce an open cellular cloud pattern that oscillates between different, weakly stable states. The oscillations are a result of precipitation causing downward motion and outflow from clouds that were previously positively buoyant. The evaporating precipitation drives air down to the Earth's surface, where it diverges and collides with the outflows of neighbouring precipitating cells. These colliding outflows form surface convergence zones and new cloud formation. In turn, the newly formed clouds produce precipitation and new colliding outflow patterns that are displaced from the previous ones. As successive cycles of this kind unfold, convergence zones alternate with divergence zones and new cloud patterns emerge to replace old ones. The result is an oscillating, self-organized system with a characteristic cell size and precipitation frequency.

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Nanoscale scanning probe ferromagnetic resonance imaging using localized modes.

Publication Date: 2010 Aug 12 PMID: 20703302
Authors: Lee, I. - Obukhov, Y. - Xiang, G. - Hauser, A. - Yang, F. - Banerjee, P. - Pelekhov, D. V. - Hammel, P. C.
Journal: Nature

The discovery of new phenomena in layered and nanostructured magnetic devices is driving rapid growth in nanomagnetics research. Resulting applications such as giant magnetoresistive field sensors and spin torque devices are fuelling advances in information and communications technology, magnetoelectronic sensing and biomedicine. There is an urgent need for high-resolution magnetic-imaging tools capable of characterizing these complex, often buried, nanoscale structures. Conventional ferromagnetic resonance (FMR) provides quantitative information about ferromagnetic materials and interacting multicomponent magnetic structures with spectroscopic precision and can distinguish components of complex bulk samples through their distinctive spectroscopic features. However, it lacks the sensitivity to probe nanoscale volumes and has no imaging capabilities. Here we demonstrate FMR imaging through spin-wave localization. Although the strong interactions in a ferromagnet favour the excitation of extended collective modes, we show that the intense, spatially confined magnetic field of the micromagnetic probe tip used in FMR force microscopy can be used to localize the FMR mode immediately beneath the probe. We demonstrate FMR modes localized within volumes having 200 nm lateral dimensions, and improvements of the approach may allow these dimensions to be decreased to tens of nanometres. Our study shows that this approach is capable of providing the microscopic detail required for the characterization of ferromagnets used in fields ranging from spintronics to biomagnetism. This method is applicable to buried and surface magnets, and, being a resonance technique, measures local internal fields and other magnetic properties with spectroscopic precision.

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Scale-free structural organization of oxygen interstitials in La(2)CuO(4+y).

Publication Date: 2010 Aug 12 PMID: 20703301
Authors: Fratini, M. - Poccia, N. - Ricci, A. - Campi, G. - Burghammer, M. - Aeppli, G. - Bianconi, A.
Journal: Nature

It is well known that the microstructures of the transition-metal oxides, including the high-transition-temperature (high-T(c)) copper oxide superconductors, are complex. This is particularly so when there are oxygen interstitials or vacancies, which influence the bulk properties. For example, the oxygen interstitials in the spacer layers separating the superconducting CuO(2) planes undergo ordering phenomena in Sr(2)O(1+y)CuO(2) (ref. 9), YBa(2)Cu(3)O(6+y) (ref. 10) and La(2)CuO(4+y) (refs 11-15) that induce enhancements in the transition temperatures with no changes in hole concentrations. It is also known that complex systems often have a scale-invariant structural organization, but hitherto none had been found in high-T(c) materials. Here we report that the ordering of oxygen interstitials in the La(2)O(2+y) spacer layers of La(2)CuO(4+y) high-T(c) superconductors is characterized by a fractal distribution up to a maximum limiting size of 400 mum. Intriguingly, these fractal distributions of dopants seem to enhance superconductivity at high temperature.

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Mammalian microRNAs predominantly act to decrease target mRNA levels.

Publication Date: 2010 Aug 12 PMID: 20703300
Authors: Guo, H. - Ingolia, N. T. - Weissman, J. S. - Bartel, D. P.
Journal: Nature

MicroRNAs (miRNAs) are endogenous approximately 22-nucleotide RNAs that mediate important gene-regulatory events by pairing to the mRNAs of protein-coding genes to direct their repression. Repression of these regulatory targets leads to decreased translational efficiency and/or decreased mRNA levels, but the relative contributions of these two outcomes have been largely unknown, particularly for endogenous targets expressed at low-to-moderate levels. Here, we use ribosome profiling to measure the overall effects on protein production and compare these to simultaneously measured effects on mRNA levels. For both ectopic and endogenous miRNA regulatory interactions, lowered mRNA levels account for most (>/=84%) of the decreased protein production. These results show that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output.

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Mesenchymal and haematopoietic stem cells form a unique bone marrow niche.

Publication Date: 2010 Aug 12 PMID: 20703299
Authors: Mendez-Ferrer, S. - Michurina, T. V. - Ferraro, F. - Mazloom, A. R. - Macarthur, B. D. - Lira, S. A. - Scadden, D. T. - Ma'ayan, A. - Enikolopov, G. N. - Frenette, P. S.
Journal: Nature

The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.

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Palaeoanthropology: Australopithecine butchers.

Publication Date: 2010 Aug 12 PMID: 20703298
Authors: Braun, D. R.
Journal: Nature

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Behavioural neuroscience: Genes and the anxious brain.

Publication Date: 2010 Aug 12 PMID: 20703297
Authors: Meyer-Lindenberg, A.
Journal: Nature

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High-temperature superconductivity: The benefit of fractal dirt.

Publication Date: 2010 Aug 12 PMID: 20703295
Authors: Zaanen, J.
Journal: Nature

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Plant pathology: Sudden larch death.

Publication Date: 2010 Aug 12 PMID: 20703294
Authors: Brasier, C. - Webber, J.
Journal: Nature

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Neuroscience: A mine of imprinted genes.

Publication Date: 2010 Aug 12 PMID: 20703293
Authors: Keverne, E. B.
Journal: Nature

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Geochemistry: Relict mantle from Earth's birth.

Publication Date: 2010 Aug 12 PMID: 20703292
Authors: Graham, D.
Journal: Nature

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Information theory: A signal take on speech.

Publication Date: 2010 Aug 12 PMID: 20703291
Authors: Lewicki, M. S.
Journal: Nature

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Which way for genetic-test regulation? Assign regulation appropriate to the level of risk.

Publication Date: 2010 Aug 12 PMID: 20703288
Authors: Javitt, G.
Journal: Nature

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Which way for genetic-test regulation? Leave test interpretation to specialists.

Publication Date: 2010 Aug 12 PMID: 20703287
Authors: Beaudet, A. L.
Journal: Nature

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Concerns regarding sinking of South Korean warship.

Publication Date: 2010 Aug 12 PMID: 20703286
Authors: Kim, K. S.
Journal: Nature

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Problems in Turkish science run deeper than petty disputes.

Publication Date: 2010 Aug 12 PMID: 20703285
Authors: Kaya, F.
Journal: Nature

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Press release and media distort complex message.

Publication Date: 2010 Aug 12 PMID: 20703284
Authors: Marin, V. H. - Delgado, L. E. - Tironi, A.
Journal: Nature

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Difference between interim and final acid-rain reports.

Publication Date: 2010 Aug 12 PMID: 20703283
Authors: Oreskes, N. - Conway, E. M.
Journal: Nature

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Oceanography: Dead in the water.

Publication Date: 2010 Aug 12 PMID: 20703282
Authors: Gewin, V.
Journal: Nature

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Francis Collins: One year at the helm.

