Nature

Serial translocation by means of circular intermediates underlies colour sidedness in cattle.

Publication Date: 2012 Feb 2 PMID: 22297974
Authors: Durkin, K. - Coppieters, W. - Drogemuller, C. - Ahariz, N. - Cambisano, N. - Druet, T. - Fasquelle, C. - Haile, A. - Horin, P. - Huang, L. - Kamatani, Y. - Karim, L. - Lathrop, M. - Moser, S. - Oldenbroek, K. - Rieder, S. - Sartelet, A. - Solkner, J. - Stalhammar, H. - Zelenika, D. - Zhang, Z. - Leeb, T. - Georges, M. - Charlier, C.
Journal: Nature

Colour sidedness is a dominantly inherited phenotype of cattle characterized by the polarization of pigmented sectors on the flanks, snout and ear tips. It is also referred to as 'lineback' or 'witrik' (which means white back), as colour-sided animals typically display a white band along their spine. Colour sidedness is documented at least since the Middle Ages and is presently segregating in several cattle breeds around the globe, including in Belgian blue and brown Swiss. Here we report that colour sidedness is determined by a first allele on chromosome 29 (Cs(29)), which results from the translocation of a 492-kilobase chromosome 6 segment encompassing KIT to chromosome 29, and a second allele on chromosome 6 (Cs(6)), derived from the first by repatriation of fused 575-kilobase chromosome 6 and 29 sequences to the KIT locus. We provide evidence that both translocation events involved circular intermediates. This is the first example, to our knowledge, of a phenotype determined by homologous yet non-syntenic alleles that result from a novel copy-number-variant-generating mechanism.

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Decadal to monthly timescales of magma transfer and reservoir growth at a caldera volcano.

Publication Date: 2012 Feb 2 PMID: 22297973
Authors: Druitt, T. H. - Costa, F. - Deloule, E. - Dungan, M. - Scaillet, B.
Journal: Nature

Caldera-forming volcanic eruptions are low-frequency, high-impact events capable of discharging tens to thousands of cubic kilometres of magma explosively on timescales of hours to days, with devastating effects on local and global scales. Because no such eruption has been monitored during its long build-up phase, the precursor phenomena are not well understood. Geophysical signals obtained during recent episodes of unrest at calderas such as Yellowstone, USA, and Campi Flegrei, Italy, are difficult to interpret, and the conditions necessary for large eruptions are poorly constrained. Here we present a study of pre-eruptive magmatic processes and their timescales using chemically zoned crystals from the 'Minoan' caldera-forming eruption of Santorini volcano, Greece, which occurred in the late 1600s BC. The results provide insights into how rapidly large silicic systems may pass from a quiescent state to one on the edge of eruption. Despite the large volume of erupted magma (40-60 cubic kilometres), and the 18,000-year gestation period between the Minoan eruption and the previous major eruption, most crystals in the Minoan magma record processes that occurred less than about 100 years before the eruption. Recharge of the magma reservoir by large volumes of silicic magma (and some mafic magma) occurred during the century before eruption, and mixing between different silicic magma batches was still taking place during the final months. Final assembly of large silicic magma reservoirs may occur on timescales that are geologically very short by comparison with the preceding repose period, with major growth phases immediately before eruption. These observations have implications for the monitoring of long-dormant, but potentially active, caldera systems.

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Nonlinear material behaviour of spider silk yields robust webs.

Publication Date: 2012 Feb 2 PMID: 22297972
Authors: Cranford, S. W. - Tarakanova, A. - Pugno, N. M. - Buehler, M. J.
Journal: Nature

Natural materials are renowned for exquisite designs that optimize function, as illustrated by the elasticity of blood vessels, the toughness of bone and the protection offered by nacre. Particularly intriguing are spider silks, with studies having explored properties ranging from their protein sequence to the geometry of a web. This material system, highly adapted to meet a spider's many needs, has superior mechanical properties. In spite of much research into the molecular design underpinning the outstanding performance of silk fibres, and into the mechanical characteristics of web-like structures, it remains unknown how the mechanical characteristics of spider silk contribute to the integrity and performance of a spider web. Here we report web deformation experiments and simulations that identify the nonlinear response of silk threads to stress--involving softening at a yield point and substantial stiffening at large strain until failure--as being crucial to localize load-induced deformation and resulting in mechanically robust spider webs. Control simulations confirmed that a nonlinear stress response results in superior resistance to structural defects in the web compared to linear elastic or elastic-plastic (softening) material behaviour. We also show that under distributed loads, such as those exerted by wind, the stiff behaviour of silk under small deformation, before the yield point, is essential in maintaining the web's structural integrity. The superior performance of silk in webs is therefore not due merely to its exceptional ultimate strength and strain, but arises from the nonlinear response of silk threads to strain and their geometrical arrangement in a web.

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Direct frequency comb spectroscopy in the extreme ultraviolet.

Publication Date: 2012 Feb 2 PMID: 22297971
Authors: Cingoz, A. - Yost, D. C. - Allison, T. K. - Ruehl, A. - Fermann, M. E. - Hartl, I. - Ye, J.
Journal: Nature

The development of the optical frequency comb (a spectrum consisting of a series of evenly spaced lines) has revolutionized metrology and precision spectroscopy owing to its ability to provide a precise and direct link between microwave and optical frequencies. A further advance in frequency comb technology is the generation of frequency combs in the extreme-ultraviolet spectral range by means of high-harmonic generation in a femtosecond enhancement cavity. Until now, combs produced by this method have lacked sufficient power for applications, a drawback that has also hampered efforts to observe phase coherence of the high-repetition-rate pulse train produced by high-harmonic generation, which is an extremely nonlinear process. Here we report the generation of extreme-ultraviolet frequency combs, reaching wavelengths of 40 nanometres, by coupling a high-power near-infrared frequency comb to a robust femtosecond enhancement cavity. These combs are powerful enough for us to observe single-photon spectroscopy signals for both an argon transition at 82 nanometres and a neon transition at 63 nanometres, thus confirming the combs' coherence in the extreme ultraviolet. The absolute frequency of the argon transition has been determined by direct frequency comb spectroscopy. The resolved ten-megahertz linewidth of the transition, which is limited by the temperature of the argon atoms, is unprecedented in this spectral region and places a stringent upper limit on the linewidth of individual comb teeth. Owing to the lack of continuous-wave lasers, extreme-ultraviolet frequency combs are at present the only promising route to extending ultrahigh-precision spectroscopy to the spectral region below 100 nanometres. At such wavelengths there is a wide range of applications, including the spectroscopy of electronic transitions in molecules, experimental tests of bound-state and many-body quantum electrodynamics in singly ionized helium and neutral helium, the development of next-generation 'nuclear' clocks and searches for variation of fundamental constants using the enhanced sensitivity of highly charged ions.

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Quantum-coherent coupling of a mechanical oscillator to an optical cavity mode.

Publication Date: 2012 Feb 2 PMID: 22297970
Authors: Verhagen, E. - Deleglise, S. - Weis, S. - Schliesser, A. - Kippenberg, T. J.
Journal: Nature

Optical laser fields have been widely used to achieve quantum control over the motional and internal degrees of freedom of atoms and ions, molecules and atomic gases. A route to controlling the quantum states of macroscopic mechanical oscillators in a similar fashion is to exploit the parametric coupling between optical and mechanical degrees of freedom through radiation pressure in suitably engineered optical cavities. If the optomechanical coupling is 'quantum coherent'--that is, if the coherent coupling rate exceeds both the optical and the mechanical decoherence rate--quantum states are transferred from the optical field to the mechanical oscillator and vice versa. This transfer allows control of the mechanical oscillator state using the wide range of available quantum optical techniques. So far, however, quantum-coherent coupling of micromechanical oscillators has only been achieved using microwave fields at millikelvin temperatures. Optical experiments have not attained this regime owing to the large mechanical decoherence rates and the difficulty of overcoming optical dissipation. Here we achieve quantum-coherent coupling between optical photons and a micromechanical oscillator. Simultaneously, coupling to the cold photon bath cools the mechanical oscillator to an average occupancy of 1.7 +/- 0.1 motional quanta. Excitation with weak classical light pulses reveals the exchange of energy between the optical light field and the micromechanical oscillator in the time domain at the level of less than one quantum on average. This optomechanical system establishes an efficient quantum interface between mechanical oscillators and optical photons, which can provide decoherence-free transport of quantum states through optical fibres. Our results offer a route towards the use of mechanical oscillators as quantum transducers or in microwave-to-optical quantum links.

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Precision measurement: A comb in the extreme ultraviolet.

Publication Date: 2012 Feb 2 PMID: 22297969
Authors: Young, L.
Journal: Nature

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Molecular motors: A staggering giant.

Publication Date: 2012 Feb 2 PMID: 22297968
Authors: Walter, W. J. - Diez, S.
Journal: Nature

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Surface chemistry: Crystal cuts on the nanoscale.

Publication Date: 2012 Feb 2 PMID: 22297966
Authors: Yang, P.
Journal: Nature

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Neuroscience: Reward alters specific connections.

Publication Date: 2012 Feb 2 PMID: 22297965
Authors: Holy, T. E.
Journal: Nature

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Volcanology: Greek inflation circa 1600 BC.

Publication Date: 2012 Feb 2 PMID: 22297964
Authors: Blundy, J. - Rust, A.
Journal: Nature

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Philip D. Lawley (1927-2011).

Publication Date: 2012 Feb 2 PMID: 22297963
Authors: Venitt, S. - Phillips, D. H.
Journal: Nature

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Asian medicine: Protect rare plants.

Publication Date: 2012 Feb 2 PMID: 22297962
Authors: Zhang, H. F. - Yang, X. H.
Journal: Nature

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Asian medicine: Japan's paradigm.

Publication Date: 2012 Feb 2 PMID: 22297961
Authors: Cameron, S. - Reissenweber, H. - Watanabe, K.
Journal: Nature

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Asian medicine: Call for more safety data.

Publication Date: 2012 Feb 2 PMID: 22297960
Authors: Xu, J. - Liu, M. - Xia, Z.
Journal: Nature

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Regulation: Safety-test initiatives for nanomaterials.

Publication Date: 2012 Feb 2 PMID: 22297959
Authors: Riego-Sintes, J.
Journal: Nature

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Asian medicine: Many unique types.

Publication Date: 2012 Feb 2 PMID: 22297958
Authors: Lee, H.
Journal: Nature

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Asian medicine: A fungus in decline.

Publication Date: 2012 Feb 2 PMID: 22297957
Authors: Shrestha, U. B.
Journal: Nature

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Literature: Wonders and ologies.

Publication Date: 2012 Feb 2 PMID: 22297955
Authors: Jenkins, A.
Journal: Nature

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Conservation: Bring elephants to Australia?

Publication Date: 2012 Feb 2 PMID: 22297953
Authors: Bowman, D.
Journal: Nature

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Public health: The toxic truth about sugar.

Publication Date: 2012 Feb 2 PMID: 22297952
Authors: Lustig, R. H. - Schmidt, L. A. - Brindis, C. D.
Journal: Nature

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Vaccine development: Man vs MRSA.

Publication Date: 2012 Feb 2 PMID: 22297951
Authors: McKenna, M.
Journal: Nature

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Marine ecology: Attack of the blobs.

Publication Date: 2012 Feb 2 PMID: 22297950
Authors: Schrope, M.
Journal: Nature

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Japan plans to merge major science bodies.

Publication Date: 2012 Feb 2 PMID: 22297949
Authors: Fuyuno, I.
Journal: Nature

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Genomics ace quits Japan.

Publication Date: 2012 Feb 2 PMID: 22297948
Authors: Cyranoski, D.
Journal: Nature

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Dipole hunt stuck in neutral.

Publication Date: 2012 Feb 2 PMID: 22297947
Authors: Reich, E. S.
Journal: Nature

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Informed consent on trial.

Publication Date: 2012 Feb 2 PMID: 22297946
Authors: Cressey, D.
Journal: Nature

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Stem-cell agency faces budget dilemma.

Publication Date: 2012 Feb 2 PMID: 22297945
Authors: Hayden, E. C.
Journal: Nature

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Diagnostics tome comes under fire.

Publication Date: 2012 Feb 2 PMID: 22297944
Authors: Ledford, H.
Journal: Nature

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The great Arctic oil race begins.

Publication Date: 2012 Feb 2 PMID: 22297943
Authors: Schiermeier, Q.
Journal: Nature

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Global health hits crisis point.

Publication Date: 2012 Feb 2 PMID: 22297931
Authors: Garrett, L.
Journal: Nature

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Damage limitation.

