Nature

Transitions.

Publication Date: 2010 Mar 4 PMID: 20203613
Authors: Erlanson, D.
Journal: Nature

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Opposing microRNA families regulate self-renewal in mouse embryonic stem cells.

Publication Date: 2010 Mar 4 PMID: 20203612
Authors: Melton, C. - Judson, R. L. - Blelloch, R.
Journal: Nature

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SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.

Publication Date: 2010 Mar 4 PMID: 20203611
Authors: Hirschey, M. D. - Shimazu, T. - Goetzman, E. - Jing, E. - Schwer, B. - Lombard, D. B. - Grueter, C. A. - Harris, C. - Biddinger, S. - Ilkayeva, O. R. - Stevens, R. D. - Li, Y. - Saha, A. K. - Ruderman, N. B. - Bain, J. R. - Newgard, C. B. - Farese, R. V. Jr - Alt, F. W. - Kahn, C. R. - Verdin, E.
Journal: Nature

Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.

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Circulating mitochondrial DAMPs cause inflammatory responses to injury.

Publication Date: 2010 Mar 4 PMID: 20203610
Authors: Zhang, Q. - Raoof, M. - Chen, Y. - Sumi, Y. - Sursal, T. - Junger, W. - Brohi, K. - Itagaki, K. - Hauser, C. J.
Journal: Nature

Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs) that activate innate immunity. Mitochondria are evolutionary endosymbionts that were derived from bacteria and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll-like receptor (TLR) 9, respectively. MTDs promote PMN Ca(2+) flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial 'enemies within' by cellular injury is a key link between trauma, inflammation and SIRS.

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Changes in Hox genes' structure and function during the evolution of the squamate body plan.

Publication Date: 2010 Mar 4 PMID: 20203609
Authors: Di-Poi, N. - Montoya-Burgos, J. I. - Miller, H. - Pourquie, O. - Milinkovitch, M. C. - Duboule, D.
Journal: Nature

Hox genes are central to the specification of structures along the anterior-posterior body axis, and modifications in their expression have paralleled the emergence of diversity in vertebrate body plans. Here we describe the genomic organization of Hox clusters in different reptiles and show that squamates have accumulated unusually large numbers of transposable elements at these loci, reflecting extensive genomic rearrangements of coding and non-coding regulatory regions. Comparative expression analyses between two species showing different axial skeletons, the corn snake and the whiptail lizard, revealed major alterations in Hox13 and Hox10 expression features during snake somitogenesis, in line with the expansion of both caudal and thoracic regions. Variations in both protein sequences and regulatory modalities of posterior Hox genes suggest how this genetic system has dealt with its intrinsic collinear constraint to accompany the substantial morphological radiation observed in this group.

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Ecologically distinct dinosaurian sister group shows early diversification of Ornithodira.

Publication Date: 2010 Mar 4 PMID: 20203608
Authors: Nesbitt, S. J. - Sidor, C. A. - Irmis, R. B. - Angielczyk, K. D. - Smith, R. M. - Tsuji, L. A.
Journal: Nature

The early evolutionary history of Ornithodira (avian-line archosaurs) has hitherto been documented by incomplete (Lagerpeton) or unusually specialized forms (pterosaurs and Silesaurus). Recently, a variety of Silesaurus-like taxa have been reported from the Triassic period of both Gondwana and Laurasia, but their relationships to each other and to dinosaurs remain a subject of debate. Here we report on a new avian-line archosaur from the early Middle Triassic (Anisian) of Tanzania. Phylogenetic analysis places Asilisaurus kongwe gen. et sp. nov. as an avian-line archosaur and a member of the Silesauridae, which is here considered the sister taxon to Dinosauria. Silesaurids were diverse and had a wide distribution by the Late Triassic, with a novel ornithodiran bauplan including leaf-shaped teeth, a beak-like lower jaw, long, gracile limbs, and a quadrupedal stance. Our analysis suggests that the dentition and diet of silesaurids, ornithischians and sauropodomorphs evolved independently from a plesiomorphic carnivorous form. As the oldest avian-line archosaur, Asilisaurus demonstrates the antiquity of both Ornithodira and the dinosaurian lineage. The initial diversification of Archosauria, previously documented by crocodilian-line archosaurs in the Anisian, can now be shown to include a contemporaneous avian-line radiation. The unparalleled taxonomic diversity of the Manda archosaur assemblage indicates that archosaur diversification was well underway by the Middle Triassic or earlier.