Publication Date: 2010 Aug 12 PMID: 20703281
Authors: Wadman, M.
Journal: Nature

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Supercomputing for the birds.

Publication Date: 2010 Aug 12 PMID: 20703280
Authors: Marris, E.
Journal: Nature

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Mountain mining damages streams.

Publication Date: 2010 Aug 12 PMID: 20703278
Authors: Gilbert, N.
Journal: Nature

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France digs deep for nuclear waste.

Publication Date: 2010 Aug 12 PMID: 20703277
Authors: Butler, D.
Journal: Nature

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Power struggle hits Swedish institute.

Publication Date: 2010 Aug 12 PMID: 20703276
Authors: Abbott, A.
Journal: Nature

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Upbeat oil report questioned.

Publication Date: 2010 Aug 12 PMID: 20703275
Authors: Schrope, M.
Journal: Nature

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Journal club. A glaciologist ponders iceberg calving from a safe distance.

Publication Date: 2010 Aug 12 PMID: 20703269
Authors: Howat, I.
Journal: Nature

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Standard issue.

Publication Date: 2010 Aug 12 PMID: 20703263
Authors:
Journal: Nature

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Cheap shots.

Publication Date: 2010 Aug 12 PMID: 20703262
Authors:
Journal: Nature

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The prion protein as a receptor for amyloid-beta.

Publication Date: 2010 Aug 12 PMID: 20703260
Authors: Kessels, H. W. - Nguyen, L. N. - Nabavi, S. - Malinow, R.
Journal: Nature

Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (LTP), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. Lauren et al. suggested that binding between oligomeric amyloid-beta (a form of amyloid-beta thought to be most active) and the cellular prion protein (PrP(C)) is necessary for synaptic perturbations. Here we show that PrP(C) is not required for amyloid-beta-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-beta-mediated synaptic defects do not require PrP(c).

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Production of p53 gene knockout rats by homologous recombination in embryonic stem cells.

Publication Date: 2010 Aug 11 PMID: 20703227
Authors: Tong, C. - Li, P. - Wu, N. L. - Yan, Y. - Ying, Q. L.
Journal: Nature

The use of homologous recombination to modify genes in embryonic stem (ES) cells provides a powerful means to elucidate gene function and create disease models. Application of this technology to engineer genes in rats has not previously been possible because of the absence of germline-competent ES cells in this species. We have recently established authentic rat ES cells. Here we report the generation of gene knockout rats using the ES-cell-based gene targeting technology. We designed a targeting vector to disrupt the tumour suppressor gene p53 (also known as Tp53) in rat ES cells by means of homologous recombination. p53 gene-targeted rat ES cells can be routinely generated. Furthermore, the p53 gene-targeted mutation in the rat ES-cell genome can transmit through the germ line via ES-cell rat chimaeras to create p53 gene knockout rats. The rat is the most widely used animal model in biological research. The establishment of gene targeting technology in rat ES cells, in combination with advances in genomics and the vast amount of research data on physiology and pharmacology in this species, now provide a powerful new platform for the study of human disease.

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Statistical inference for noisy nonlinear ecological dynamic systems.

Publication Date: 2010 Aug 26 PMID: 20703226
Authors: Wood, S. N.
Journal: Nature

Chaotic ecological dynamic systems defy conventional statistical analysis. Systems with near-chaotic dynamics are little better. Such systems are almost invariably driven by endogenous dynamic processes plus demographic and environmental process noise, and are only observable with error. Their sensitivity to history means that minute changes in the driving noise realization, or the system parameters, will cause drastic changes in the system trajectory. This sensitivity is inherited and amplified by the joint probability density of the observable data and the process noise, rendering it useless as the basis for obtaining measures of statistical fit. Because the joint density is the basis for the fit measures used by all conventional statistical methods, this is a major theoretical shortcoming. The inability to make well-founded statistical inferences about biological dynamic models in the chaotic and near-chaotic regimes, other than on an ad hoc basis, leaves dynamic theory without the methods of quantitative validation that are essential tools in the rest of biological science. Here I show that this impasse can be resolved in a simple and general manner, using a method that requires only the ability to simulate the observed data on a system from the dynamic model about which inferences are required. The raw data series are reduced to phase-insensitive summary statistics, quantifying local dynamic structure and the distribution of observations. Simulation is used to obtain the mean and the covariance matrix of the statistics, given model parameters, allowing the construction of a 'synthetic likelihood' that assesses model fit. This likelihood can be explored using a straightforward Markov chain Monte Carlo sampler, but one further post-processing step returns pure likelihood-based inference. I apply the method to establish the dynamic nature of the fluctuations in Nicholson's classic blowfly experiments.

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OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma.

Publication Date: 2010 Sep 2 PMID: 20693987
Authors: Medina, P. P. - Nolde, M. - Slack, F. J.
Journal: Nature

MicroRNAs (miRNAs) belong to a recently discovered class of small RNA molecules that regulate gene expression at the post-transcriptional level. miRNAs have crucial functions in the development and establishment of cell identity, and aberrant metabolism or expression of miRNAs has been linked to human diseases, including cancer. Components of the miRNA machinery and miRNAs themselves are involved in many cellular processes that are altered in cancer, such as differentiation, proliferation and apoptosis. Some miRNAs, referred to as oncomiRs, show differential expression levels in cancer and are able to affect cellular transformation, carcinogenesis and metastasis, acting either as oncogenes or tumour suppressors. The phenomenon of 'oncogene addiction' reveals that despite the multistep nature of tumorigenesis, targeting of certain single oncogenes can have therapeutic value, and the possibility of oncomiR addiction has been proposed but never demonstrated. MicroRNA-21 (miR-21) is a unique miRNA in that it is overexpressed in most tumour types analysed so far. Despite great interest in miR-21, most of the data implicating it in cancer have been obtained through miRNA profiling and limited in vitro functional assays. To explore the role of miR-21 in cancer in vivo, we used Cre and Tet-off technologies to generate mice conditionally expressing miR-21. Here we show that overexpression of miR-21 leads to a pre-B malignant lymphoid-like phenotype, demonstrating that mir-21 is a genuine oncogene. When miR-21 was inactivated, the tumours regressed completely in a few days, partly as a result of apoptosis. These results demonstrate that tumours can become addicted to oncomiRs and support efforts to treat human cancers through pharmacological inactivation of miRNAs such as miR-21.

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MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake.

Publication Date: 2010 Aug 8 PMID: 20693986
Authors: Perocchi, F. - Gohil, V. M. - Girgis, H. S. - Bao, X. R. - McCombs, J. E. - Palmer, A. E. - Mootha, V. K.
Journal: Nature

Mitochondrial calcium uptake has a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients and regulating cell death. The biophysical properties of mitochondrial calcium uptake have been studied in detail, but the underlying proteins remain elusive. Here we use an integrative strategy to predict human genes involved in mitochondrial calcium entry based on clues from comparative physiology, evolutionary genomics and organelle proteomics. RNA interference against 13 top candidates highlighted one gene, CBARA1, that we call hereafter mitochondrial calcium uptake 1 (MICU1). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells, and attenuates the metabolic coupling between cytosolic calcium transients and activation of matrix dehydrogenases. MICU1 is associated with the mitochondrial inner membrane and has two canonical EF hands that are essential for its activity, indicating a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high-capacity mitochondrial calcium uptake. Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease.

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Branched tricarboxylic acid metabolism in Plasmodium falciparum.