Publication Date: 2012 Feb 2 PMID: 22297930
Authors:
Journal: Nature

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The low-level nuclear threat.

Publication Date: 2012 Feb 2 PMID: 22297929
Authors:
Journal: Nature

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Poles apart.

Publication Date: 2012 Feb 2 PMID: 22297928
Authors:
Journal: Nature

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Enhancer decommissioning by LSD1 during embryonic stem cell differentiation.

Publication Date: 2012 Feb 1 PMID: 22297846
Authors: Whyte, W. A. - Bilodeau, S. - Orlando, D. A. - Hoke, H. A. - Frampton, G. M. - Foster, C. T. - Cowley, S. M. - Young, R. A.
Journal: Nature

Transcription factors and chromatin modifiers are important in the programming and reprogramming of cellular states during development. Transcription factors bind to enhancer elements and recruit coactivators and chromatin-modifying enzymes to facilitate transcription initiation. During differentiation a subset of these enhancers must be silenced, but the mechanisms underlying enhancer silencing are poorly understood. Here we show that the histone demethylase lysine-specific demethylase 1 (LSD1; ref. 5), which demethylates histone H3 on Lys 4 or Lys 9 (H3K4/K9), is essential in decommissioning enhancers during the differentiation of mouse embryonic stem cells (ESCs). LSD1 occupies enhancers of active genes that are critical for control of the state of ESCs. However, LSD1 is not essential for the maintenance of ESC identity. Instead, ESCs lacking LSD1 activity fail to differentiate fully, and ESC-specific enhancers fail to undergo the histone demethylation events associated with differentiation. At active enhancers, LSD1 is a component of the NuRD (nucleosome remodelling and histone deacetylase) complex, which contains additional subunits that are necessary for ESC differentiation. We propose that the LSD1-NuRD complex decommissions enhancers of the pluripotency program during differentiation, which is essential for the complete shutdown of the ESC gene expression program and the transition to new cell states.

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Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity.

Publication Date: 2012 Feb 1 PMID: 22297845
Authors: Henao-Mejia, J. - Elinav, E. - Jin, C. - Hao, L. - Mehal, W. Z. - Strowig, T. - Thaiss, C. A. - Kau, A. L. - Eisenbarth, S. C. - Jurczak, M. J. - Camporez, J. P. - Shulman, G. I. - Gordon, J. I. - Hoffman, H. M. - Flavell, R. A.
Journal: Nature

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-alpha expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.

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Realization of three-qubit quantum error correction with superconducting circuits.

Publication Date: 2012 Feb 1 PMID: 22297844
Authors: Reed, M. D. - Dicarlo, L. - Nigg, S. E. - Sun, L. - Frunzio, L. - Girvin, S. M. - Schoelkopf, R. J.
Journal: Nature

Quantum computers could be used to solve certain problems exponentially faster than classical computers, but are challenging to build because of their increased susceptibility to errors. However, it is possible to detect and correct errors without destroying coherence, by using quantum error correcting codes. The simplest of these are three-quantum-bit (three-qubit) codes, which map a one-qubit state to an entangled three-qubit state; they can correct any single phase-flip or bit-flip error on one of the three qubits, depending on the code used. Here we demonstrate such phase- and bit-flip error correcting codes in a superconducting circuit. We encode a quantum state, induce errors on the qubits and decode the error syndrome-a quantum state indicating which error has occurred-by reversing the encoding process. This syndrome is then used as the input to a three-qubit gate that corrects the primary qubit if it was flipped. As the code can recover from a single error on any qubit, the fidelity of this process should decrease only quadratically with error probability. We implement the correcting three-qubit gate (known as a conditional-conditional NOT, or Toffoli, gate) in 63 nanoseconds, using an interaction with the third excited state of a single qubit. We find 85 +/- 1 per cent fidelity to the expected classical action of this gate, and 78 +/- 1 per cent fidelity to the ideal quantum process matrix. Using this gate, we perform a single pass of both quantum bit- and phase-flip error correction and demonstrate the predicted first-order insensitivity to errors. Concatenation of these two codes in a nine-qubit device would correct arbitrary single-qubit errors. In combination with recent advances in superconducting qubit coherence times, this could lead to scalable quantum technology.

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Policy: Adaptations of avian flu virus are a cause for concern.

Publication Date: 2012 Jan 31 PMID: 22294204
Authors: Berns, K. I. - Casadevall, A. - Cohen, M. L. - Ehrlich, S. A. - Enquist, L. W. - Fitch, J. P. - Franz, D. R. - Fraser-Liggett, C. M. - Grant, C. M. - Imperiale, M. J. - Kanabrocki, J. - Keim, P. S. - Lemon, S. M. - Levy, S. B. - Lumpkin, J. R. - Miller, J. F. - Murch, R. - Nance, M. E. - Osterholm, M. T. - Relman, D. A. - Roth, J. A. - Vidaver, A. K.
Journal: Nature

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Q&A: Reasons for proposed redaction of flu paper.

Publication Date: 2012 Jan 31 PMID: 22294203
Authors: Keim, P. S.
Journal: Nature

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China: The gates are open.

Publication Date: 2012 Jan 26 PMID: 22288084
Authors: Qiu, J.
Journal: Nature

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Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy.

Publication Date: 2012 Jan 29 PMID: 22286062
Authors: Chen, G. - Bradford, W. D. - Seidel, C. W. - Li, R.
Journal: Nature

Aneuploidy-the state of having uneven numbers of chromosomes-is a hallmark of cancer and a feature identified in yeast from diverse habitats. Recent studies have shown that aneuploidy is a form of large-effect mutation that is able to confer adaptive phenotypes under diverse stress conditions. Here we investigate whether pleiotropic stress could induce aneuploidy in budding yeast (Saccharomyces cerevisae). We show that whereas diverse stress conditions can induce an increase in chromosome instability, proteotoxic stress, caused by transient Hsp90 (also known as Hsp82 or Hsc82) inhibition or heat shock, markedly increased chromosome instability to produce a cell population with high karyotype diversity. The induced chromosome instability is linked to an evolutionarily conserved role for the Hsp90 chaperone complex in kinetochore assembly. Continued growth in the presence of an Hsp90 inhibitor resulted in the emergence of drug-resistant colonies with chromosome XV gain. This drug-resistance phenotype is a quantitative trait involving copy number increases of at least two genes located on chromosome XV. Short-term exposure to Hsp90 stress potentiated fast adaptation to unrelated cytotoxic compounds by means of different aneuploid chromosome stoichiometries. These findings demonstrate that aneuploidy is a form of stress-inducible mutation in eukaryotes, capable of fuelling rapid phenotypic evolution and drug resistance, and reveal a new role for Hsp90 in regulating the emergence of adaptive traits under stress.

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Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

Publication Date: 2012 Jan 29 PMID: 22286061
Authors: Schwartzentruber, J. - Korshunov, A. - Liu, X. Y. - Jones, D. T. - Pfaff, E. - Jacob, K. - Sturm, D. - Fontebasso, A. M. - Quang, D. A. - Tonjes, M. - Hovestadt, V. - Albrecht, S. - Kool, M. - Nantel, A. - Konermann, C. - Lindroth, A. - Jager, N. - Rausch, T. - Ryzhova, M. - Korbel, J. O. - Hielscher, T. - Hauser, P. - Garami, M. - Klekner, A. - Bognar, L. - Ebinger, M. - Schuhmann, M. U. - Scheurlen, W. - Pekrun, A. - Fruhwald, M. C. - Roggendorf, W. - Kramm, C. - Durken, M. - Atkinson, J. - Lepage, P. - Montpetit, A. - Zakrzewska, M. - Zakrzewski, K. - Liberski, P. P. - Dong, Z. - Siegel, P. - Kulozik, A. E. - Zapatka, M. - Guha, A. - Malkin, D. - Felsberg, J. - Reifenberger, G. - von Deimling, A. - Ichimura, K. - Collins, V. P. - Witt, H. - Milde, T. - Witt, O. - Zhang, C. - Castelo-Branco, P. - Lichter, P. - Faury, D. - Tabori, U. - Plass, C. - Majewski, J. - Pfister, S. M. - Jabado, N.
Journal: Nature

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

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Structural and functional conservation of key domains in InsP(3) and ryanodine receptors.

Publication Date: 2012 Jan 29 PMID: 22286060
Authors: Seo, M. D. - Velamakanni, S. - Ishiyama, N. - Stathopulos, P. B. - Rossi, A. M. - Khan, S. A. - Dale, P. - Li, C. - Ames, J. B. - Ikura, M. - Taylor, C. W.
Journal: Nature

Inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca(2+) channels. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP(3)R gating is initiated by InsP(3) binding to the InsP(3)-binding core (IBC, residues 224-604 of InsP(3)R1) and it requires the suppressor domain (SD, residues 1-223 of InsP(3)R1). Here we present structures of the amino-terminal region (NT, residues 1-604) of rat InsP(3)R1 with (3.6 A) and without (3.0 A) InsP(3) bound. The arrangement of the three NT domains, SD, IBC-beta and IBC-alpha, identifies two discrete interfaces (alpha and beta) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP(3)R and of the ABC domains docked into RyR are remarkably similar. The importance of the alpha-interface for activation of InsP(3)R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations. Binding of InsP(3) causes partial closure of the clam-like IBC, disrupting the beta-interface and pulling the SD towards the IBC. This reorients an exposed SD loop ('hotspot' (HS) loop) that is essential for InsP(3)R activation. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP(3)R, and an InsP(3)R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP(3) and blocked by ryanodine. Activation mechanisms are conserved between InsP(3)R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-beta or B domain), to gate the pore.

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G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody.

Publication Date: 2012 Jan 29 PMID: 22286059
Authors: Hino, T. - Arakawa, T. - Iwanari, H. - Yurugi-Kobayashi, T. - Ikeda-Suno, C. - Nakada-Nakura, Y. - Kusano-Arai, O. - Weyand, S. - Shimamura, T. - Nomura, N. - Cameron, A. D. - Kobayashi, T. - Hamakubo, T. - Iwata, S. - Murata, T.
Journal: Nature

G-protein-coupled receptors are the largest class of cell-surface receptors, and these membrane proteins exist in equilibrium between inactive and active states. Conformational changes induced by extracellular ligands binding to G-protein-coupled receptors result in a cellular response through the activation of G proteins. The A(2A) adenosine receptor (A(2A)AR) is responsible for regulating blood flow to the cardiac muscle and is important in the regulation of glutamate and dopamine release in the brain. Here we report the raising of a mouse monoclonal antibody against human A(2A)AR that prevents agonist but not antagonist binding to the extracellular ligand-binding pocket, and describe the structure of A(2A)AR in complex with the antibody Fab fragment (Fab2838). This structure reveals that Fab2838 recognizes the intracellular surface of A(2A)AR and that its complementarity-determining region, CDR-H3, penetrates into the receptor. CDR-H3 is located in a similar position to the G-protein carboxy-terminal fragment in the active opsin structure and to CDR-3 of the nanobody in the active beta(2)-adrenergic receptor structure, but locks A(2A)AR in an inactive conformation. These results suggest a new strategy to modulate the activity of G-protein-coupled receptors.

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Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR.

Publication Date: 2012 Jan 26 PMID: 22281684
Authors: Prahallad, A. - Sun, C. - Huang, S. - Di Nicolantonio, F. - Salazar, R. - Zecchin, D. - Beijersbergen, R. L. - Bardelli, A. - Bernards, R.
Journal: Nature

Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, we find that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10% of all colon cancers), for which there are currently no targeted treatment options available, might benefit from combination therapy consisting of BRAF and EGFR inhibitors.

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Social networks and cooperation in hunter-gatherers.

Publication Date: 2012 Jan 26 PMID: 22281599
Authors: Apicella, C. L. - Marlowe, F. W. - Fowler, J. H. - Christakis, N. A.
Journal: Nature

Social networks show striking structural regularities, and both theory and evidence suggest that networks may have facilitated the development of large-scale cooperation in humans. Here, we characterize the social networks of the Hadza, a population of hunter-gatherers in Tanzania. We show that Hadza networks have important properties also seen in modernized social networks, including a skewed degree distribution, degree assortativity, transitivity, reciprocity, geographic decay and homophily. We demonstrate that Hadza camps exhibit high between-group and low within-group variation in public goods game donations. Network ties are also more likely between people who give the same amount, and the similarity in cooperative behaviour extends up to two degrees of separation. Social distance appears to be as important as genetic relatedness and physical proximity in explaining assortativity in cooperation. Our results suggest that certain elements of social network structure may have been present at an early point in human history. Also, early humans may have formed ties with both kin and non-kin, based in part on their tendency to cooperate. Social networks may thus have contributed to the emergence of cooperation.