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Helical crack-front instability in mixed-mode fracture.

Publication Date: 2010 Mar 4 PMID: 20203607
Authors: Pons, A. J. - Karma, A.
Journal: Nature

Planar crack propagation under pure tension loading (mode I) is generally stable. However, it becomes universally unstable with the superposition of a shear stress parallel to the crack front (mode III). Under this mixed-mode (I + III) loading configuration, an initially flat parent crack segments into an array of daughter cracks that rotate towards a direction of maximum tensile stress. This segmentation produces stepped fracture surfaces with characteristic 'lance-shaped' markings observed in a wide range of engineering and geological materials. The origin of this instability remains poorly understood and a theory with which to predict the surface roughness scale is lacking. Here we perform large-scale simulations of mixed-mode I + III brittle fracture using a continuum phase-field method that describes the complete three-dimensional crack-front evolution. The simulations reveal that planar crack propagation is linearly unstable against helical deformations of the crack front, which evolve nonlinearly into a segmented array of finger-shaped daughter cracks. Furthermore, during their evolution, facets gradually coarsen owing to the growth competition of daughter cracks in striking analogy with the coarsening of finger patterns observed in nonequilibrium growth phenomena. We show that the dynamically preferred unstable wavelength is governed by the balance of the destabilizing effect of far-field stresses and the stabilizing effect of cohesive forces on the process zone scale, and we derive a theoretical estimate for this scale using a new propagation law for curved cracks in three dimensions. The rotation angles of coarsened facets are also compared to theoretical predictions and available experimental data.

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Reinventing germanium avalanche photodetector for nanophotonic on-chip optical interconnects.

Publication Date: 2010 Mar 4 PMID: 20203606
Authors: Assefa, S. - Xia, F. - Vlasov, Y. A.
Journal: Nature

Integration of optical communication circuits directly into high-performance microprocessor chips can enable extremely powerful computer systems. A germanium photodetector that can be monolithically integrated with silicon transistor technology is viewed as a key element in connecting chip components with infrared optical signals. Such a device should have the capability to detect very-low-power optical signals at very high speed. Although germanium avalanche photodetectors (APD) using charge amplification close to avalanche breakdown can achieve high gain and thus detect low-power optical signals, they are universally considered to suffer from an intolerably high amplification noise characteristic of germanium. High gain with low excess noise has been demonstrated using a germanium layer only for detection of light signals, with amplification taking place in a separate silicon layer. However, the relatively thick semiconductor layers that are required in such structures limit APD speeds to about 10 GHz, and require excessively high bias voltages of around 25 V (ref. 12). Here we show how nanophotonic and nanoelectronic engineering aimed at shaping optical and electrical fields on the nanometre scale within a germanium amplification layer can overcome the otherwise intrinsically poor noise characteristics, achieving a dramatic reduction of amplification noise by over 70 per cent. By generating strongly non-uniform electric fields, the region of impact ionization in germanium is reduced to just 30 nm, allowing the device to benefit from the noise reduction effects that arise at these small distances. Furthermore, the smallness of the APDs means that a bias voltage of only 1.5 V is required to achieve an avalanche gain of over 10 dB with operational speeds exceeding 30 GHz. Monolithic integration of such a device into computer chips might enable applications beyond computer optical interconnects-in telecommunications, secure quantum key distribution, and subthreshold ultralow-power transistors.

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Superconductivity in alkali-metal-doped picene.

Publication Date: 2010 Mar 4 PMID: 20203605
Authors: Mitsuhashi, R. - Suzuki, Y. - Yamanari, Y. - Mitamura, H. - Kambe, T. - Ikeda, N. - Okamoto, H. - Fujiwara, A. - Yamaji, M. - Kawasaki, N. - Maniwa, Y. - Kubozono, Y.
Journal: Nature

Efforts to identify and develop new superconducting materials continue apace, motivated by both fundamental science and the prospects for application. For example, several new superconducting material systems have been developed in the recent past, including calcium-intercalated graphite compounds, boron-doped diamond and-most prominently-iron arsenides such as LaO(1-x)F(x)FeAs (ref. 3). In the case of organic superconductors, however, no new material system with a high superconducting transition temperature (T(c)) has been discovered in the past decade. Here we report that intercalating an alkali metal into picene, a wide-bandgap semiconducting solid hydrocarbon, produces metallic behaviour and superconductivity. Solid potassium-intercalated picene (K(x)picene) shows T(c) values of 7 K and 18 K, depending on the metal content. The drop of magnetization in K(x)picene solids at the transition temperature is sharp (<2 K), similar to the behaviour of Ca-intercalated graphite. The T(c) of 18 K is comparable to that of K-intercalated C(60) (ref. 4). This discovery of superconductivity in K(x)picene shows that organic hydrocarbons are promising candidates for improved T(c) values.