Publication Date: 2010 Aug 5 PMID: 20686576
Authors: Olszewski, K. L. - Mather, M. W. - Morrisey, J. M. - Garcia, B. A. - Vaidya, A. B. - Rabinowitz, J. D. - Llinas, M.
Journal: Nature

A central hub of carbon metabolism is the tricarboxylic acid cycle, which serves to connect the processes of glycolysis, gluconeogenesis, respiration, amino acid synthesis and other biosynthetic pathways. The protozoan intracellular malaria parasites (Plasmodium spp.), however, have long been suspected of possessing a significantly streamlined carbon metabolic network in which tricarboxylic acid metabolism plays a minor role. Blood-stage Plasmodium parasites rely almost entirely on glucose fermentation for energy and consume minimal amounts of oxygen, yet the parasite genome encodes all of the enzymes necessary for a complete tricarboxylic acid cycle. Here, by tracing (13)C-labelled compounds using mass spectrometry we show that tricarboxylic acid metabolism in the human malaria parasite Plasmodium falciparum is largely disconnected from glycolysis and is organized along a fundamentally different architecture from the canonical textbook pathway. We find that this pathway is not cyclic, but rather is a branched structure in which the major carbon sources are the amino acids glutamate and glutamine. As a consequence of this branched architecture, several reactions must run in the reverse of the standard direction, thereby generating two-carbon units in the form of acetyl-coenzyme A. We further show that glutamine-derived acetyl-coenzyme A is used for histone acetylation, whereas glucose-derived acetyl-coenzyme A is used to acetylate amino sugars. Thus, the parasite has evolved two independent production mechanisms for acetyl-coenzyme A with different biological functions. These results significantly clarify our understanding of the Plasmodium metabolic network and highlight the ability of altered variants of central carbon metabolism to arise in response to unique environments.

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Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells.

Publication Date: 2010 Aug 5 PMID: 20686575
Authors: Garcia-Perez, J. L. - Morell, M. - Scheys, J. O. - Kulpa, D. A. - Morell, S. - Carter, C. C. - Hammer, G. D. - Collins, K. L. - O'Shea, K. S. - Menendez, P. - Moran, J. V.
Journal: Nature

Long interspersed element-1 (LINE-1 or L1) retrotransposition continues to affect human genome evolution. L1s can retrotranspose in the germline, during early development and in select somatic cells; however, the host response to L1 retrotransposition remains largely unexplored. Here we show that reporter genes introduced into the genome of various human embryonic carcinoma-derived cell lines (ECs) by L1 retrotransposition are rapidly and efficiently silenced either during or immediately after their integration. Treating ECs with histone deacetylase inhibitors rapidly reverses this silencing, and chromatin immunoprecipitation experiments revealed that reactivation of the reporter gene was correlated with changes in chromatin status at the L1 integration site. Under our assay conditions, rapid silencing was also observed when reporter genes were delivered into ECs by mouse L1s and a zebrafish LINE-2 element, but not when similar reporter genes were delivered into ECs by Moloney murine leukaemia virus or human immunodeficiency virus, suggesting that these integration events are silenced by distinct mechanisms. Finally, we demonstrate that subjecting ECs to culture conditions that promote differentiation attenuates the silencing of reporter genes delivered by L1 retrotransposition, but that differentiation, in itself, is not sufficient to reactivate previously silenced reporter genes. Thus, our data indicate that ECs differ from many differentiated cells in their ability to silence reporter genes delivered by L1 retrotransposition.

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Predicting protein structures with a multiplayer online game.

Publication Date: 2010 Aug 5 PMID: 20686574
Authors: Cooper, S. - Khatib, F. - Treuille, A. - Barbero, J. - Lee, J. - Beenen, M. - Leaver-Fay, A. - Baker, D. - Popovic, Z. - Players, F.
Journal: Nature

People exert large amounts of problem-solving effort playing computer games. Simple image- and text-recognition tasks have been successfully 'crowd-sourced' through games, but it is not clear if more complex scientific problems can be solved with human-directed computing. Protein structure prediction is one such problem: locating the biologically relevant native conformation of a protein is a formidable computational challenge given the very large size of the search space. Here we describe Foldit, a multiplayer online game that engages non-scientists in solving hard prediction problems. Foldit players interact with protein structures using direct manipulation tools and user-friendly versions of algorithms from the Rosetta structure prediction methodology, while they compete and collaborate to optimize the computed energy. We show that top-ranked Foldit players excel at solving challenging structure refinement problems in which substantial backbone rearrangements are necessary to achieve the burial of hydrophobic residues. Players working collaboratively develop a rich assortment of new strategies and algorithms; unlike computational approaches, they explore not only the conformational space but also the space of possible search strategies. The integration of human visual problem-solving and strategy development capabilities with traditional computational algorithms through interactive multiplayer games is a powerful new approach to solving computationally-limited scientific problems.

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The evolution of mammal-like crocodyliforms in the Cretaceous Period of Gondwana.

Publication Date: 2010 Aug 5 PMID: 20686573
Authors: O'Connor, P. M. - Sertich, J. J. - Stevens, N. J. - Roberts, E. M. - Gottfried, M. D. - Hieronymus, T. L. - Jinnah, Z. A. - Ridgely, R. - Ngasala, S. E. - Temba, J.
Journal: Nature

Fossil crocodyliforms discovered in recent years have revealed a level of morphological and ecological diversity not exhibited by extant members of the group. This diversity is particularly notable among taxa of the Cretaceous Period (144-65 million years ago) recovered from former Gondwanan landmasses. Here we report the discovery of a new species of Cretaceous notosuchian crocodyliform from the Rukwa Rift Basin of southwestern Tanzania. This small-bodied form deviates significantly from more typical crocodyliform craniodental morphologies, having a short, broad skull, robust lower jaw, and a dentition with relatively few teeth that nonetheless show marked heterodonty. The presence of morphologically complex, complementary upper and lower molariform teeth suggests a degree of crown-crown contact during jaw adduction that is unmatched among known crocodyliforms, paralleling the level of occlusal complexity seen in mammals and their extinct relatives. The presence of another small-bodied mammal-like crocodyliform in the Cretaceous of Gondwana indicates that notosuchians probably filled niches and inhabited ecomorphospace that were otherwise occupied by mammals on northern continents.

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Melting-induced stratification above the Earth's inner core due to convective translation.

Publication Date: 2010 Aug 5 PMID: 20686572
Authors: Alboussiere, T. - Deguen, R. - Melzani, M.
Journal: Nature

In addition to its global North-South anisotropy, there are two other enigmatic seismological observations related to the Earth's inner core: asymmetry between its eastern and western hemispheres and the presence of a layer of reduced seismic velocity at the base of the outer core. This 250-km-thick layer has been interpreted as a stably stratified region of reduced composition in light elements. Here we show that this layer can be generated by simultaneous crystallization and melting at the surface of the inner core, and that a translational mode of thermal convection in the inner core can produce enough melting and crystallization on each hemisphere respectively for the dense layer to develop. The dynamical model we propose introduces a clear asymmetry between a melting and a crystallizing hemisphere which forms a basis for also explaining the East-West asymmetry. The present translation rate is found to be typically 100 million years for the inner core to be entirely renewed, which is one to two orders of magnitude faster than the growth rate of the inner core's radius. The resulting strong asymmetry of buoyancy flux caused by light elements is anticipated to have an impact on the dynamics of the outer core and on the geodynamo.

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Real-time observation of valence electron motion.