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Atomic inner-shell X-ray laser at 1.46 nanometres pumped by an X-ray free-electron laser.

Publication Date: 2012 Jan 26 PMID: 22281598
Authors: Rohringer, N. - Ryan, D. - London, R. A. - Purvis, M. - Albert, F. - Dunn, J. - Bozek, J. D. - Bostedt, C. - Graf, A. - Hill, R. - Hau-Riege, S. P. - Rocca, J. J.
Journal: Nature

Since the invention of the laser more than 50 years ago, scientists have striven to achieve amplification on atomic transitions of increasingly shorter wavelength. The introduction of X-ray free-electron lasers makes it possible to pump new atomic X-ray lasers with ultrashort pulse duration, extreme spectral brightness and full temporal coherence. Here we describe the implementation of an X-ray laser in the kiloelectronvolt energy regime, based on atomic population inversion and driven by rapid K-shell photo-ionization using pulses from an X-ray free-electron laser. We established a population inversion of the Kalpha transition in singly ionized neon at 1.46 nanometres (corresponding to a photon energy of 849 electronvolts) in an elongated plasma column created by irradiation of a gas medium. We observed strong amplified spontaneous emission from the end of the excited plasma. This resulted in femtosecond-duration, high-intensity X-ray pulses of much shorter wavelength and greater brilliance than achieved with previous atomic X-ray lasers. Moreover, this scheme provides greatly increased wavelength stability, monochromaticity and improved temporal coherence by comparison with present-day X-ray free-electron lasers. The atomic X-ray lasers realized here may be useful for high-resolution spectroscopy and nonlinear X-ray studies.

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Light-cone-like spreading of correlations in a quantum many-body system.

Publication Date: 2012 Jan 26 PMID: 22281597
Authors: Cheneau, M. - Barmettler, P. - Poletti, D. - Endres, M. - Schauss, P. - Fukuhara, T. - Gross, C. - Bloch, I. - Kollath, C. - Kuhr, S.
Journal: Nature

In relativistic quantum field theory, information propagation is bounded by the speed of light. No such limit exists in the non-relativistic case, although in real physical systems, short-range interactions may be expected to restrict the propagation of information to finite velocities. The question of how fast correlations can spread in quantum many-body systems has been long studied. The existence of a maximal velocity, known as the Lieb-Robinson bound, has been shown theoretically to exist in several interacting many-body systems (for example, spins on a lattice)--such systems can be regarded as exhibiting an effective light cone that bounds the propagation speed of correlations. The existence of such a 'speed of light' has profound implications for condensed matter physics and quantum information, but has not been observed experimentally. Here we report the time-resolved detection of propagating correlations in an interacting quantum many-body system. By quenching a one-dimensional quantum gas in an optical lattice, we reveal how quasiparticle pairs transport correlations with a finite velocity across the system, resulting in an effective light cone for the quantum dynamics. Our results open perspectives for understanding the relaxation of closed quantum systems far from equilibrium, and for engineering the efficient quantum channels necessary for fast quantum computations.

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Generation of scaled protogalactic seed magnetic fields in laser-produced shock waves.

Publication Date: 2012 Jan 26 PMID: 22281596
Authors: Gregori, G. - Ravasio, A. - Murphy, C. D. - Schaar, K. - Baird, A. - Bell, A. R. - Benuzzi-Mounaix, A. - Bingham, R. - Constantin, C. - Drake, R. P. - Edwards, M. - Everson, E. T. - Gregory, C. D. - Kuramitsu, Y. - Lau, W. - Mithen, J. - Niemann, C. - Park, H. S. - Remington, B. A. - Reville, B. - Robinson, A. P. - Ryutov, D. D. - Sakawa, Y. - Yang, S. - Woolsey, N. C. - Koenig, M. - Miniati, F.
Journal: Nature

The standard model for the origin of galactic magnetic fields is through the amplification of seed fields via dynamo or turbulent processes to the level consistent with present observations. Although other mechanisms may also operate, currents from misaligned pressure and temperature gradients (the Biermann battery process) inevitably accompany the formation of galaxies in the absence of a primordial field. Driven by geometrical asymmetries in shocks associated with the collapse of protogalactic structures, the Biermann battery is believed to generate tiny seed fields to a level of about 10(-21) gauss (refs 7, 8). With the advent of high-power laser systems in the past two decades, a new area of research has opened in which, using simple scaling relations, astrophysical environments can effectively be reproduced in the laboratory. Here we report the results of an experiment that produced seed magnetic fields by the Biermann battery effect. We show that these results can be scaled to the intergalactic medium, where turbulence, acting on timescales of around 700 million years, can amplify the seed fields sufficiently to affect galaxy evolution.

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Endothelial and perivascular cells maintain haematopoietic stem cells.

Publication Date: 2012 Jan 26 PMID: 22281595
Authors: Ding, L. - Saunders, T. L. - Enikolopov, G. - Morrison, S. J.
Journal: Nature

Several cell types have been proposed to create niches for haematopoietic stem cells (HSCs). However, the expression patterns of HSC maintenance factors have not been systematically studied and no such factor has been conditionally deleted from any candidate niche cell. Thus, the cellular sources of these factors are undetermined. Stem cell factor (SCF; also known as KITL) is a key niche component that maintains HSCs. Here, using Scf(gfp) knock-in mice, we found that Scf was primarily expressed by perivascular cells throughout the bone marrow. HSC frequency and function were not affected when Scf was conditionally deleted from haematopoietic cells, osteoblasts, nestin-cre- or nestin-creER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or leptin receptor (Lepr)-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. Thus, HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.

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Drug discovery: Chemical beauty contest.

Publication Date: 2012 Jan 26 PMID: 22281594
Authors: Leeson, P.
Journal: Nature

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Technology: A deeper peek into living organisms.

Publication Date: 2012 Jan 26 PMID: 22281592
Authors: Cesari, F. - Nath, D.
Journal: Nature

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Stem cells: The right neighbour.

Publication Date: 2012 Jan 26 PMID: 22281591
Authors: Shestopalov, I. A. - Zon, L. I.
Journal: Nature

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Laser science: Even harder X-rays.

Publication Date: 2012 Jan 26 PMID: 22281590
Authors: Marangos, J.
Journal: Nature

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Nanotechnology: Shape matters.

Publication Date: 2012 Jan 26 PMID: 22281589
Authors: Glotzer, S. C.
Journal: Nature

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Social science: Hunter-gatherer cooperation.

Publication Date: 2012 Jan 26 PMID: 22281588
Authors: Henrich, J.
Journal: Nature

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Astronomy: A new class of planet.

Publication Date: 2012 Jan 26 PMID: 22281587
Authors: Southworth, J.
Journal: Nature

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Neuroscience: Spikes timed through inhibition.

Publication Date: 2012 Jan 26 PMID: 22281586
Authors: Medina, J. F. - Khodakhah, K.
Journal: Nature

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James Crow (1916-2012).

Publication Date: 2012 Jan 26 PMID: 22281585
Authors: Kondrashov, A.
Journal: Nature

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Informed consent: Biobank donors should have a say.

Publication Date: 2012 Jan 26 PMID: 22281584
Authors: Spencer, B. - Koutaissoff, D. - Lehr, H. A.
Journal: Nature

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Indigenous communities: Train local experts to help conserve forests.

Publication Date: 2012 Jan 26 PMID: 22281583
Authors: Peters, C. M. - Alexiades, M. - Laird, S. A.
Journal: Nature

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Science funding: Provocative questions in cancer research.

Publication Date: 2012 Jan 26 PMID: 22281578
Authors: Varmus, H. - Harlow, E.
Journal: Nature

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Climate policy: Oil's tipping point has passed.

Publication Date: 2012 Jan 26 PMID: 22281577
Authors: Murray, J. - King, D.
Journal: Nature

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Going paperless: The digital lab.

Publication Date: 2012 Jan 26 PMID: 22281576
Authors: Giles, J.
Journal: Nature

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Underwater archaeology: Hunt for the ancient mariner.

Publication Date: 2012 Jan 26 PMID: 22281575
Authors: Marchant, J.
Journal: Nature

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French institute prepares for gene-therapy push.

Publication Date: 2012 Jan 26 PMID: 22281573
Authors: Abbott, A.
Journal: Nature

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Candidates play to the right on science.

Publication Date: 2012 Jan 26 PMID: 22281572
Authors: Young, S.
Journal: Nature

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Research in Asia heats up.

Publication Date: 2012 Jan 26 PMID: 22281571
Authors: Reich, E. S.
Journal: Nature

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UK sets sights on gene therapy in eggs.

Publication Date: 2012 Jan 26 PMID: 22281570
Authors: Callaway, E.
Journal: Nature

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Caution urged for mutant flu work.

Publication Date: 2012 Jan 26 PMID: 22281569
Authors: Butler, D.
Journal: Nature

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Cultural history holds back Chinese research.

Publication Date: 2012 Jan 26 PMID: 22281557
Authors: Gong, P.
Journal: Nature

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Fertile union.

Publication Date: 2012 Jan 26 PMID: 22281556
Authors:
Journal: Nature

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Notes on screen.

Publication Date: 2012 Jan 26 PMID: 22281555
Authors:
Journal: Nature

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Access all areas.

Publication Date: 2012 Jan 26 PMID: 22281554
Authors:
Journal: Nature

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Conditional modulation of spike-timing-dependent plasticity for olfactory learning.

Publication Date: 2012 Feb 2 PMID: 22278062
Authors: Cassenaer, S. - Laurent, G.
Journal: Nature

Mushroom bodies are a well-known site for associative learning in insects. Yet the precise mechanisms that underlie plasticity there and ensure their specificity remain elusive. In locusts, the synapses between the intrinsic mushroom body neurons and their postsynaptic targets obey a Hebbian spike-timing-dependent plasticity (STDP) rule. Although this property homeostatically regulates the timing of mushroom body output, its potential role in associative learning is unknown. Here we show in vivo that pre-post pairing causing STDP can, when followed by the local delivery of a reinforcement-mediating neuromodulator, specify the synapses that will undergo an associative change. At these synapses, and there only, the change is a transformation of the STDP rule itself. These results illustrate the multiple actions of STDP, including a role in associative learning, despite potential temporal dissociation between the pairings that specify synaptic modification and the delivery of reinforcement-mediating neuromodulator signals.

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Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist.

Publication Date: 2012 Jan 25 PMID: 22278061
Authors: Haga, K. - Kruse, A. C. - Asada, H. - Yurugi-Kobayashi, T. - Shiroishi, M. - Zhang, C. - Weis, W. I. - Okada, T. - Kobilka, B. K. - Haga, T. - Kobayashi, T.
Journal: Nature

The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

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Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells.

Publication Date: 2012 Jan 25 PMID: 22278060
Authors: Israel, M. A. - Yuan, S. H. - Bardy, C. - Reyna, S. M. - Mu, Y. - Herrera, C. - Hefferan, M. P. - Van Gorp, S. - Nazor, K. L. - Boscolo, F. S. - Carson, C. T. - Laurent, L. C. - Marsala, M. - Gage, F. H. - Remes, A. M. - Koo, E. H. - Goldstein, L. S.
Journal: Nature

Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-beta precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-beta(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3beta (aGSK-3beta). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with beta-secretase inhibitors, but not gamma-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3beta levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-beta, in GSK-3beta activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.

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Creation and diagnosis of a solid-density plasma with an X-ray free-electron laser.