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Linking dwarf galaxies to halo building blocks with the most metal-poor star in Sculptor.

Publication Date: 2010 Mar 4 PMID: 20203604
Authors: Frebel, A. - Kirby, E. N. - Simon, J. D.
Journal: Nature

Current cosmological models indicate that the Milky Way's stellar halo was assembled from many smaller systems. On the basis of the apparent absence of the most metal-poor stars in present-day dwarf galaxies, recent studies claimed that the true Galactic building blocks must have been vastly different from the surviving dwarfs. The discovery of an extremely iron-poor star (S1020549) in the Sculptor dwarf galaxy based on a medium-resolution spectrum cast some doubt on this conclusion. Verification of the iron-deficiency, however, and measurements of additional elements, such as the alpha-element Mg, are necessary to demonstrate that the same type of stars produced the metals found in dwarf galaxies and the Galactic halo. Only then can dwarf galaxy stars be conclusively linked to early stellar halo assembly. Here we report high-resolution spectroscopic abundances for 11 elements in S1020549, confirming its iron abundance of less than 1/4,000th that of the Sun, and showing that the overall abundance pattern follows that seen in low-metallicity halo stars, including the alpha-elements. Such chemical similarity indicates that the systems destroyed to form the halo billions of years ago were not fundamentally different from the progenitors of present-day dwarfs, and suggests that the early chemical enrichment of all galaxies may be nearly identical.

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A human gut microbial gene catalogue established by metagenomic sequencing.

Publication Date: 2010 Mar 4 PMID: 20203603
Authors: Qin, J. - Li, R. - Raes, J. - Arumugam, M. - Burgdorf, K. S. - Manichanh, C. - Nielsen, T. - Pons, N. - Levenez, F. - Yamada, T. - Mende, D. R. - Li, J. - Xu, J. - Li, S. - Li, D. - Cao, J. - Wang, B. - Liang, H. - Zheng, H. - Xie, Y. - Tap, J. - Lepage, P. - Bertalan, M. - Batto, J. M. - Hansen, T. - Le Paslier, D. - Linneberg, A. - Nielsen, H. B. - Pelletier, E. - Renault, P. - Sicheritz-Ponten, T. - Turner, K. - Zhu, H. - Yu, C. - Li, S. - Jian, M. - Zhou, Y. - Li, Y. - Zhang, X. - Li, S. - Qin, N. - Yang, H. - Wang, J. - Brunak, S. - Dore, J. - Guarner, F. - Kristiansen, K. - Pedersen, O. - Parkhill, J. - Weissenbach, J. - Antolin, M. - Artiguenave, F. - Blottiere, H. - Borruel, N. - Bruls, T. - Casellas, F. - Chervaux, C. - Cultrone, A. - Delorme, C. - Denariaz, G. - Dervyn, R. - Forte, M. - Friss, C. - van de Guchte, M. - Guedon, E. - Haimet, F. - Jamet, A. - Juste, C. - Kaci, G. - Kleerebezem, M. - Knol, J. - Kristensen, M. - Layec, S. - Le Roux, K. - Leclerc, M. - Maguin, E. - Melo Minardi, R. - Oozeer, R. - Rescigno, M. - Sanchez, N. - Tims, S. - Torrejon, T. - Varela, E. - de Vos, W. - Winogradsky, Y. - Zoetendal, E. - Bork, P. - Ehrlich, S. D. - Wang, J.
Journal: Nature

To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.

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Quantum computers.

Publication Date: 2010 Mar 4 PMID: 20203602
Authors: Ladd, T. D. - Jelezko, F. - Laflamme, R. - Nakamura, Y. - Monroe, C. - O'Brien, J. L.
Journal: Nature

Over the past several decades, quantum information science has emerged to seek answers to the question: can we gain some advantage by storing, transmitting and processing information encoded in systems that exhibit unique quantum properties? Today it is understood that the answer is yes, and many research groups around the world are working towards the highly ambitious technological goal of building a quantum computer, which would dramatically improve computational power for particular tasks. A number of physical systems, spanning much of modern physics, are being developed for quantum computation. However, it remains unclear which technology, if any, will ultimately prove successful. Here we describe the latest developments for each of the leading approaches and explain the major challenges for the future.