Publication Date: 2010 Aug 5 PMID: 20686571
Authors: Goulielmakis, E. - Loh, Z. H. - Wirth, A. - Santra, R. - Rohringer, N. - Yakovlev, V. S. - Zherebtsov, S. - Pfeifer, T. - Azzeer, A. M. - Kling, M. F. - Leone, S. R. - Krausz, F.
Journal: Nature

The superposition of quantum states drives motion on the atomic and subatomic scales, with the energy spacing of the states dictating the speed of the motion. In the case of electrons residing in the outer (valence) shells of atoms and molecules which are separated by electronvolt energies, this means that valence electron motion occurs on a subfemtosecond to few-femtosecond timescale (1 fs = 10(-15) s). In the absence of complete measurements, the motion can be characterized in terms of a complex quantity, the density matrix. Here we report an attosecond pump-probe measurement of the density matrix of valence electrons in atomic krypton ions. We generate the ions with a controlled few-cycle laser field and then probe them through the spectrally resolved absorption of an attosecond extreme-ultraviolet pulse, which allows us to observe in real time the subfemtosecond motion of valence electrons over a multifemtosecond time span. We are able to completely characterize the quantum mechanical electron motion and determine its degree of coherence in the specimen of the ensemble. Although the present study uses a simple, prototypical open system, attosecond transient absorption spectroscopy should be applicable to molecules and solid-state materials to reveal the elementary electron motions that control physical, chemical and biological properties and processes.

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Loss-free and active optical negative-index metamaterials.

Publication Date: 2010 Aug 5 PMID: 20686570
Authors: Xiao, S. - Drachev, V. P. - Kildishev, A. V. - Ni, X. - Chettiar, U. K. - Yuan, H. K. - Shalaev, V. M.
Journal: Nature

The recently emerged fields of metamaterials and transformation optics promise a family of exciting applications such as invisibility, optical imaging with deeply subwavelength resolution and nanophotonics with the potential for much faster information processing. The possibility of creating optical negative-index metamaterials (NIMs) using nanostructured metal-dielectric composites has triggered intense basic and applied research over the past several years. However, the performance of all NIM applications is significantly limited by the inherent and strong energy dissipation in metals, especially in the near-infrared and visible wavelength ranges. Generally the losses are orders of magnitude too large for the proposed applications, and the reduction of losses with optimized designs seems to be out of reach. One way of addressing this issue is to incorporate gain media into NIM designs. However, whether NIMs with low loss can be achieved has been the subject of theoretical debate. Here we experimentally demonstrate that the incorporation of gain material in the high-local-field areas of a metamaterial makes it possible to fabricate an extremely low-loss and active optical NIM. The original loss-limited negative refractive index and the figure of merit (FOM) of the device have been drastically improved with loss compensation in the visible wavelength range between 722 and 738 nm. In this range, the NIM becomes active such that the sum of the light intensities in transmission and reflection exceeds the intensity of the incident beam. At a wavelength of 737 nm, the negative refractive index improves from -0.66 to -1.017 and the FOM increases from 1 to 26. At 738 nm, the FOM is expected to become macroscopically large, of the order of 10(6). This study demonstrates the possibility of fabricating an optical negative-index metamaterial that is not limited by the inherent loss in its metal constituent.

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Quantum entanglement between an optical photon and a solid-state spin qubit.

Publication Date: 2010 Aug 5 PMID: 20686569
Authors: Togan, E. - Chu, Y. - Trifonov, A. S. - Jiang, L. - Maze, J. - Childress, L. - Dutt, M. V. - Sorensen, A. S. - Hemmer, P. R. - Zibrov, A. S. - Lukin, M. D.
Journal: Nature

Quantum entanglement is among the most fascinating aspects of quantum theory. Entangled optical photons are now widely used for fundamental tests of quantum mechanics and applications such as quantum cryptography. Several recent experiments demonstrated entanglement of optical photons with trapped ions, atoms and atomic ensembles, which are then used to connect remote long-term memory nodes in distributed quantum networks. Here we realize quantum entanglement between the polarization of a single optical photon and a solid-state qubit associated with the single electronic spin of a nitrogen vacancy centre in diamond. Our experimental entanglement verification uses the quantum eraser technique, and demonstrates that a high degree of control over interactions between a solid-state qubit and the quantum light field can be achieved. The reported entanglement source can be used in studies of fundamental quantum phenomena and provides a key building block for the solid-state realization of quantum optical networks.

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A ground-layer adaptive optics system with multiple laser guide stars.

Publication Date: 2010 Aug 5 PMID: 20686568
Authors: Hart, M. - Milton, N. M. - Baranec, C. - Powell, K. - Stalcup, T. - McCarthy, D. - Kulesa, C. - Bendek, E.
Journal: Nature

To determine the influence of the environment on star formation, we need to study the process in the extreme conditions of massive young star clusters ( approximately 10(4) solar masses) near the centre of our own Galaxy. Observations must be carried out in the near infrared because of very high extinction in visible light within the Galactic plane. We need high resolution to identify cluster members from their peculiar motions, and because most such clusters span more than 1', efficient observation demands a wide field of view. There is at present no space-based facility that meets all these criteria. Ground-based telescopes can in principle make such observations when fitted with ground-layer adaptive optics (GLAO), which removes the optical aberration caused by atmospheric turbulence up to an altitude of approximately 500 m (refs 7-10). A GLAO system that uses multiple laser guide stars has been developed at the 6.5-m MMT telescope, in Arizona. In previous tests, the system improved the resolution of the telescope by 30-50%, limited by wavefront error in the optics, but that was insufficient to allow rapid determination of cluster membership. Here we report observations of the core of the globular cluster M3 made after commissioning a sensor to monitor and remove slowly varying aberration in the optics. In natural seeing of 0.7'', the point spread function at 2.2-mum wavelength was sharpened uniformly to 0.3'' over a field of at least 2'. The wide-field resolution was enhanced by a factor of two to three over previous work, with better uniformity, and extends to a wavelength of 1.2 mum. Entire stellar clusters may be examined in a single pointing, and cluster membership can be determined from two such observations separated by just one year.

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The Amphimedon queenslandica genome and the evolution of animal complexity.

Publication Date: 2010 Aug 5 PMID: 20686567
Authors: Srivastava, M. - Simakov, O. - Chapman, J. - Fahey, B. - Gauthier, M. E. - Mitros, T. - Richards, G. S. - Conaco, C. - Dacre, M. - Hellsten, U. - Larroux, C. - Putnam, N. H. - Stanke, M. - Adamska, M. - Darling, A. - Degnan, S. M. - Oakley, T. H. - Plachetzki, D. C. - Zhai, Y. - Adamski, M. - Calcino, A. - Cummins, S. F. - Goodstein, D. M. - Harris, C. - Jackson, D. J. - Leys, S. P. - Shu, S. - Woodcroft, B. J. - Vervoort, M. - Kosik, K. S. - Manning, G. - Degnan, B. M. - Rokhsar, D. S.
Journal: Nature

Sponges are an ancient group of animals that diverged from other metazoans over 600 million years ago. Here we present the draft genome sequence of Amphimedon queenslandica, a demosponge from the Great Barrier Reef, and show that it is remarkably similar to other animal genomes in content, structure and organization. Comparative analysis enabled by the sequencing of the sponge genome reveals genomic events linked to the origin and early evolution of animals, including the appearance, expansion and diversification of pan-metazoan transcription factor, signalling pathway and structural genes. This diverse 'toolkit' of genes correlates with critical aspects of all metazoan body plans, and comprises cell cycle control and growth, development, somatic- and germ-cell specification, cell adhesion, innate immunity and allorecognition. Notably, many of the genes associated with the emergence of animals are also implicated in cancer, which arises from defects in basic processes associated with metazoan multicellularity.

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From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.