Publication Date: 2012 Feb 2 PMID: 22278059
Authors: Vinko, S. M. - Ciricosta, O. - Cho, B. I. - Engelhorn, K. - Chung, H. K. - Brown, C. R. - Burian, T. - Chalupsky, J. - Falcone, R. W. - Graves, C. - Hajkova, V. - Higginbotham, A. - Juha, L. - Krzywinski, J. - Lee, H. J. - Messerschmidt, M. - Murphy, C. D. - Ping, Y. - Scherz, A. - Schlotter, W. - Toleikis, S. - Turner, J. J. - Vysin, L. - Wang, T. - Wu, B. - Zastrau, U. - Zhu, D. - Lee, R. W. - Heimann, P. A. - Nagler, B. - Wark, J. S.
Journal: Nature

Matter with a high energy density (>10(5) joules per cm(3)) is prevalent throughout the Universe, being present in all types of stars and towards the centre of the giant planets; it is also relevant for inertial confinement fusion. Its thermodynamic and transport properties are challenging to measure, requiring the creation of sufficiently long-lived samples at homogeneous temperatures and densities. With the advent of the Linac Coherent Light Source (LCLS) X-ray laser, high-intensity radiation (>10(17) watts per cm(2), previously the domain of optical lasers) can be produced at X-ray wavelengths. The interaction of single atoms with such intense X-rays has recently been investigated. An understanding of the contrasting case of intense X-ray interaction with dense systems is important from a fundamental viewpoint and for applications. Here we report the experimental creation of a solid-density plasma at temperatures in excess of 10(6) kelvin on inertial-confinement timescales using an X-ray free-electron laser. We discuss the pertinent physics of the intense X-ray-matter interactions, and illustrate the importance of electron-ion collisions. Detailed simulations of the interaction process conducted with a radiative-collisional code show good qualitative agreement with the experimental results. We obtain insights into the evolution of the charge state distribution of the system, the electron density and temperature, and the timescales of collisional processes. Our results should inform future high-intensity X-ray experiments involving dense samples, such as X-ray diffractive imaging of biological systems, material science investigations, and the study of matter in extreme conditions.

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Gated regulation of CRAC channel ion selectivity by STIM1.

Publication Date: 2012 Jan 25 PMID: 22278058
Authors: McNally, B. A. - Somasundaram, A. - Yamashita, M. - Prakriya, M.
Journal: Nature

Two defining functional features of ion channels are ion selectivity and channel gating. Ion selectivity is generally considered an immutable property of the open channel structure, whereas gating involves transitions between open and closed channel states, typically without changes in ion selectivity. In store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels, the molecular mechanism of channel gating by the CRAC channel activator, stromal interaction molecule 1 (STIM1), remains unknown. CRAC channels are distinguished by a very high Ca(2+) selectivity and are instrumental in generating sustained intracellular calcium concentration elevations that are necessary for gene expression and effector function in many eukaryotic cells. Here we probe the central features of the STIM1 gating mechanism in the human CRAC channel protein, ORAI1, and identify V102, a residue located in the extracellular region of the pore, as a candidate for the channel gate. Mutations at V102 produce constitutively active CRAC channels that are open even in the absence of STIM1. Unexpectedly, although STIM1-free V102 mutant channels are not Ca(2+)-selective, their Ca(2+) selectivity is dose-dependently boosted by interactions with STIM1. Similar enhancement of Ca(2+) selectivity is also seen in wild-type ORAI1 channels by increasing the number of STIM1 activation domains that are directly tethered to ORAI1 channels, or by increasing the relative expression of full-length STIM1. Thus, exquisite Ca(2+) selectivity is not an intrinsic property of CRAC channels but rather a tuneable feature that is bestowed on otherwise non-selective ORAI1 channels by STIM1. Our results demonstrate that STIM1-mediated gating of CRAC channels occurs through an unusual mechanism in which permeation and gating are closely coupled.

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H5N1: Flu transmission work is urgent.

Publication Date: 2012 Jan 25 PMID: 22278057
Authors: Kawaoka, Y.
Journal: Nature

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High-throughput decoding of antitrypanosomal drug efficacy and resistance.

Publication Date: 2012 Jan 25 PMID: 22278056
Authors: Alsford, S. - Eckert, S. - Baker, N. - Glover, L. - Sanchez-Flores, A. - Leung, K. F. - Turner, D. J. - Field, M. C. - Berriman, M. - Horn, D.
Journal: Nature

The concept of disease-specific chemotherapy was developed a century ago. Dyes and arsenical compounds that displayed selectivity against trypanosomes were central to this work, and the drugs that emerged remain in use for treating human African trypanosomiasis (HAT). The importance of understanding the mechanisms underlying selective drug action and resistance for the development of improved HAT therapies has been recognized, but these mechanisms have remained largely unknown. Here we use all five current HAT drugs for genome-scale RNA interference target sequencing (RIT-seq) screens in Trypanosoma brucei, revealing the transporters, organelles, enzymes and metabolic pathways that function to facilitate antitrypanosomal drug action. RIT-seq profiling identifies both known drug importers and the only known pro-drug activator, and links more than fifty additional genes to drug action. A bloodstream stage-specific invariant surface glycoprotein (ISG75) family mediates suramin uptake, and the AP1 adaptin complex, lysosomal proteases and major lysosomal transmembrane protein, as well as spermidine and N-acetylglucosamine biosynthesis, all contribute to suramin action. Further screens link ubiquinone availability to nitro-drug action, plasma membrane P-type H(+)-ATPases to pentamidine action, and trypanothione and several putative kinases to melarsoprol action. We also demonstrate a major role for aquaglyceroporins in pentamidine and melarsoprol cross-resistance. These advances in our understanding of mechanisms of antitrypanosomal drug efficacy and resistance will aid the rational design of new therapies and help to combat drug resistance, and provide unprecedented molecular insight into the mode of action of antitrypanosomal drugs.

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Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001.

Publication Date: 2012 Feb 2 PMID: 22266943
Authors: DeVore, N. M. - Scott, E. E.
Journal: Nature

Cytochrome P450 17A1 (also known as CYP17A1 and cytochrome P450c17) catalyses the biosynthesis of androgens in humans. As prostate cancer cells proliferate in response to androgen steroids, CYP17A1 inhibition is a new strategy to prevent androgen synthesis and treat lethal metastatic castration-resistant prostate cancer, but drug development has been hampered by lack of information regarding the structure of CYP17A1. Here we report X-ray crystal structures of CYP17A1, which were obtained in the presence of either abiraterone, a first-in-class steroidal inhibitor recently approved by the US Food and Drug Administration for late-stage prostate cancer, or TOK-001, an inhibitor that is currently undergoing clinical trials. Both of these inhibitors bind the haem iron, forming a 60 degrees angle above the haem plane and packing against the central I helix with the 3beta-OH interacting with aspargine 202 in the F helix. Notably, this binding mode differs substantially from those that are predicted by homology models and from steroids in other cytochrome P450 enzymes with known structures, and some features of this binding mode are more similar to steroid receptors. Whereas the overall structure of CYP17A1 provides a rationale for understanding many mutations that are found in patients with steroidogenic diseases, the active site reveals multiple steric and hydrogen bonding features that will facilitate a better understanding of the enzyme's dual hydroxylase and lyase catalytic capabilities and assist in rational drug design. Specifically, structure-based design is expected to aid development of inhibitors that bind only CYP17A1 and solely inhibit its androgen-generating lyase activity to improve treatment of prostate and other hormone-responsive cancers.

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Adenylylation control by intra- or intermolecular active-site obstruction in Fic proteins.

Publication Date: 2012 Feb 2 PMID: 22266942
Authors: Engel, P. - Goepfert, A. - Stanger, F. V. - Harms, A. - Schmidt, A. - Schirmer, T. - Dehio, C.
Journal: Nature

Fic proteins that are defined by the ubiquitous FIC (filamentation induced by cyclic AMP) domain are known to catalyse adenylylation (also called AMPylation); that is, the transfer of AMP onto a target protein. In mammalian cells, adenylylation of small GTPases through Fic proteins injected by pathogenic bacteria can cause collapse of the actin cytoskeleton and cell death. It is unknown how this potentially deleterious adenylylation activity is regulated in the widespread Fic proteins that are found in all domains of life and that are thought to have critical roles in intrinsic signalling processes. Here we show that FIC-domain-mediated adenylylation is controlled by a conserved mechanism of ATP-binding-site obstruction that involves an inhibitory alpha-helix (alpha(inh)) with a conserved (S/T)XXXE(G/N) motif, and that in this mechanism the invariable glutamate competes with ATP gamma-phosphate binding. Consistent with this, FIC-domain-mediated growth arrest of bacteria by the VbhT toxin of Bartonella schoenbuchensis is intermolecularly repressed by the VbhA antitoxin through tight binding of its alpha(inh) to the FIC domain of VbhT, as shown by structure and function analysis. Furthermore, structural comparisons with other bacterial Fic proteins, such as Fic of Neisseria meningitidis and of Shewanella oneidensis, show that alpha(inh) frequently constitutes an amino-terminal or carboxy-terminal extension to the FIC domain, respectively, partially obstructing the ATP binding site in an intramolecular manner. After mutation of the inhibitory motif in various Fic proteins, including the human homologue FICD (also known as HYPE), adenylylation activity is considerably boosted, consistent with the anticipated relief of inhibition. Structural homology modelling of all annotated Fic proteins indicates that inhibition by alpha(inh) is universal and conserved through evolution, as the inhibitory motif is present in approximately 90% of all putatively adenylylation-active FIC domains, including examples from all domains of life and from viruses. Future studies should reveal how intrinsic or extrinsic factors modulate adenylylation activity by weakening the interaction of alpha(inh) with the FIC active site.

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Crystal structure of the channelrhodopsin light-gated cation channel.

Publication Date: 2012 Jan 22 PMID: 22266941
Authors: Kato, H. E. - Zhang, F. - Yizhar, O. - Ramakrishnan, C. - Nishizawa, T. - Hirata, K. - Ito, J. - Aita, Y. - Tsukazaki, T. - Hayashi, S. - Hegemann, P. - Maturana, A. D. - Ishitani, R. - Deisseroth, K. - Nureki, O.
Journal: Nature

Channelrhodopsins (ChRs) are light-gated cation channels derived from algae that have shown experimental utility in optogenetics; for example, neurons expressing ChRs can be optically controlled with high temporal precision within systems as complex as freely moving mammals. Although ChRs have been broadly applied to neuroscience research, little is known about the molecular mechanisms by which these unusual and powerful proteins operate. Here we present the crystal structure of a ChR (a C1C2 chimaera between ChR1 and ChR2 from Chlamydomonas reinhardtii) at 2.3 A resolution. The structure reveals the essential molecular architecture of ChRs, including the retinal-binding pocket and cation conduction pathway. This integration of structural and electrophysiological analyses provides insight into the molecular basis for the remarkable function of ChRs, and paves the way for the precise and principled design of ChR variants with novel properties.

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Maternal and paternal genomes contribute equally to the transcriptome of early plant embryos.

Publication Date: 2012 Feb 2 PMID: 22266940
Authors: Nodine, M. D. - Bartel, D. P.
Journal: Nature

In animals, maternal gene products deposited into eggs regulate embryonic development before activation of the zygotic genome. In plants, an analogous period of prolonged maternal control over embryogenesis is thought to occur based on some gene-expression studies. However, other gene-expression studies and genetic analyses show that some transcripts must derive from the early zygotic genome, implying that the prevailing model does not fully explain the nature of zygotic genome activation in plants. To determine the maternal, paternal and zygotic contributions to the early embryonic transcriptome, we sequenced the transcripts of hybrid embryos from crosses between two polymorphic inbred lines of Arabidopsis thaliana and used single-nucleotide polymorphisms diagnostic of each parental line to quantify parental contributions. Although some transcripts seemed to be either inherited from primarily one parent or transcribed from imprinted loci, the vast majority of transcripts were produced in near-equal amounts from both maternal and paternal alleles, even during the initial stages of embryogenesis. Results of reporter experiments and analyses of transcripts from genes that are not expressed in sperm and egg indicate early and widespread zygotic transcription. Thus, in contrast to early animal embryogenesis, early plant embryogenesis is mostly under zygotic control.

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Pause on avian flu transmission studies.

Publication Date: 2012 Jan 26 PMID: 22266939
Authors: Fouchier, R. A. - Garcia-Sastre, A. - Kawaoka, Y.
Journal: Nature

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Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Publication Date: 2012 Feb 2 PMID: 22266938
Authors: Boyden, L. M. - Choi, M. - Choate, K. A. - Nelson-Williams, C. J. - Farhi, A. - Toka, H. R. - Tikhonova, I. R. - Bjornson, R. - Mane, S. M. - Colussi, G. - Lebel, M. - Gordon, R. D. - Semmekrot, B. A. - Poujol, A. - Valimaki, M. J. - De Ferrari, M. E. - Sanjad, S. A. - Gutkin, M. - Karet, F. E. - Tucci, J. R. - Stockigt, J. R. - Keppler-Noreuil, K. M. - Porter, C. C. - Anand, S. K. - Whiteford, M. L. - Davis, I. D. - Dewar, S. B. - Bettinelli, A. - Fadrowski, J. J. - Belsha, C. W. - Hunley, T. E. - Nelson, R. D. - Trachtman, H. - Cole, T. R. - Pinsk, M. - Bockenhauer, D. - Shenoy, M. - Vaidyanathan, P. - Foreman, J. W. - Rasoulpour, M. - Thameem, F. - Al-Shahrouri, H. Z. - Radhakrishnan, J. - Gharavi, A. G. - Goilav, B. - Lifton, R. P.
Journal: Nature

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

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Plant biology: Equal-parenting policy.