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Obituary: marshall nirenberg (1927-2010).

Publication Date: 2010 Mar 4 PMID: 20203601
Authors: Caskey, C. T.
Journal: Nature

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Developmental genetics: Time for teeth.

Publication Date: 2010 Mar 4 PMID: 20203600
Authors: Shadan, S.
Journal: Nature

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Materials science: Mind the helical crack.

Publication Date: 2010 Mar 4 PMID: 20203599
Authors: Buehler, M. J. - Xu, Z.
Journal: Nature

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Clinical immunology: Culprits with evolutionary ties.

Publication Date: 2010 Mar 4 PMID: 20203598
Authors: Calfee, C. S. - Matthay, M. A.
Journal: Nature

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Materials science: Hydrocarbon superconductors.

Publication Date: 2010 Mar 4 PMID: 20203597
Authors: Rosseinsky, M. J. - Prassides, K.
Journal: Nature

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50 & 100 years ago.

Publication Date: 2010 Mar 4 PMID: 20203596
Authors:
Journal: Nature

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Microscopy: When mica and water meet.

Publication Date: 2010 Mar 4 PMID: 20203595
Authors: Frenken, J. W. - Oosterkamp, T. H.
Journal: Nature

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Behavioural neurobiology: The treacherous scent of a human.

Publication Date: 2010 Mar 4 PMID: 20203594
Authors: Leal, W. S.
Journal: Nature

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Q&A: Joanna Cole on writing science books for kids.

Publication Date: 2010 Mar 4 PMID: 20203593
Authors: Jones, N.
Journal: Nature

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Autism and animal insight.

Publication Date: 2010 Mar 4 PMID: 20203592
Authors: Jamison, W. - Wynne, C.
Journal: Nature

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Why you shouldn't always follow the crowd.

Publication Date: 2010 Mar 4 PMID: 20203591
Authors: Buchanan, M.
Journal: Nature

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Is there anybody out there?

Publication Date: 2010 Mar 4 PMID: 20203590
Authors: McKay, C.
Journal: Nature

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Stop laser uranium enrichment.

Publication Date: 2010 Mar 4 PMID: 20203589
Authors: Slakey, F. - Cohen, L. R.
Journal: Nature

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Spring awakening planned for Mars rover Spirit.

Publication Date: 2010 Mar 4 PMID: 20203588
Authors: Squyres, S.
Journal: Nature

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Esaki diode is still a radio star, half a century on.

Publication Date: 2010 Mar 4 PMID: 20203587
Authors: Esaki, L. - Arakawa, Y. - Kitamura, M.
Journal: Nature

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Foundations could allocate money more productively.

Publication Date: 2010 Mar 4 PMID: 20203586
Authors: Eisenstadter, I.
Journal: Nature

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South Africa: telescopes raise the nation's sights.

Publication Date: 2010 Mar 4 PMID: 20203585
Authors: Whitelock, P.
Journal: Nature

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South Africa: aiming to be premier global astronomy hub.

Publication Date: 2010 Mar 4 PMID: 20203584
Authors: Adam, R.
Journal: Nature

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Myth-busting about first mass-produced human cell line.

Publication Date: 2010 Mar 4 PMID: 20203583
Authors: Hayflick, L.
Journal: Nature

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South Africa: big science should stay on the agenda.

Publication Date: 2010 Mar 4 PMID: 20203582
Authors: Chown, S. L.
Journal: Nature

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World view: Curing climate backlash.

Publication Date: 2010 Mar 4 PMID: 20203581
Authors: Sarewitz, D.
Journal: Nature

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Non-proliferation: Borderline detection.

Publication Date: 2010 Mar 4 PMID: 20203580
Authors: Weinberger, S.
Journal: Nature

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Chinese bioscience: The sequence factory.

Publication Date: 2010 Mar 4 PMID: 20203579
Authors: Cyranoski, D.
Journal: Nature

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Weapons labs to thrive as Obama trims nukes.

Publication Date: 2010 Mar 4 PMID: 20203578
Authors: Tollefson, J.
Journal: Nature

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The labours of Fotis Kafatos.

Publication Date: 2010 Mar 4 PMID: 20203577
Authors: Gilbert, N.
Journal: Nature

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Fat rats skew research results.