Publication Date: 2010 Aug 5 PMID: 20686566
Authors: Musunuru, K. - Strong, A. - Frank-Kamenetsky, M. - Lee, N. E. - Ahfeldt, T. - Sachs, K. V. - Li, X. - Li, H. - Kuperwasser, N. - Ruda, V. M. - Pirruccello, J. P. - Muchmore, B. - Prokunina-Olsson, L. - Hall, J. L. - Schadt, E. E. - Morales, C. R. - Lund-Katz, S. - Phillips, M. C. - Wong, J. - Cantley, W. - Racie, T. - Ejebe, K. G. - Orho-Melander, M. - Melander, O. - Koteliansky, V. - Fitzgerald, K. - Krauss, R. M. - Cowan, C. A. - Kathiresan, S. - Rader, D. J.
Journal: Nature

Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.

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Biological, clinical and population relevance of 95 loci for blood lipids.

Publication Date: 2010 Aug 5 PMID: 20686565
Authors: Teslovich, T. M. - Musunuru, K. - Smith, A. V. - Edmondson, A. C. - Stylianou, I. M. - Koseki, M. - Pirruccello, J. P. - Ripatti, S. - Chasman, D. I. - Willer, C. J. - Johansen, C. T. - Fouchier, S. W. - Isaacs, A. - Peloso, G. M. - Barbalic, M. - Ricketts, S. L. - Bis, J. C. - Aulchenko, Y. S. - Thorleifsson, G. - Feitosa, M. F. - Chambers, J. - Orho-Melander, M. - Melander, O. - Johnson, T. - Li, X. - Guo, X. - Li, M. - Shin Cho, Y. - Jin Go, M. - Jin Kim, Y. - Lee, J. Y. - Park, T. - Kim, K. - Sim, X. - Twee-Hee Ong, R. - Croteau-Chonka, D. C. - Lange, L. A. - Smith, J. D. - Song, K. - Hua Zhao, J. - Yuan, X. - Luan, J. - Lamina, C. - Ziegler, A. - Zhang, W. - Zee, R. Y. - Wright, A. F. - Witteman, J. C. - Wilson, J. F. - Willemsen, G. - Wichmann, H. E. - Whitfield, J. B. - Waterworth, D. M. - Wareham, N. J. - Waeber, G. - Vollenweider, P. - Voight, B. F. - Vitart, V. - Uitterlinden, A. G. - Uda, M. - Tuomilehto, J. - Thompson, J. R. - Tanaka, T. - Surakka, I. - Stringham, H. M. - Spector, T. D. - Soranzo, N. - Smit, J. H. - Sinisalo, J. - Silander, K. - Sijbrands, E. J. - Scuteri, A. - Scott, J. - Schlessinger, D. - Sanna, S. - Salomaa, V. - Saharinen, J. - Sabatti, C. - Ruokonen, A. - Rudan, I. - Rose, L. M. - Roberts, R. - Rieder, M. - Psaty, B. M. - Pramstaller, P. P. - Pichler, I. - Perola, M. - Penninx, B. W. - Pedersen, N. L. - Pattaro, C. - Parker, A. N. - Pare, G. - Oostra, B. A. - O'Donnell, C. J. - Nieminen, M. S. - Nickerson, D. A. - Montgomery, G. W. - Meitinger, T. - McPherson, R. - McCarthy, M. I. - McArdle, W. - Masson, D. - Martin, N. G. - Marroni, F. - Mangino, M. - Magnusson, P. K. - Lucas, G. - Luben, R. - Loos, R. J. - Lokki, M. L. - Lettre, G. - Langenberg, C. - Launer, L. J. - Lakatta, E. G. - Laaksonen, R. - Kyvik, K. O. - Kronenberg, F. - Konig, I. R. - Khaw, K. T. - Kaprio, J. - Kaplan, L. M. - Johansson, A. - Jarvelin, M. R. - Cecile J W Janssens, A. - Ingelsson, E. - Igl, W. - Kees Hovingh, G. - Hottenga, J. J. - Hofman, A. - Hicks, A. A. - Hengstenberg, C. - Heid, I. M. - Hayward, C. - Havulinna, A. S. - Hastie, N. D. - Harris, T. B. - Haritunians, T. - Hall, A. S. - Gyllensten, U. - Guiducci, C. - Groop, L. C. - Gonzalez, E. - Gieger, C. - Freimer, N. B. - Ferrucci, L. - Erdmann, J. - Elliott, P. - Ejebe, K. G. - Doring, A. - Dominiczak, A. F. - Demissie, S. - Deloukas, P. - de Geus, E. J. - de Faire, U. - Crawford, G. - Collins, F. S. - Chen, Y. D. - Caulfield, M. J. - Campbell, H. - Burtt, N. P. - Bonnycastle, L. L. - Boomsma, D. I. - Boekholdt, S. M. - Bergman, R. N. - Barroso, I. - Bandinelli, S. - Ballantyne, C. M. - Assimes, T. L. - Quertermous, T. - Altshuler, D. - Seielstad, M. - Wong, T. Y. - Tai, E. S. - Feranil, A. B. - Kuzawa, C. W. - Adair, L. S. - Taylor, H. A. Jr - Borecki, I. B. - Gabriel, S. B. - Wilson, J. G. - Holm, H. - Thorsteinsdottir, U. - Gudnason, V. - Krauss, R. M. - Mohlke, K. L. - Ordovas, J. M. - Munroe, P. B. - Kooner, J. S. - Tall, A. R. - Hegele, R. A. - Kastelein, J. J. - Schadt, E. E. - Rotter, J. I. - Boerwinkle, E. - Strachan, D. P. - Mooser, V. - Stefansson, K. - Reilly, M. P. - Samani, N. J. - Schunkert, H. - Cupples, L. A. - Sandhu, M. S. - Ridker, P. M. - Rader, D. J. - van Duijn, C. M. - Peltonen, L. - Abecasis, G. R. - Boehnke, M. - Kathiresan, S.
Journal: Nature

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

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Obituary: Harry Whittington (1916-2010).

Publication Date: 2010 Aug 5 PMID: 20686564
Authors: Briggs, D. E.
Journal: Nature

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Inorganic chemistry: Cation o' nine tails.

Publication Date: 2010 Aug 5 PMID: 20686563
Authors: Arnold, P. L.
Journal: Nature

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Genomics: Variations in blood lipids.

Publication Date: 2010 Aug 5 PMID: 20686562
Authors: Shuldiner, A. R. - Pollin, T. I.
Journal: Nature

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Metabolism: Malaria parasite stands out.

Publication Date: 2010 Aug 5 PMID: 20686561
Authors: Ginsburg, H.
Journal: Nature

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Neuroanatomy: From fin to forelimb.

Publication Date: 2010 Aug 5 PMID: 20686560
Authors: Ridd, K.
Journal: Nature

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Spectroscopy: Attosecond prints of electrons.

Publication Date: 2010 Aug 5 PMID: 20686559
Authors: Smirnova, O.
Journal: Nature

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Crohn's disease: Genes, viruses and microbes.

Publication Date: 2010 Aug 5 PMID: 20686558
Authors: Simmons, A.
Journal: Nature

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Ecology: Close relatives are bad news.

Publication Date: 2010 Aug 5 PMID: 20686557
Authors: Lewis, O. T.
Journal: Nature

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Earth science: An inner core slip-sliding away.

Publication Date: 2010 Aug 5 PMID: 20686556
Authors: Bergman, M. I.
Journal: Nature

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Harnessing telecoms cables for science.