Publication Date: 2012 Feb 2 PMID: 22266937
Authors: Hale, C. J. - Jacobsen, S. E.
Journal: Nature

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Outreach: Field hospitality.

Publication Date: 2012 Jan 19 PMID: 22263234
Authors: Laursen, L.
Journal: Nature

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Kimberlite ascent by assimilation-fuelled buoyancy.

Publication Date: 2012 Jan 19 PMID: 22258614
Authors: Russell, J. K. - Porritt, L. A. - Lavallee, Y. - Dingwell, D. B.
Journal: Nature

Kimberlite magmas have the deepest origin of all terrestrial magmas and are exclusively associated with cratons. During ascent, they travel through about 150 kilometres of cratonic mantle lithosphere and entrain seemingly prohibitive loads (more than 25 per cent by volume) of mantle-derived xenoliths and xenocrysts (including diamond). Kimberlite magmas also reputedly have higher ascent rates than other xenolith-bearing magmas. Exsolution of dissolved volatiles (carbon dioxide and water) is thought to be essential to provide sufficient buoyancy for the rapid ascent of these dense, crystal-rich magmas. The cause and nature of such exsolution, however, remains elusive and is rarely specified. Here we use a series of high-temperature experiments to demonstrate a mechanism for the spontaneous, efficient and continuous production of this volatile phase. This mechanism requires parental melts of kimberlite to originate as carbonatite-like melts. In transit through the mantle lithosphere, these silica-undersaturated melts assimilate mantle minerals, especially orthopyroxene, driving the melt to more silicic compositions, and causing a marked drop in carbon dioxide solubility. The solubility drop manifests itself immediately in a continuous and vigorous exsolution of a fluid phase, thereby reducing magma density, increasing buoyancy, and driving the rapid and accelerating ascent of the increasingly kimberlitic magma. Our model provides an explanation for continuous ascent of magmas laden with high volumes of dense mantle cargo, an explanation for the chemical diversity of kimberlite, and a connection between kimberlites and cratons.

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Coherent singlet-triplet oscillations in a silicon-based double quantum dot.

Publication Date: 2012 Jan 19 PMID: 22258613
Authors: Maune, B. M. - Borselli, M. G. - Huang, B. - Ladd, T. D. - Deelman, P. W. - Holabird, K. S. - Kiselev, A. A. - Alvarado-Rodriguez, I. - Ross, R. S. - Schmitz, A. E. - Sokolich, M. - Watson, C. A. - Gyure, M. F. - Hunter, A. T.
Journal: Nature

Silicon is more than the dominant material in the conventional microelectronics industry: it also has potential as a host material for emerging quantum information technologies. Standard fabrication techniques already allow the isolation of single electron spins in silicon transistor-like devices. Although this is also possible in other materials, silicon-based systems have the advantage of interacting more weakly with nuclear spins. Reducing such interactions is important for the control of spin quantum bits because nuclear fluctuations limit quantum phase coherence, as seen in recent experiments in GaAs-based quantum dots. Advances in reducing nuclear decoherence effects by means of complex control still result in coherence times much shorter than those seen in experiments on large ensembles of impurity-bound electrons in bulk silicon crystals. Here we report coherent control of electron spins in two coupled quantum dots in an undoped Si/SiGe heterostructure and show that this system has a nuclei-induced dephasing time of 360 nanoseconds, which is an increase by nearly two orders of magnitude over similar measurements in GaAs-based quantum dots. The degree of phase coherence observed, combined with fast, gated electrical initialization, read-out and control, should motivate future development of silicon-based quantum information processors.

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Gravitational detection of a low-mass dark satellite galaxy at cosmological distance.

Publication Date: 2012 Jan 19 PMID: 22258612
Authors: Vegetti, S. - Lagattuta, D. J. - McKean, J. P. - Auger, M. W. - Fassnacht, C. D. - Koopmans, L. V.
Journal: Nature

The mass function of dwarf satellite galaxies that are observed around Local Group galaxies differs substantially from simulations based on cold dark matter: the simulations predict many more dwarf galaxies than are seen. The Local Group, however, may be anomalous in this regard. A massive dark satellite in an early-type lens galaxy at a redshift of 0.222 was recently found using a method based on gravitational lensing, suggesting that the mass fraction contained in substructure could be higher than is predicted from simulations. The lack of very low-mass detections, however, prohibited any constraint on their mass function. Here we report the presence of a (1.9 +/- 0.1) x 10(8) M dark satellite galaxy in the Einstein ring system JVAS B1938+666 (ref. 11) at a redshift of 0.881, where M denotes the solar mass. This satellite galaxy has a mass similar to that of the Sagittarius galaxy, which is a satellite of the Milky Way. We determine the logarithmic slope of the mass function for substructure beyond the local Universe to be 1.1(+0.6)(-0.4), with an average mass fraction of 3.3(+3.6)(-1.8) per cent, by combining data on both of these recently discovered galaxies. Our results are consistent with the predictions from cold dark matter simulations at the 95 per cent confidence level, and therefore agree with the view that galaxies formed hierarchically in a Universe composed of cold dark matter.

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The Amazon basin in transition.

Publication Date: 2012 Jan 19 PMID: 22258611
Authors: Davidson, E. A. - de Araujo, A. C. - Artaxo, P. - Balch, J. K. - Brown, I. F. - C Bustamante, M. M. - Coe, M. T. - DeFries, R. S. - Keller, M. - Longo, M. - Munger, J. W. - Schroeder, W. - Soares-Filho, B. S. - Souza, C. M. Jr - Wofsy, S. C.
Journal: Nature

Agricultural expansion and climate variability have become important agents of disturbance in the Amazon basin. Recent studies have demonstrated considerable resilience of Amazonian forests to moderate annual drought, but they also show that interactions between deforestation, fire and drought potentially lead to losses of carbon storage and changes in regional precipitation patterns and river discharge. Although the basin-wide impacts of land use and drought may not yet surpass the magnitude of natural variability of hydrologic and biogeochemical cycles, there are some signs of a transition to a disturbance-dominated regime. These signs include changing energy and water cycles in the southern and eastern portions of the Amazon basin.

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The contribution of bone to whole-organism physiology.

Publication Date: 2012 Jan 19 PMID: 22258610
Authors: Karsenty, G. - Ferron, M.
Journal: Nature

The mouse genetic revolution has shown repeatedly that most organs have more functions than expected. This has led to the realization that, in addition to a molecular and cellular approach, there is a need for a whole-organism study of physiology. The skeleton is an example of how a whole-organism approach to physiology can broaden the functions of a given organ, reveal connections of this organ with others such as the brain, pancreas and gut, and shed new light on the pathogenesis of degenerative diseases affecting multiple organs.

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Clonal evolution in cancer.

Publication Date: 2012 Jan 19 PMID: 22258609
Authors: Greaves, M. - Maley, C. C.
Journal: Nature

Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The dynamics are complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control.

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The promise of induced pluripotent stem cells in research and therapy.

Publication Date: 2012 Jan 19 PMID: 22258608
Authors: Robinton, D. A. - Daley, G. Q.
Journal: Nature

The field of stem-cell biology has been catapulted forward by the startling development of reprogramming technology. The ability to restore pluripotency to somatic cells through the ectopic co-expression of reprogramming factors has created powerful new opportunities for modelling human diseases and offers hope for personalized regenerative cell therapies. While the field is racing ahead, some researchers are pausing to evaluate whether induced pluripotent stem cells are indeed the true equivalents of embryonic stem cells and whether subtle differences between these types of cell might affect their research applications and therapeutic potential.

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The DNA damage response and cancer therapy.

Publication Date: 2012 Jan 19 PMID: 22258607
Authors: Lord, C. J. - Ashworth, A.
Journal: Nature

Genomic instability is one of the most pervasive characteristics of tumour cells and is probably the combined effect of DNA damage, tumour-specific DNA repair defects, and a failure to stop or stall the cell cycle before the damaged DNA is passed on to daughter cells. Although these processes drive genomic instability and ultimately the disease process, they also provide therapeutic opportunities. A better understanding of the cellular response to DNA damage will not only inform our knowledge of cancer development but also help to refine the classification as well as the treatment of the disease.

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Inflammasomes in health and disease.

Publication Date: 2012 Jan 19 PMID: 22258606
Authors: Strowig, T. - Henao-Mejia, J. - Elinav, E. - Flavell, R.
Journal: Nature

Inflammasomes are a group of protein complexes built around several proteins, including NLRP3, NLRC4, AIM2 and NLRP6. Recognition of a diverse range of microbial, stress and damage signals by inflammasomes results in direct activation of caspase-1, which subsequently induces secretion of potent pro-inflammatory cytokines and a form of cell death called pyroptosis. Inflammasome-mediated processes are important during microbial infections and also in regulating both metabolic processes and mucosal immune responses. We review the functions of the different inflammasome complexes and discuss how aberrations in them are implicated in the pathogenesis of human diseases.

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Frontiers in biology.

Publication Date: 2012 Jan 19 PMID: 22258605
Authors: Eccleston, A. - Eggleston, A. - Heemels, M. T. - Marte, B. - Weiss, U.
Journal: Nature

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Cancer: Reprogramming clinical outcome.

Publication Date: 2012 Jan 19 PMID: 22258604
Authors: Deblois, G. - Giguere, V.
Journal: Nature

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Organic chemistry: Stabilizers cause instability.

Publication Date: 2012 Jan 19 PMID: 22258603
Authors: Clayden, J.
Journal: Nature

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Cell cycle: A division duet.

Publication Date: 2012 Jan 19 PMID: 22258602
Authors: Wittenberg, C.
Journal: Nature

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Galaxy formation: Distant dwarfs.

Publication Date: 2012 Jan 19 PMID: 22258600
Authors: Schmidt, R. W.
Journal: Nature

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Genomics: The path to retinoblastoma.

Publication Date: 2012 Jan 19 PMID: 22258599
Authors: Sage, J. - Cleary, M. L.
Journal: Nature

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Paul Mead Doty (1920-2011).

Publication Date: 2012 Jan 19 PMID: 22258598
Authors: Rice, S. A. - Haselkorn, R.
Journal: Nature

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Asian medicine: Small species at risk.

Publication Date: 2012 Jan 19 PMID: 22258597
Authors: Nijman, V. - Nekaris, K. A. - Bickford, D. P.
Journal: Nature

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Leap year: Rare day to highlight rare diseases.

Publication Date: 2012 Jan 19 PMID: 22258596
Authors: Gasser, S. M. - Lupski, J. R. - Le Cam, Y. - Menzel, O.
Journal: Nature

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Overfishing: Call to split fisheries at home and abroad.

Publication Date: 2012 Jan 19 PMID: 22258595
Authors: Sumaila, U. R.
Journal: Nature

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Pharmaceutical industry: Investors unfazed by drug-patent expiry.

Publication Date: 2012 Jan 19 PMID: 22258594
Authors: Brindley, D. - Reeve, B. - Mason, C.
Journal: Nature

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Philanthropy: The price of charity.

Publication Date: 2012 Jan 19 PMID: 22258589
Authors: Aebischer, P.
Journal: Nature

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Alternative funding: Sponsor my science.

Publication Date: 2012 Jan 19 PMID: 22258588
Authors: Ledford, H.
Journal: Nature

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Finding philanthropy: Like it? Pay for it.

Publication Date: 2012 Jan 19 PMID: 22258587
Authors: Giles, J.
Journal: Nature

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Gemini's twin telescopes reboot.

Publication Date: 2012 Jan 19 PMID: 22258586
Authors: Hand, E.
Journal: Nature

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Russian drug law hinders clinical trials.

Publication Date: 2012 Jan 19 PMID: 22258585
Authors: Katsnelson, A.
Journal: Nature

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Murders unlikely to slow Iran's nuclear efforts.

Publication Date: 2012 Jan 19 PMID: 22258584
Authors: Weinberger, S.
Journal: Nature

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Evolution advocate turns to climate.

Publication Date: 2012 Jan 19 PMID: 22258583
Authors: Young, S.
Journal: Nature

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Database tallies US emissions.

Publication Date: 2012 Jan 19 PMID: 22258582
Authors: Tollefson, J.
Journal: Nature

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Pollutants key to climate fix.

Publication Date: 2012 Jan 19 PMID: 22258581
Authors: Tollefson, J.
Journal: Nature

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Break down boundaries in climate research.