Publication Date: 2010 Aug 5 PMID: 20686551
Authors: You, Y.
Journal: Nature

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UK coalition's funding plan accelerates trends Labour started.

Publication Date: 2010 Aug 5 PMID: 20686550
Authors: Bown, W. C.
Journal: Nature

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World view: Not by experts alone.

Publication Date: 2010 Aug 5 PMID: 20686548
Authors: Sarewitz, D.
Journal: Nature

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Citizen science: People power.

Publication Date: 2010 Aug 5 PMID: 20686547
Authors: Hand, E.
Journal: Nature

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Deepwater Horizon: A scientist at the centre of the spill.

Publication Date: 2010 Aug 5 PMID: 20686546
Authors: Schrope, M.
Journal: Nature

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US report pins down future biosecurity.

Publication Date: 2010 Aug 5 PMID: 20686545
Authors: Wadman, M.
Journal: Nature

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Drug safety crackdown revs up.

Publication Date: 2010 Aug 5 PMID: 20686544
Authors: Ledford, H.
Journal: Nature

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Salamander's egg surprise.

Publication Date: 2010 Aug 5 PMID: 20686543
Authors: Petherick, A.
Journal: Nature

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'Tough' chief to defend MRC.

Publication Date: 2010 Aug 5 PMID: 20686542
Authors: Cressey, D.
Journal: Nature

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UK embryo agency faces the axe.

Publication Date: 2010 Aug 5 PMID: 20686541
Authors: Cressey, D.
Journal: Nature

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Sponge genome goes deep.

Publication Date: 2010 Aug 5 PMID: 20686540
Authors: Mann, A.
Journal: Nature

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Demand for malaria drug soars.

Publication Date: 2010 Aug 5 PMID: 20686539
Authors: Van Noorden, R.
Journal: Nature

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Journal club. A conservation biologist considers the role of nature reserves in a warming world.

Publication Date: 2010 Aug 5 PMID: 20686533
Authors: Sax, D.
Journal: Nature

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Domestic science.

Publication Date: 2010 Aug 5 PMID: 20686527
Authors:
Journal: Nature

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Slow progress.

Publication Date: 2010 Aug 5 PMID: 20686526
Authors:
Journal: Nature

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Type IIA topoisomerase inhibition by a new class of antibacterial agents.

Publication Date: 2010 Aug 19 PMID: 20686482
Authors: Bax, B. D. - Chan, P. F. - Eggleston, D. S. - Fosberry, A. - Gentry, D. R. - Gorrec, F. - Giordano, I. - Hann, M. M. - Hennessy, A. - Hibbs, M. - Huang, J. - Jones, E. - Jones, J. - Brown, K. K. - Lewis, C. J. - May, E. W. - Saunders, M. R. - Singh, O. - Spitzfaden, C. E. - Shen, C. - Shillings, A. - Theobald, A. J. - Wohlkonig, A. - Pearson, N. D. - Gwynn, M. N.
Journal: Nature

Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class.

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Rb regulates fate choice and lineage commitment in vivo.

Publication Date: 2010 Aug 26 PMID: 20686481
Authors: Calo, E. - Quintero-Estades, J. A. - Danielian, P. S. - Nedelcu, S. - Berman, S. D. - Lees, J. A.
Journal: Nature

Mutation of the retinoblastoma gene (RB1) tumour suppressor occurs in one-third of all human tumours and is particularly associated with retinoblastoma and osteosarcoma. Numerous functions have been ascribed to the product of the human RB1 gene, the retinoblastoma protein (pRb). The best known is pRb's ability to promote cell-cycle exit through inhibition of the E2F transcription factors and the transcriptional repression of genes encoding cell-cycle regulators. In addition, pRb has been shown in vitro to regulate several transcription factors that are master differentiation inducers. Depending on the differentiation factor and cellular context, pRb can either suppress or promote their transcriptional activity. For example, pRb binds to Runx2 and potentiates its ability to promote osteogenic differentiation in vitro. In contrast, pRb acts with E2F to suppress peroxisome proliferator-activated receptor gamma subunit (PPAR-gamma), the master activator of adipogenesis. Because osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that pRb might play a role in the choice between these two fates. However, so far, there is no evidence for this in vivo. Here we use mouse models to address this hypothesis in mesenchymal tissue development and tumorigenesis. Our data show that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo.

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A ribosome-associating factor chaperones tail-anchored membrane proteins.

Publication Date: 2010 Aug 26 PMID: 20676083
Authors: Mariappan, M. - Li, X. - Stefanovic, S. - Sharma, A. - Mateja, A. - Keenan, R. J. - Hegde, R. S.
Journal: Nature

Hundreds of proteins are inserted post-translationally into the endoplasmic reticulum (ER) membrane by a single carboxy-terminal transmembrane domain (TMD). During targeting through the cytosol, the hydrophobic TMD of these tail-anchored (TA) proteins requires constant chaperoning to prevent aggregation or inappropriate interactions. A central component of this targeting system is TRC40, a conserved cytosolic factor that recognizes the TMD of TA proteins and delivers them to the ER for insertion. The mechanism that permits TRC40 to find and capture its TA protein cargos effectively in a highly crowded cytosol is unknown. Here we identify a conserved three-protein complex composed of Bat3, TRC35 and Ubl4A that facilitates TA protein capture by TRC40. This Bat3 complex is recruited to ribosomes synthesizing membrane proteins, interacts with the TMDs of newly released TA proteins, and transfers them to TRC40 for targeting. Depletion of the Bat3 complex allows non-TRC40 factors to compete for TA proteins, explaining their mislocalization in the analogous yeast deletion strains. Thus, the Bat3 complex acts as a TMD-selective chaperone that effectively channels TA proteins to the TRC40 insertion pathway.

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Structure of the torque ring of the flagellar motor and the molecular basis for rotational switching.

Publication Date: 2010 Aug 19 PMID: 20676082
Authors: Lee, L. K. - Ginsburg, M. A. - Crovace, C. - Donohoe, M. - Stock, D.
Journal: Nature

The flagellar motor drives the rotation of flagellar filaments at hundreds of revolutions per second, efficiently propelling bacteria through viscous media. The motor uses the potential energy from an electrochemical gradient of cations across the cytoplasmic membrane to generate torque. A rapid switch from anticlockwise to clockwise rotation determines whether a bacterium runs smoothly forward or tumbles to change its trajectory. A protein called FliG forms a ring in the rotor of the flagellar motor that is involved in the generation of torque through an interaction with the cation-channel-forming stator subunit MotA. FliG has been suggested to adopt distinct conformations that induce switching but these structural changes and the molecular mechanism of switching are unknown. Here we report the molecular structure of the full-length FliG protein, identify conformational changes that are involved in rotational switching and uncover the structural basis for the formation of the FliG torque ring. This allows us to propose a model of the complete ring and switching mechanism in which conformational changes in FliG reverse the electrostatic charges involved in torque generation.

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Diverse somatic mutation patterns and pathway alterations in human cancers.

Publication Date: 2010 Aug 12 PMID: 20668451
Authors: Kan, Z. - Jaiswal, B. S. - Stinson, J. - Janakiraman, V. - Bhatt, D. - Stern, H. M. - Yue, P. - Haverty, P. M. - Bourgon, R. - Zheng, J. - Moorhead, M. - Chaudhuri, S. - Tomsho, L. P. - Peters, B. A. - Pujara, K. - Cordes, S. - Davis, D. P. - Carlton, V. E. - Yuan, W. - Li, L. - Wang, W. - Eigenbrot, C. - Kaminker, J. S. - Eberhard, D. A. - Waring, P. - Schuster, S. C. - Modrusan, Z. - Zhang, Z. - Stokoe, D. - de Sauvage, F. J. - Faham, M. - Seshagiri, S.
Journal: Nature

The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics. Here we report the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for galpha subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Galpha subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.