Publication Date: 2012 Jan 19 PMID: 22258570
Authors: Artaxo, P.
Journal: Nature

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Cap in hand.

Publication Date: 2012 Jan 19 PMID: 22258569
Authors:
Journal: Nature

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Face up to fraud.

Publication Date: 2012 Jan 19 PMID: 22258568
Authors:
Journal: Nature

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Antarctic Treaty is cold comfort.

Publication Date: 2012 Jan 19 PMID: 22258567
Authors:
Journal: Nature

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Genetic contributions to stability and change in intelligence from childhood to old age.

Publication Date: 2012 Jan 18 PMID: 22258510
Authors: Deary, I. J. - Yang, J. - Davies, G. - Harris, S. E. - Tenesa, A. - Liewald, D. - Luciano, M. - Lopez, L. M. - Gow, A. J. - Corley, J. - Redmond, P. - Fox, H. C. - Rowe, S. J. - Haggarty, P. - McNeill, G. - Goddard, M. E. - Porteous, D. J. - Whalley, L. J. - Starr, J. M. - Visscher, P. M.
Journal: Nature

Understanding the determinants of healthy mental ageing is a priority for society today. So far, we know that intelligence differences show high stability from childhood to old age and there are estimates of the genetic contribution to intelligence at different ages. However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative. Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated individuals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years). We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated individuals. We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change.

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Genome-wide structure and organization of eukaryotic pre-initiation complexes.

Publication Date: 2012 Jan 18 PMID: 22258509
Authors: Rhee, H. S. - Pugh, B. F.
Journal: Nature

Transcription and regulation of genes originate from transcription pre-initiation complexes (PICs). Their structural and positional organization across eukaryotic genomes is unknown. Here we applied lambda exonuclease to chromatin immunoprecipitates (termed ChIP-exo) to examine the precise location of 6,045 PICs in Saccharomyces. PICs, including RNA polymerase II and protein complexes TFIIA, TFIIB, TFIID (or TBP), TFIIE, TFIIF, TFIIH and TFIIK were positioned within promoters and excluded from coding regions. Exonuclease patterns were in agreement with crystallographic models of the PIC, and were sufficiently precise to identify TATA-like elements at so-called TATA-less promoters. These PICs and their transcription start sites were positionally constrained at TFIID-engaged downstream +1 nucleosomes. At TATA-box-containing promoters, which are depleted of TFIID, a +1 nucleosome was positioned to be in competition with the PIC, which may allow greater latitude in start-site selection. Our genomic localization of messenger RNA and non-coding RNA PICs reveals that two PICs, in inverted orientation, may occupy the flanking borders of nucleosome-free regions. Their unambiguous detection may help distinguish bona fide genes from transcriptional noise.

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Neuron-type-specific signals for reward and punishment in the ventral tegmental area.

Publication Date: 2012 Feb 2 PMID: 22258508
Authors: Cohen, J. Y. - Haesler, S. - Vong, L. - Lowell, B. B. - Uchida, N.
Journal: Nature

Dopamine has a central role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (that is, reward prediction error), but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neuron based on responses to odours and outcomes: approximately half of the neurons (type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with reward prediction error coding; the other half of neurons showed persistent activity during the delay between odour and outcome that was modulated positively (type II, 31%) or negatively (type III, 18%) by the value of outcomes. Whereas the activity of type I neurons was sensitive to actual outcomes (that is, when the reward was delivered as expected compared to when it was unexpectedly omitted), the activity of type II and type III neurons was determined predominantly by reward-predicting odours. We 'tagged' dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of type I and all GABAergic neurons were of type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate reward prediction error.

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DNA breaks and chromosome pulverization from errors in mitosis.

Publication Date: 2012 Feb 2 PMID: 22258507
Authors: Crasta, K. - Ganem, N. J. - Dagher, R. - Lantermann, A. B. - Ivanova, E. V. - Pan, Y. - Nezi, L. - Protopopov, A. - Chowdhury, D. - Pellman, D.
Journal: Nature

The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement.

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Pathway complexity in supramolecular polymerization.

Publication Date: 2012 Jan 26 PMID: 22258506
Authors: Korevaar, P. A. - George, S. J. - Markvoort, A. J. - Smulders, M. M. - Hilbers, P. A. - Schenning, A. P. - De Greef, T. F. - Meijer, E. W.
Journal: Nature

Self-assembly provides an attractive route to functional organic materials, with properties and hence performance depending sensitively on the organization of the molecular building blocks. Molecular organization is a direct consequence of the pathways involved in the supramolecular assembly process, which is more amenable to detailed study when using one-dimensional systems. In the case of protein fibrils, formation and growth have been attributed to complex aggregation pathways that go beyond traditional concepts of homogeneous and secondary nucleation events. The self-assembly of synthetic supramolecular polymers has also been studied and even modulated, but our quantitative understanding of the processes involved remains limited. Here we report time-resolved observations of the formation of supramolecular polymers from pi-conjugated oligomers. Our kinetic experiments show the presence of a kinetically favoured metastable assembly that forms quickly but then transforms into the thermodynamically favoured form. Quantitative insight into the kinetic experiments was obtained from kinetic model calculations, which revealed two parallel and competing pathways leading to assemblies with opposite helicity. These insights prompt us to use a chiral tartaric acid as an auxiliary to change the thermodynamic preference of the assembly process. We find that we can force aggregation completely down the kinetically favoured pathway so that, on removal of the auxiliary, we obtain only metastable assemblies.

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Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis.

Publication Date: 2012 Jan 26 PMID: 22258505
Authors: He, C. - Bassik, M. C. - Moresi, V. - Sun, K. - Wei, Y. - Zou, Z. - An, Z. - Loh, J. - Fisher, J. - Sun, Q. - Korsmeyer, S. - Packer, M. - May, H. I. - Hill, J. A. - Virgin, H. W. - Gilpin, C. - Xiao, G. - Bassel-Duby, R. - Scherer, P. E. - Levine, B.
Journal: Nature

Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.

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Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism.

Publication Date: 2012 Jan 26 PMID: 22246326
Authors: Steinhauser, M. L. - Bailey, A. P. - Senyo, S. E. - Guillermier, C. - Perlstein, T. S. - Gould, A. P. - Lee, R. T. - Lechene, C. P.
Journal: Nature

Mass spectrometry with stable isotope labels has been seminal in discovering the dynamic state of living matter, but is limited to bulk tissues or cells. We developed multi-isotope imaging mass spectrometry (MIMS) that allowed us to view and measure stable isotope incorporation with submicrometre resolution. Here we apply MIMS to diverse organisms, including Drosophila, mice and humans. We test the 'immortal strand hypothesis', which predicts that during asymmetric stem cell division chromosomes containing older template DNA are segregated to the daughter destined to remain a stem cell, thus insuring lifetime genetic stability. After labelling mice with (15)N-thymidine from gestation until post-natal week 8, we find no (15)N label retention by dividing small intestinal crypt cells after a four-week chase. In adult mice administered (15)N-thymidine pulse-chase, we find that proliferating crypt cells dilute the (15)N label, consistent with random strand segregation. We demonstrate the broad utility of MIMS with proof-of-principle studies of lipid turnover in Drosophila and translation to the human haematopoietic system. These studies show that MIMS provides high-resolution quantification of stable isotope labels that cannot be obtained using other techniques and that is broadly applicable to biological and medical research.

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Preventing pandemics: The fight over flu.

Publication Date: 2012 Jan 19 PMID: 22246325
Authors:
Journal: Nature

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Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion.

Publication Date: 2012 Jan 15 PMID: 22246324
Authors: Thurston, T. L. - Wandel, M. P. - von Muhlinen, N. - Foeglein, A. - Randow, F.
Journal: Nature

Autophagy defends the mammalian cytosol against bacterial infection. Efficient pathogen engulfment is mediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating. Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation. Galectin 8 monitors endosomal and lysosomal integrity and detects bacterial invasion by binding host glycans exposed on damaged Salmonella-containing vacuoles. By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. Galectin-8-dependent recruitment of NDP52 to Salmonella-containing vesicles is transient and followed by ubiquitin-dependent NDP52 recruitment. Because galectin 8 also detects sterile damage to endosomes or lysosomes, as well as invasion by Listeria or Shigella, we suggest that galectin 8 serves as a versatile receptor for vesicle-damaging pathogens. Our results illustrate how cells deploy the danger receptor galectin 8 to combat infection by monitoring endosomal and lysosomal integrity on the basis of the specific lack of complex carbohydrates in the cytosol.

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Multi-isotope imaging mass spectrometry reveals slow protein turnover in hair-cell stereocilia.

Publication Date: 2012 Jan 26 PMID: 22246323
Authors: Zhang, D. S. - Piazza, V. - Perrin, B. J. - Rzadzinska, A. K. - Poczatek, J. C. - Wang, M. - Prosser, H. M. - Ervasti, J. M. - Corey, D. P. - Lechene, C. P.
Journal: Nature

Hair cells of the inner ear are not normally replaced during an animal's life, and must continually renew components of their various organelles. Among these are the stereocilia, each with a core of several hundred actin filaments that arise from their apical surfaces and that bear the mechanotransduction apparatus at their tips. Actin turnover in stereocilia has previously been studied by transfecting neonatal rat hair cells in culture with a beta-actin-GFP fusion, and evidence was found that actin is replaced, from the top down, in 2-3 days. Overexpression of the actin-binding protein espin causes elongation of stereocilia within 12-24 hours, also suggesting rapid regulation of stereocilia lengths. Similarly, the mechanosensory 'tip links' are replaced in 5-10 hours after cleavage in chicken and mammalian hair cells. In contrast, turnover in chick stereocilia in vivo is much slower. It might be that only certain components of stereocilia turn over quickly, that rapid turnover occurs only in neonatal animals, only in culture, or only in response to a challenge like breakage or actin overexpression. Here we quantify protein turnover by feeding animals with a (15)N-labelled precursor amino acid and using multi-isotope imaging mass spectrometry to measure appearance of new protein. Surprisingly, in adult frogs and mice and in neonatal mice, in vivo and in vitro, the stereocilia were remarkably stable, incorporating newly synthesized protein at <10% per day. Only stereocilia tips had rapid turnover and no treadmilling was observed. Other methods confirmed this: in hair cells expressing beta-actin-GFP we bleached fiducial lines across hair bundles, but they did not move in 6 days. When we stopped expression of beta- or gamma-actin with tamoxifen-inducible recombination, neither actin isoform left the stereocilia, except at the tips. Thus, rapid turnover in stereocilia occurs only at the tips and not by a treadmilling process.

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A novel sensor to map auxin response and distribution at high spatio-temporal resolution.

Publication Date: 2012 Feb 2 PMID: 22246322
Authors: Brunoud, G. - Wells, D. M. - Oliva, M. - Larrieu, A. - Mirabet, V. - Burrow, A. H. - Beeckman, T. - Kepinski, S. - Traas, J. - Bennett, M. J. - Vernoux, T.
Journal: Nature

Auxin is a key plant morphogenetic signal but tools to analyse dynamically its distribution and signalling during development are still limited. Auxin perception directly triggers the degradation of Aux/IAA repressor proteins. Here we describe a novel Aux/IAA-based auxin signalling sensor termed DII-VENUS that was engineered in the model plant Arabidopsis thaliana. The VENUS fast maturing form of yellow fluorescent protein was fused in-frame to the Aux/IAA auxin-interaction domain (termed domain II; DII) and expressed under a constitutive promoter. We initially show that DII-VENUS abundance is dependent on auxin, its TIR1/AFBs co-receptors and proteasome activities. Next, we demonstrate that DII-VENUS provides a map of relative auxin distribution at cellular resolution in different tissues. DII-VENUS is also rapidly degraded in response to auxin and we used it to visualize dynamic changes in cellular auxin distribution successfully during two developmental responses, the root gravitropic response and lateral organ production at the shoot apex. Our results illustrate the value of developing response input sensors such as DII-VENUS to provide high-resolution spatio-temporal information about hormone distribution and response during plant growth and development.

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Bridge funding: How to stay afloat.

Publication Date: 2012 Jan 12 PMID: 22242219
Authors: Perkel, J.
Journal: Nature

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Modelling the rheology of MgO under Earth's mantle pressure, temperature and strain rates.