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Global patterns and predictors of marine biodiversity across taxa.

Publication Date: 2010 Aug 26 PMID: 20668450
Authors: Tittensor, D. P. - Mora, C. - Jetz, W. - Lotze, H. K. - Ricard, D. - Berghe, E. V. - Worm, B.
Journal: Nature

Global patterns of species richness and their structuring forces have fascinated biologists since Darwin and provide critical context for contemporary studies in ecology, evolution and conservation. Anthropogenic impacts and the need for systematic conservation planning have further motivated the analysis of diversity patterns and processes at regional to global scales. Whereas land diversity patterns and their predictors are known for numerous taxa, our understanding of global marine diversity has been more limited, with recent findings revealing some striking contrasts to widely held terrestrial paradigms. Here we examine global patterns and predictors of species richness across 13 major species groups ranging from zooplankton to marine mammals. Two major patterns emerged: coastal species showed maximum diversity in the Western Pacific, whereas oceanic groups consistently peaked across broad mid-latitudinal bands in all oceans. Spatial regression analyses revealed sea surface temperature as the only environmental predictor highly related to diversity across all 13 taxa. Habitat availability and historical factors were also important for coastal species, whereas other predictors had less significance. Areas of high species richness were disproportionately concentrated in regions with medium or higher human impacts. Our findings indicate a fundamental role of temperature or kinetic energy in structuring cross-taxon marine biodiversity, and indicate that changes in ocean temperature, in conjunction with other human impacts, may ultimately rearrange the global distribution of life in the ocean.

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Wnt11 patterns a myocardial electrical gradient through regulation of the L-type Ca(2+) channel.

Publication Date: 2010 Aug 12 PMID: 20657579
Authors: Panakova, D. - Werdich, A. A. - Macrae, C. A.
Journal: Nature

Electrical gradients are critical for many biological processes, including the normal function of excitable tissues, left-right patterning, organogenesis and wound healing. The fundamental mechanisms that regulate the establishment and maintenance of such electrical polarities are poorly understood. Here we identify a gradient of electrical coupling across the developing ventricular myocardium using high-speed optical mapping of transmembrane potentials and calcium concentrations in the zebrafish heart. We excluded a role for differences in cellular excitability, connexin localization, tissue geometry and mechanical inputs, but in contrast we were able to demonstrate that non-canonical Wnt11 signals are required for the genesis of this myocardial electrical gradient. Although the traditional planar cell polarity pathway is not involved, we obtained evidence that Wnt11 acts to set up this gradient of electrical coupling through effects on transmembrane Ca(2+) conductance mediated by the L-type calcium channel. These data reveal a previously unrecognized role for Wnt/Ca(2+) signalling in establishing an electrical gradient in the plane of the developing cardiac epithelium through modulation of ion-channel function. The regulation of cellular coupling through such mechanisms may be a general property of non-canonical Wnt signals.

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Dynamics and mechanism of repair of ultraviolet-induced (6-4) photoproduct by photolyase.

Publication Date: 2010 Aug 12 PMID: 20657578
Authors: Li, J. - Liu, Z. - Tan, C. - Guo, X. - Wang, L. - Sancar, A. - Zhong, D.
Journal: Nature

One of the detrimental effects of ultraviolet radiation on DNA is the formation of the (6-4) photoproduct, 6-4PP, between two adjacent pyrimidine rings. This lesion interferes with replication and transcription, and may result in mutation and cell death. In many organisms, a flavoenzyme called photolyase uses blue light energy to repair the 6-4PP (ref. 3). The molecular mechanism of the repair reaction is poorly understood. Here, we use ultrafast spectroscopy to show that the key step in the repair photocycle is acyclic proton transfer between the enzyme and the substrate. By femtosecond synchronization of the enzymatic dynamics with the repair function, we followed the function evolution and observed direct electron transfer from the excited flavin cofactor to the 6-4PP in 225 picoseconds, but surprisingly fast back electron transfer in 50 picoseconds without repair. We found that the catalytic proton transfer between a histidine residue in the active site and the 6-4PP, induced by the initial photoinduced electron transfer from the excited flavin cofactor to 6-4PP, occurs in 425 picoseconds and leads to 6-4PP repair in tens of nanoseconds. These key dynamics define the repair photocycle and explain the underlying molecular mechanism of the enzyme's modest efficiency.

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Regulation of myeloid leukaemia by the cell-fate determinant Musashi.

Publication Date: 2010 Aug 5 PMID: 20639863
Authors: Ito, T. - Kwon, H. Y. - Zimdahl, B. - Congdon, K. L. - Blum, J. - Lento, W. E. - Zhao, C. - Lagoo, A. - Gerrard, G. - Foroni, L. - Goldman, J. - Goh, H. - Kim, S. H. - Kim, D. W. - Chuah, C. - Oehler, V. G. - Radich, J. P. - Jordan, C. T. - Reya, T.
Journal: Nature

Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signalling axis. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias.

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Microbial metalloproteomes are largely uncharacterized.

Publication Date: 2010 Aug 5 PMID: 20639861
Authors: Cvetkovic, A. - Menon, A. L. - Thorgersen, M. P. - Scott, J. W. - Poole, F. L. 2nd - Jenney, F. E. Jr - Lancaster, W. A. - Praissman, J. L. - Shanmukh, S. - Vaccaro, B. J. - Trauger, S. A. - Kalisiak, E. - Apon, J. V. - Siuzdak, G. - Yannone, S. M. - Tainer, J. A. - Adams, M. W.
Journal: Nature

Metal ion cofactors afford proteins virtually unlimited catalytic potential, enable electron transfer reactions and have a great impact on protein stability. Consequently, metalloproteins have key roles in most biological processes, including respiration (iron and copper), photosynthesis (manganese) and drug metabolism (iron). Yet, predicting from genome sequence the numbers and types of metal an organism assimilates from its environment or uses in its metalloproteome is currently impossible because metal coordination sites are diverse and poorly recognized. We present here a robust, metal-based approach to determine all metals an organism assimilates and identify its metalloproteins on a genome-wide scale. This shifts the focus from classical protein-based purification to metal-based identification and purification by liquid chromatography, high-throughput tandem mass spectrometry (HT-MS/MS) and inductively coupled plasma mass spectrometry (ICP-MS) to characterize cytoplasmic metalloproteins from an exemplary microorganism (Pyrococcus furiosus). Of 343 metal peaks in chromatography fractions, 158 did not match any predicted metalloprotein. Unassigned peaks included metals known to be used (cobalt, iron, nickel, tungsten and zinc; 83 peaks) plus metals the organism was not thought to assimilate (lead, manganese, molybdenum, uranium and vanadium; 75 peaks). Purification of eight of 158 unexpected metal peaks yielded four novel nickel- and molybdenum-containing proteins, whereas four purified proteins contained sub-stoichiometric amounts of misincorporated lead and uranium. Analyses of two additional microorganisms (Escherichia coli and Sulfolobus solfataricus) revealed species-specific assimilation of yet more unexpected metals. Metalloproteomes are therefore much more extensive and diverse than previously recognized, and promise to provide key insights for cell biology, microbial growth and toxicity mechanisms.

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Social learning promotes institutions for governing the commons.