Publication Date: 2012 Jan 12 PMID: 22237109
Authors: Cordier, P. - Amodeo, J. - Carrez, P.
Journal: Nature

Plate tectonics, which shapes the surface of Earth, is the result of solid-state convection in Earth's mantle over billions of years. Simply driven by buoyancy forces, mantle convection is complicated by the nature of the convecting materials, which are not fluids but polycrystalline rocks. Crystalline materials can flow as the result of the motion of defects--point defects, dislocations, grain boundaries and so on. Reproducing in the laboratory the extreme deformation conditions of the mantle is extremely challenging. In particular, experimental strain rates are at least six orders of magnitude larger than in nature. Here we show that the rheology of MgO at the pressure, temperature and strain rates of the mantle is accessible by multiscale numerical modelling starting from first principles and with no adjustable parameters. Our results demonstrate that extremely low strain rates counteract the influence of pressure. In the mantle, MgO deforms in the athermal regime and this leads to a very weak phase. It is only in the lowermost lower mantle that the pressure effect could dominate and that, under the influence of lattice friction, a viscosity of the order of 10(21)-10(22) pascal seconds can be defined for MgO.

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One or more bound planets per Milky Way star from microlensing observations.

Publication Date: 2012 Jan 12 PMID: 22237108
Authors: Cassan, A. - Kubas, D. - Beaulieu, J. P. - Dominik, M. - Horne, K. - Greenhill, J. - Wambsganss, J. - Menzies, J. - Williams, A. - Jorgensen, U. G. - Udalski, A. - Bennett, D. P. - Albrow, M. D. - Batista, V. - Brillant, S. - Caldwell, J. A. - Cole, A. - Coutures, C. h. - Cook, K. H. - Dieters, S. - Prester, D. D. - Donatowicz, J. - Fouque, P. - Hill, K. - Kains, N. - Kane, S. - Marquette, J. B. - Martin, R. - Pollard, K. R. - Sahu, K. C. - Vinter, C. - Warren, D. - Watson, B. - Zub, M. - Sumi, T. - Szymanski, M. K. - Kubiak, M. - Poleski, R. - Soszynski, I. - Ulaczyk, K. - Pietrzynski, G. - Wyrzykowski, L.
Journal: Nature

Most known extrasolar planets (exoplanets) have been discovered using the radial velocity or transit methods. Both are biased towards planets that are relatively close to their parent stars, and studies find that around 17-30% (refs 4, 5) of solar-like stars host a planet. Gravitational microlensing, on the other hand, probes planets that are further away from their stars. Recently, a population of planets that are unbound or very far from their stars was discovered by microlensing. These planets are at least as numerous as the stars in the Milky Way. Here we report a statistical analysis of microlensing data (gathered in 2002-07) that reveals the fraction of bound planets 0.5-10 AU (Sun-Earth distance) from their stars. We find that 17(+6)(-9)% of stars host Jupiter-mass planets (0.3-10 M(J), where M(J) = 318 M( plus sign in circle) and M( plus sign in circle) is Earth's mass). Cool Neptunes (10-30 M( plus sign in circle)) and super-Earths (5-10 M( plus sign in circle)) are even more common: their respective abundances per star are 52(+22)(-29)% and 62(+35)(-37)%. We conclude that stars are orbited by planets as a rule, rather than the exception.

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An absence of ex-companion stars in the type Ia supernova remnant SNR 0509-67.5.

Publication Date: 2012 Jan 12 PMID: 22237107
Authors: Schaefer, B. E. - Pagnotta, A.
Journal: Nature

A type Ia supernova is thought to begin with the explosion of a white dwarf star. The explosion could be triggered by the merger of two white dwarfs (a 'double-degenerate' origin), or by mass transfer from a companion star (the 'single-degenerate' path). The identity of the progenitor is still controversial; for example, a recent argument against the single-degenerate origin has been widely rejected. One way to distinguish between the double- and single-degenerate progenitors is to look at the centre of a known type Ia supernova remnant to see whether any former companion star is present. A likely ex-companion star for the progenitor of the supernova observed by Tycho Brahe has been identified, but that claim is still controversial. Here we report that the central region of the supernova remnant SNR 0509-67.5 (the site of a type Ia supernova 400 +/- 50 years ago, based on its light echo) in the Large Magellanic Cloud contains no ex-companion star to a visual magnitude limit of 26.9 (an absolute magnitude of M(V) = +8.4) within a region of radius 1.43 arcseconds. (This corresponds to the 3sigma maximum distance to which a companion could have been 'kicked' by the explosion.) This lack of any ex-companion star to deep limits rules out all published single-degenerate models for this supernova. The only remaining possibility is that the progenitor of this particular type Ia supernova was a double-degenerate system.

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The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.

Publication Date: 2012 Jan 12 PMID: 22237106
Authors: Zhang, J. - Ding, L. - Holmfeldt, L. - Wu, G. - Heatley, S. L. - Payne-Turner, D. - Easton, J. - Chen, X. - Wang, J. - Rusch, M. - Lu, C. - Chen, S. C. - Wei, L. - Collins-Underwood, J. R. - Ma, J. - Roberts, K. G. - Pounds, S. B. - Ulyanov, A. - Becksfort, J. - Gupta, P. - Huether, R. - Kriwacki, R. W. - Parker, M. - McGoldrick, D. J. - Zhao, D. - Alford, D. - Espy, S. - Bobba, K. C. - Song, G. - Pei, D. - Cheng, C. - Roberts, S. - Barbato, M. I. - Campana, D. - Coustan-Smith, E. - Shurtleff, S. A. - Raimondi, S. C. - Kleppe, M. - Cools, J. - Shimano, K. A. - Hermiston, M. L. - Doulatov, S. - Eppert, K. - Laurenti, E. - Notta, F. - Dick, J. E. - Basso, G. - Hunger, S. P. - Loh, M. L. - Devidas, M. - Wood, B. - Winter, S. - Dunsmore, K. P. - Fulton, R. S. - Fulton, L. L. - Hong, X. - Harris, C. C. - Dooling, D. J. - Ochoa, K. - Johnson, K. J. - Obenauer, J. C. - Evans, W. E. - Pui, C. H. - Naeve, C. W. - Ley, T. J. - Mardis, E. R. - Wilson, R. K. - Downing, J. R. - Mullighan, C. G.
Journal: Nature

Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

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Cognition: Your face looks familiar.

Publication Date: 2012 Jan 12 PMID: 22237105
Authors: Chittka, L. - Dyer, A.
Journal: Nature

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Earth science: Limits of the power law.

Publication Date: 2012 Jan 12 PMID: 22237104
Authors: Walker, A. M.
Journal: Nature

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Applied physics: Nanowire electronics comes of age.

Publication Date: 2012 Jan 12 PMID: 22237103
Authors: Palacios, T.
Journal: Nature

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Astrophysics: Progenitors of type Ia supernovae.

Publication Date: 2012 Jan 12 PMID: 22237101
Authors: Ruiz-Lapuente, P.
Journal: Nature

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Sequencing data: A genomic network to monitor Earth.

Publication Date: 2012 Jan 12 PMID: 22237100
Authors: Davies, N. - Field, D. - Genomic Observatories, N. e. t. w. o. r. k.
Journal: Nature

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Water management: Reduce urban flood vulnerability.

Publication Date: 2012 Jan 12 PMID: 22237099
Authors: Ziegler, A. D.
Journal: Nature

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Nuclear power: India should exploit renewable energy.

Publication Date: 2012 Jan 12 PMID: 22237098
Authors: Agoramoorthy, G.
Journal: Nature

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Scientific misconduct: Latest MMR 'dispute' is a straw man.

Publication Date: 2012 Jan 12 PMID: 22237097
Authors: Deer, B.
Journal: Nature

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Conservation science: A market approach to saving the whales.

Publication Date: 2012 Jan 12 PMID: 22237092
Authors: Costello, C. - Gaines, S. - Gerber, L. R.
Journal: Nature

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Climate policy: Deadline 2015.

Publication Date: 2012 Jan 12 PMID: 22237091
Authors: Jacobs, M.
Journal: Nature

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Research ethics: Zero tolerance.

Publication Date: 2012 Jan 12 PMID: 22237090
Authors: Cyranoski, D.
Journal: Nature

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Stem-cell research: Never say die.

Publication Date: 2012 Jan 12 PMID: 22237089
Authors: Lok, C.
Journal: Nature

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US translational-science centre gets under way.

Publication Date: 2012 Jan 12 PMID: 22237088
Authors: Wadman, M.
Journal: Nature

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Radio array starts work.

Publication Date: 2012 Jan 12 PMID: 22237085
Authors: Hand, E.
Journal: Nature

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Rules tighten on use of antibiotics on farms.

Publication Date: 2012 Jan 12 PMID: 22237084
Authors: Gilbert, N.
Journal: Nature

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Disaster toll tallied.

Publication Date: 2012 Jan 12 PMID: 22237083
Authors: Schiermeier, Q.
Journal: Nature

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Greek science on the brink.

Publication Date: 2012 Jan 12 PMID: 22237082
Authors: Abbott, A.
Journal: Nature

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France 'imagines the unimaginable'.

Publication Date: 2012 Jan 12 PMID: 22237081
Authors: Butler, D.
Journal: Nature

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Don't censor life-saving science.

Publication Date: 2012 Jan 12 PMID: 22237069
Authors: Palese, P.
Journal: Nature

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Whales for sale.

Publication Date: 2012 Jan 12 PMID: 22237068
Authors:
Journal: Nature

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Get tough on nuclear safety.

Publication Date: 2012 Jan 12 PMID: 22237067
Authors:
Journal: Nature

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A long stretch.

Publication Date: 2012 Jan 12 PMID: 22237066
Authors:
Journal: Nature

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Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.

Publication Date: 2012 Jan 26 PMID: 22237025
Authors: Ding, L. - Ley, T. J. - Larson, D. E. - Miller, C. A. - Koboldt, D. C. - Welch, J. S. - Ritchey, J. K. - Young, M. A. - Lamprecht, T. - McLellan, M. D. - McMichael, J. F. - Wallis, J. W. - Lu, C. - Shen, D. - Harris, C. C. - Dooling, D. J. - Fulton, R. S. - Fulton, L. L. - Chen, K. - Schmidt, H. - Kalicki-Veizer, J. - Magrini, V. J. - Cook, L. - McGrath, S. D. - Vickery, T. L. - Wendl, M. C. - Heath, S. - Watson, M. A. - Link, D. C. - Tomasson, M. H. - Shannon, W. D. - Payton, J. E. - Kulkarni, S. - Westervelt, P. - Walter, M. J. - Graubert, T. A. - Mardis, E. R. - Wilson, R. K. - DiPersio, J. F.
Journal: Nature

Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.

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Complete subunit architecture of the proteasome regulatory particle.

Publication Date: 2012 Jan 11 PMID: 22237024
Authors: Lander, G. C. - Estrin, E. - Matyskiela, M. E. - Bashore, C. - Nogales, E. - Martin, A.
Journal: Nature

The proteasome is the major ATP-dependent protease in eukaryotic cells, but limited structural information restricts a mechanistic understanding of its activities. The proteasome regulatory particle, consisting of the lid and base subcomplexes, recognizes and processes polyubiquitinated substrates. Here we used electron microscopy and a new heterologous expression system for the lid to delineate the complete subunit architecture of the regulatory particle from yeast. Our studies reveal the spatial arrangement of ubiquitin receptors, deubiquitinating enzymes and the protein unfolding machinery at subnanometre resolution, outlining the substrate's path to degradation. Unexpectedly, the ATPase subunits within the base unfoldase are arranged in a spiral staircase, providing insight into potential mechanisms for substrate translocation through the central pore. Large conformational rearrangements of the lid upon holoenzyme formation suggest allosteric regulation of deubiquitination. We provide a structural basis for the ability of the proteasome to degrade a diverse set of substrates and thus regulate vital cellular processes.

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A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis.

Publication Date: 2012 Jan 26 PMID: 22237023
Authors: Bostrom, P. - Wu, J. - Jedrychowski, M. P. - Korde, A. - Ye, L. - Lo, J. C. - Rasbach, K. A. - Bostrom, E. A. - Choi, J. H. - Long, J. Z. - Kajimura, S. - Zingaretti, M. C. - Vind, B. F. - Tu, H. - Cinti, S. - Hojlund, K. - Gygi, S. P. - Spiegelman, B. M.
Journal: Nature

Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-gamma co-activator-1 alpha (PGC1-alpha). Here we show in mouse that PGC1-alpha expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.

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A novel retinoblastoma therapy from genomic and epigenetic analyses.