Publication Date: 2010 Aug 12 PMID: 20631710
Authors: Sigmund, K. - De Silva, H. - Traulsen, A. - Hauert, C.
Journal: Nature

Theoretical and empirical research highlights the role of punishment in promoting collaborative efforts. However, both the emergence and the stability of costly punishment are problematic issues. It is not clear how punishers can invade a society of defectors by social learning or natural selection, or how second-order free-riders (who contribute to the joint effort but not to the sanctions) can be prevented from drifting into a coercion-based regime and subverting cooperation. Here we compare the prevailing model of peer-punishment with pool-punishment, which consists in committing resources, before the collaborative effort, to prepare sanctions against free-riders. Pool-punishment facilitates the sanctioning of second-order free-riders, because these are exposed even if everyone contributes to the common good. In the absence of such second-order punishment, peer-punishers do better than pool-punishers; but with second-order punishment, the situation is reversed. Efficiency is traded for stability. Neither other-regarding tendencies or preferences for reciprocity and equity, nor group selection or prescriptions from higher authorities, are necessary for the emergence and stability of rudimentary forms of sanctioning institutions regulating common pool resources and enforcing collaborative efforts.

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Microtubule nucleating gamma-TuSC assembles structures with 13-fold microtubule-like symmetry.

Publication Date: 2010 Aug 12 PMID: 20631709
Authors: Kollman, J. M. - Polka, J. K. - Zelter, A. - Davis, T. N. - Agard, D. A.
Journal: Nature

Microtubules are nucleated in vivo by gamma-tubulin complexes. The 300-kDa gamma-tubulin small complex (gamma-TuSC), consisting of two molecules of gamma-tubulin and one copy each of the accessory proteins Spc97 and Spc98, is the conserved, essential core of the microtubule nucleating machinery. In metazoa multiple gamma-TuSCs assemble with other proteins into gamma-tubulin ring complexes (gamma-TuRCs). The structure of gamma-TuRC indicated that it functions as a microtubule template. Because each gamma-TuSC contains two molecules of gamma-tubulin, it was assumed that the gamma-TuRC-specific proteins are required to organize gamma-TuSCs to match 13-fold microtubule symmetry. Here we show that Saccharomyces cerevisiae gamma-TuSC forms rings even in the absence of other gamma-TuRC components. The yeast adaptor protein Spc110 stabilizes the rings into extended filaments and is required for oligomer formation under physiological buffer conditions. The 8-A cryo-electron microscopic reconstruction of the filament reveals 13 gamma-tubulins per turn, matching microtubule symmetry, with plus ends exposed for interaction with microtubules, implying that one turn of the filament constitutes a microtubule template. The domain structures of Spc97 and Spc98 suggest functions for conserved sequence motifs, with implications for the gamma-TuRC-specific proteins. The gamma-TuSC filaments nucleate microtubules at a low level, and the structure provides a strong hypothesis for how nucleation is regulated, converting this less active form to a potent nucleator.

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Regulation of heterochromatic DNA replication by histone H3 lysine 27 methyltransferases.

Publication Date: 2010 Aug 19 PMID: 20631708
Authors: Jacob, Y. - Stroud, H. - Leblanc, C. - Feng, S. - Zhuo, L. - Caro, E. - Hassel, C. - Gutierrez, C. - Michaels, S. D. - Jacobsen, S. E.
Journal: Nature

Multiple pathways prevent DNA replication from occurring more than once per cell cycle. These pathways block re-replication by strictly controlling the activity of pre-replication complexes, which assemble at specific sites in the genome called origins. Here we show that mutations in the homologous histone 3 lysine 27 (H3K27) monomethyltransferases, ARABIDOPSIS TRITHORAX-RELATED PROTEIN5 (ATXR5) and ATXR6, lead to re-replication of specific genomic locations. Most of these locations correspond to transposons and other repetitive and silent elements of the Arabidopsis genome. These sites also correspond to high levels of H3K27 monomethylation, and mutation of the catalytic SET domain is sufficient to cause the re-replication defect. Mutation of ATXR5 and ATXR6 also causes upregulation of transposon expression and has pleiotropic effects on plant development. These results uncover a novel pathway that prevents over-replication of heterochromatin in Arabidopsis.

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A novel pathway regulates memory and plasticity via SIRT1 and miR-134.

Publication Date: 2010 Aug 26 PMID: 20622856
Authors: Gao, J. - Wang, W. Y. - Mao, Y. W. - Graff, J. - Guan, J. S. - Pan, L. - Mak, G. - Kim, D. - Su, S. C. - Tsai, L. H.
Journal: Nature

The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders.

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Negative plant-soil feedback predicts tree-species relative abundance in a tropical forest.

Publication Date: 2010 Aug 5 PMID: 20581819
Authors: Mangan, S. A. - Schnitzer, S. A. - Herre, E. A. - Mack, K. M. - Valencia, M. C. - Sanchez, E. I. - Bever, J. D.
Journal: Nature

The accumulation of species-specific enemies around adults is hypothesized to maintain plant diversity by limiting the recruitment of conspecific seedlings relative to heterospecific seedlings. Although previous studies in forested ecosystems have documented patterns consistent with the process of negative feedback, these studies are unable to address which classes of enemies (for example, pathogens, invertebrates, mammals) exhibit species-specific effects strong enough to generate negative feedback, and whether negative feedback at the level of the individual tree is sufficient to influence community-wide forest composition. Here we use fully reciprocal shade-house and field experiments to test whether the performance of conspecific tree seedlings (relative to heterospecific seedlings) is reduced when grown in the presence of enemies associated with adult trees. Both experiments provide strong evidence for negative plant-soil feedback mediated by soil biota. In contrast, above-ground enemies (mammals, foliar herbivores and foliar pathogens) contributed little to negative feedback observed in the field. In both experiments, we found that tree species that showed stronger negative feedback were less common as adults in the forest community, indicating that susceptibility to soil biota may determine species relative abundance in these tropical forests. Finally, our simulation models confirm that the strength of local negative feedback that we measured is sufficient to produce the observed community-wide patterns in tree-species relative abundance. Our findings indicate that plant-soil feedback is an important mechanism that can maintain species diversity and explain patterns of tree-species relative abundance in tropical forests.

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Link communities reveal multiscale complexity in networks.

Publication Date: 2010 Aug 5 PMID: 20562860
Authors: Ahn, Y. Y. - Bagrow, J. P. - Lehmann, S.
Journal: Nature

Networks have become a key approach to understanding systems of interacting objects, unifying the study of diverse phenomena including biological organisms and human society. One crucial step when studying the structure and dynamics of networks is to identify communities: groups of related nodes that correspond to functional subunits such as protein complexes or social spheres. Communities in networks often overlap such that nodes simultaneously belong to several groups. Meanwhile, many networks are known to possess hierarchical organization, where communities are recursively grouped into a hierarchical structure. However, the fact that many real networks have communities with pervasive overlap, where each and every node belongs to more than one group, has the consequence that a global hierarchy of nodes cannot capture the relationships between overlapping groups. Here we reinvent communities as groups of links rather than nodes and show that this unorthodox approach successfully reconciles the antagonistic organizing principles of overlapping communities and hierarchy. In contrast to the existing literature, which has entirely focused on grouping nodes, link communities naturally incorporate overlap while revealing hierarchical organization. We find relevant link communities in many networks, including major biological networks such as protein-protein interaction and metabolic networks, and show that a large social network contains hierarchically organized community structures spanning inner-city to regional scales while maintaining pervasive overlap. Our results imply that link communities are fundamental building blocks that reveal overlap and hierarchical organization in networks to be two aspects of the same phenomenon.

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