Publication Date: 2012 Jan 19 PMID: 22237022
Authors: Zhang, J. - Benavente, C. A. - McEvoy, J. - Flores-Otero, J. - Ding, L. - Chen, X. - Ulyanov, A. - Wu, G. - Wilson, M. - Wang, J. - Brennan, R. - Rusch, M. - Manning, A. L. - Ma, J. - Easton, J. - Shurtleff, S. - Mullighan, C. - Pounds, S. - Mukatira, S. - Gupta, P. - Neale, G. - Zhao, D. - Lu, C. - Fulton, R. S. - Fulton, L. L. - Hong, X. - Dooling, D. J. - Ochoa, K. - Naeve, C. - Dyson, N. J. - Mardis, E. R. - Bahrami, A. - Ellison, D. - Wilson, R. K. - Downing, J. R. - Dyer, M. A.
Journal: Nature

Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.

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Transiting circumbinary planets Kepler-34 b and Kepler-35 b.

Publication Date: 2012 Jan 26 PMID: 22237021
Authors: Welsh, W. F. - Orosz, J. A. - Carter, J. A. - Fabrycky, D. C. - Ford, E. B. - Lissauer, J. J. - Prsa, A. - Quinn, S. N. - Ragozzine, D. - Short, D. R. - Torres, G. - Winn, J. N. - Doyle, L. R. - Barclay, T. - Batalha, N. - Bloemen, S. - Brugamyer, E. - Buchhave, L. A. - Caldwell, C. - Caldwell, D. A. - Christiansen, J. L. - Ciardi, D. R. - Cochran, W. D. - Endl, M. - Fortney, J. J. - Gautier, T. N. 3rd - Gilliland, R. L. - Haas, M. R. - Hall, J. R. - Holman, M. J. - Howard, A. W. - Howell, S. B. - Isaacson, H. - Jenkins, J. M. - Klaus, T. C. - Latham, D. W. - Li, J. - Marcy, G. W. - Mazeh, T. - Quintana, E. V. - Robertson, P. - Shporer, A. - Steffen, J. H. - Windmiller, G. - Koch, D. G. - Borucki, W. J.
Journal: Nature

Most Sun-like stars in the Galaxy reside in gravitationally bound pairs of stars (binaries). Although long anticipated, the existence of a 'circumbinary planet' orbiting such a pair of normal stars was not definitively established until the discovery of the planet transiting (that is, passing in front of) Kepler-16. Questions remained, however, about the prevalence of circumbinary planets and their range of orbital and physical properties. Here we report two additional transiting circumbinary planets: Kepler-34 (AB)b and Kepler-35 (AB)b, referred to here as Kepler-34 b and Kepler-35 b, respectively. Each is a low-density gas-giant planet on an orbit closely aligned with that of its parent stars. Kepler-34 b orbits two Sun-like stars every 289 days, whereas Kepler-35 b orbits a pair of smaller stars (89% and 81% of the Sun's mass) every 131 days. The planets experience large multi-periodic variations in incident stellar radiation arising from the orbital motion of the stars. The observed rate of circumbinary planets in our sample implies that more than approximately 1% of close binary stars have giant planets in nearly coplanar orbits, yielding a Galactic population of at least several million.

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Molecular recognition of a single sphingolipid species by a protein's transmembrane domain.

Publication Date: 2012 Jan 26 PMID: 22230960
Authors: Contreras, F. X. - Ernst, A. M. - Haberkant, P. - Bjorkholm, P. - Lindahl, E. - Gonen, B. - Tischer, C. - Elofsson, A. - von Heijne, G. - Thiele, C. - Pepperkok, R. - Wieland, F. - Brugger, B.
Journal: Nature

Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24 (ref. 2). Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids.

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Structure of the carboxy-terminal region of a KCNH channel.

Publication Date: 2012 Jan 26 PMID: 22230959
Authors: Brelidze, T. I. - Carlson, A. E. - Sankaran, B. - Zagotta, W. N.
Journal: Nature

The KCNH family of ion channels, comprising ether-a-go-go (EAG), EAG-related gene (ERG), and EAG-like (ELK) K(+)-channel subfamilies, is crucial for repolarization of the cardiac action potential, regulation of neuronal excitability and proliferation of tumour cells. The carboxy-terminal region of KCNH channels contains a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore. The C-linker/CNBHD is essential for proper function and trafficking of ion channels in the KCNH family. However, despite the importance of the C-linker/CNBHD for the function of KCNH channels, the structural basis of ion-channel regulation by the C-linker/CNBHD is unknown. Here we report the crystal structure of the C-linker/CNBHD of zebrafish ELK channels at 2.2-A resolution. Although the overall structure of the C-linker/CNBHD of ELK channels is similar to the cyclic-nucleotide-binding domain (CNBD) structure of the related hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channels, there are marked differences. Unlike the CNBD of HCN, the CNBHD of ELK displays a negatively charged electrostatic profile that explains the lack of binding and regulation of KCNH channels by cyclic nucleotides. Instead of cyclic nucleotide, the binding pocket is occupied by a short beta-strand. Mutations of the beta-strand shift the voltage dependence of activation to more depolarized voltages, implicating the beta-strand as an intrinsic ligand for the CNBHD of ELK channels. In both ELK and HCN channels the C-linker is the site of virtually all of the intersubunit interactions in the C-terminal region. However, in the zebrafish ELK structure there is a reorientation in the C-linker so that the subunits form dimers instead of tetramers, as observed in HCN channels. These results provide a structural framework for understanding the regulation of ion channels in the KCNH family by the C-linker/CNBHD and may guide the design of specific drugs.

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Evolutionary biology: A ratchet for protein complexity.

Publication Date: 2012 Jan 19 PMID: 22230958
Authors: Doolittle, W. F.
Journal: Nature

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Cysteinyl leukotriene type I receptor desensitization sustains Ca2+-dependent gene expression.

Publication Date: 2012 Feb 2 PMID: 22230957
Authors: Ng, S. W. - Bakowski, D. - Nelson, C. - Mehta, R. - Almeyda, R. - Bates, G. - Parekh, A. B.
Journal: Nature

Receptor desensitization is a universal mechanism to turn off a biological response; in this process, the ability of a physiological trigger to activate a cell is lost despite the continued presence of the stimulus. Receptor desensitization of G-protein-coupled receptors involves uncoupling of the receptor from its G-protein or second-messenger pathway followed by receptor internalization. G-protein-coupled cysteinyl leukotriene type I (CysLT1) receptors regulate immune-cell function and CysLT1 receptors are an established therapeutic target for allergies, including asthma. Desensitization of CysLT1 receptors arises predominantly from protein-kinase-C-dependent phosphorylation of three serine residues in the receptor carboxy terminus. Physiological concentrations of the receptor agonist leukotriene C(4) (LTC(4)) evoke repetitive cytoplasmic Ca(2+) oscillations, reflecting regenerative Ca(2+) release from stores, which is sustained by Ca(2+) entry through store-operated calcium-release-activated calcium (CRAC) channels. CRAC channels are tightly linked to expression of the transcription factor c-fos, a regulator of numerous genes important to cell growth and development. Here we show that abolishing leukotriene receptor desensitization suppresses agonist-driven gene expression in a rat cell line. Mechanistically, stimulation of non-desensitizing receptors evoked prolonged inositol-trisphosphate-mediated Ca(2+) release, which led to accelerated Ca(2+)-dependent slow inactivation of CRAC channels and a subsequent loss of excitation-transcription coupling. Hence, rather than serving to turn off a biological response, reversible desensitization of a Ca(2+) mobilizing receptor acts as an 'on' switch, sustaining long-term signalling in the immune system.

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Evolution of increased complexity in a molecular machine.

Publication Date: 2012 Jan 19 PMID: 22230956
Authors: Finnigan, G. C. - Hanson-Smith, V. - Stevens, T. H. - Thornton, J. W.
Journal: Nature

Many cellular processes are carried out by molecular 'machines'-assemblies of multiple differentiated proteins that physically interact to execute biological functions. Despite much speculation, strong evidence of the mechanisms by which these assemblies evolved is lacking. Here we use ancestral gene resurrection and manipulative genetic experiments to determine how the complexity of an essential molecular machine--the hexameric transmembrane ring of the eukaryotic V-ATPase proton pump--increased hundreds of millions of years ago. We show that the ring of Fungi, which is composed of three paralogous proteins, evolved from a more ancient two-paralogue complex because of a gene duplication that was followed by loss in each daughter copy of specific interfaces by which it interacts with other ring proteins. These losses were complementary, so both copies became obligate components with restricted spatial roles in the complex. Reintroducing a single historical mutation from each paralogue lineage into the resurrected ancestral proteins is sufficient to recapitulate their asymmetric degeneration and trigger the requirement for the more elaborate three-component ring. Our experiments show that increased complexity in an essential molecular machine evolved because of simple, high-probability evolutionary processes, without the apparent evolution of novel functions. They point to a plausible mechanism for the evolution of complexity in other multi-paralogue protein complexes.

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X-ray structures of LeuT in substrate-free outward-open and apo inward-open states.

Publication Date: 2012 Jan 26 PMID: 22230955
Authors: Krishnamurthy, H. - Gouaux, E.
Journal: Nature

Neurotransmitter sodium symporters are integral membrane proteins that remove chemical transmitters from the synapse and terminate neurotransmission mediated by serotonin, dopamine, noradrenaline, glycine and GABA (gamma-aminobutyric acid). Crystal structures of the bacterial homologue, LeuT, in substrate-bound outward-occluded and competitive inhibitor-bound outward-facing states have advanced our mechanistic understanding of neurotransmitter sodium symporters but have left fundamental questions unanswered. Here we report crystal structures of LeuT mutants in complexes with conformation-specific antibody fragments in the outward-open and inward-open states. In the absence of substrate but in the presence of sodium the transporter is outward-open, illustrating how the binding of substrate closes the extracellular gate through local conformational changes: hinge-bending movements of the extracellular halves of transmembrane domains 1, 2 and 6, together with translation of extracellular loop 4. The inward-open conformation, by contrast, involves large-scale conformational changes, including a reorientation of transmembrane domains 1, 2, 5, 6 and 7, a marked hinge bending of transmembrane domain 1a and occlusion of the extracellular vestibule by extracellular loop 4. These changes close the extracellular gate, open an intracellular vestibule, and largely disrupt the two sodium sites, thus providing a mechanism by which ions and substrate are released to the cytoplasm. The new structures establish a structural framework for the mechanism of neurotransmitter sodium symporters and their modulation by therapeutic and illicit substances.

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Structure of HDAC3 bound to co-repressor and inositol tetraphosphate.

Publication Date: 2012 Jan 19 PMID: 22230954
Authors: Watson, P. J. - Fairall, L. - Santos, G. M. - Schwabe, J. W.
Journal: Nature

Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymatic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex between an HDAC and a co-repressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor (also known as NCOR2). The structure reveals two remarkable features. First, the SMRT-DAD undergoes a large structural rearrangement on forming the complex. Second, there is an essential inositol tetraphosphate molecule--D-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P(4))--acting as an 'intermolecular glue' between the two proteins. Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P(4), which may act as a regulator--potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and opens the way to novel therapeutic opportunities.

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Women in business: Finding a way in.

Publication Date: 2012 Jan 5 PMID: 22229161
Authors: Gewin, V.
Journal: Nature

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FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas.

Publication Date: 2012 Jan 5 PMID: 22113614
Authors: Duan, S. - Cermak, L. - Pagan, J. K. - Rossi, M. - Martinengo, C. - di Celle, P. F. - Chapuy, B. - Shipp, M. - Chiarle, R. - Pagano, M.
Journal: Nature

BCL6 is the product of a proto-oncogene implicated in the pathogenesis of human B-cell lymphomas. By binding specific DNA sequences, BCL6 controls the transcription of a variety of genes involved in B-cell development, differentiation and activation. BCL6 is overexpressed in the majority of patients with aggressive diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adulthood, and transgenic mice constitutively expressing BCL6 in B cells develop DLBCLs similar to the human disease. In many DLBCL patients, BCL6 overexpression is achieved through translocation (~40%) or hypermutation of its promoter (~15%). However, many other DLBCLs overexpress BCL6 through an unknown mechanism. Here we show that BCL6 is targeted for ubiquitylation and proteasomal degradation by a SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complex that contains the orphan F-box protein FBXO11 (refs 5, 6). The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Notably, tumour-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation. Reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death. FBXO11-deleted DLBCL cells generated tumours in immunodeficient mice, and the tumorigenicity was suppressed by FBXO11 reconstitution. We reveal a molecular mechanism controlling BCL6 stability and propose that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization. The deletions/mutations found in DLBCLs are largely monoallelic, indicating that FBXO11 is a haplo-insufficient tumour suppressor gene.

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