Publication Date: 2010 Mar 4 PMID: 20203576
Authors: Cressey, D.
Journal: Nature

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University rankings smarten up.

Publication Date: 2010 Mar 4 PMID: 20203575
Authors: Butler, D.
Journal: Nature

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Unmanned planes take wing for science.

Publication Date: 2010 Mar 4 PMID: 20203574
Authors: Tollefson, J.
Journal: Nature

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Model response to Chile quake?

Publication Date: 2010 Mar 4 PMID: 20203573
Authors: Schiermeier, Q.
Journal: Nature

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News briefing: 4 March 2010.

Publication Date: 2010 Mar 4 PMID: 20203572
Authors:
Journal: Nature

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Chemical biology: With added sugar.

Publication Date: 2010 Mar 4 PMID: 20203571
Authors:
Journal: Nature

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Applied physics: Sound lasers hum along.

Publication Date: 2010 Mar 4 PMID: 20203570
Authors:
Journal: Nature

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Wildlife biology: Lizard back burden.

Publication Date: 2010 Mar 4 PMID: 20203569
Authors:
Journal: Nature

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Neuroscience: Use it or lose it.

Publication Date: 2010 Mar 4 PMID: 20203568
Authors:
Journal: Nature

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Journal club.

Publication Date: 2010 Mar 4 PMID: 20203567
Authors: Lucas, R.
Journal: Nature

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Biology: Secret code.

Publication Date: 2010 Mar 4 PMID: 20203566
Authors:
Journal: Nature

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Genetics: Gene guards.

Publication Date: 2010 Mar 4 PMID: 20203565
Authors:
Journal: Nature

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Biology: Stayin' alive.

Publication Date: 2010 Mar 4 PMID: 20203564
Authors:
Journal: Nature

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Nanotechnology: Light DNA machine.

Publication Date: 2010 Mar 4 PMID: 20203563
Authors:
Journal: Nature

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Electronics: Caught on film.

Publication Date: 2010 Mar 4 PMID: 20203562
Authors:
Journal: Nature

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Astrophysics: Old stars call out.

Publication Date: 2010 Mar 4 PMID: 20203561
Authors:
Journal: Nature

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The bigger picture.

Publication Date: 2010 Mar 4 PMID: 20203560
Authors:
Journal: Nature

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Do scientists really need a PhD?

Publication Date: 2010 Mar 4 PMID: 20203559
Authors:
Journal: Nature

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The ratings game.

Publication Date: 2010 Mar 4 PMID: 20203558
Authors:
Journal: Nature

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Heteroplasmic mitochondrial DNA mutations in normal and tumour cells.

Publication Date: 2010 Mar 3 PMID: 20200521
Authors: He, Y. - Wu, J. - Dressman, D. C. - Iacobuzio-Donahue, C. - Markowitz, S. D. - Velculescu, V. E. - Diaz Jr, L. A. - Kinzler, K. W. - Vogelstein, B. - Papadopoulos, N.
Journal: Nature

The presence of hundreds of copies of mitochondrial DNA (mtDNA) in each human cell poses a challenge for the complete characterization of mtDNA genomes by conventional sequencing technologies. Here we describe digital sequencing of mtDNA genomes with the use of massively parallel sequencing-by-synthesis approaches. Although the mtDNA of human cells is considered to be homogeneous, we found widespread heterogeneity (heteroplasmy) in the mtDNA of normal human cells. Moreover, the frequency of heteroplasmic variants varied considerably between different tissues in the same individual. In addition to the variants identified in normal tissues, cancer cells harboured further homoplasmic and heteroplasmic mutations that could also be detected in patient plasma. These studies provide insights into the nature and variability of mtDNA sequences and have implications for mitochondrial processes during embryogenesis, cancer biomarker development and forensic analysis. In particular, they demonstrate that individual humans are characterized by a complex mixture of related mitochondrial genotypes rather than a single genotype.

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IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.

Publication Date: 2010 Mar 3 PMID: 20200520
Authors: Saenz, S. A. - Siracusa, M. C. - Perrigoue, J. G. - Spencer, S. P. - Urban Jr, J. F. - Tocker, J. E. - Budelsky, A. L. - Kleinschek, M. A. - Kastelein, R. A. - Kambayashi, T. - Bhandoola, A. - Artis, D.
Journal: Nature

CD4(+) T helper 2 (T(H)2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, T(H)2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal lymphopoietin, IL33 and IL25 (also known as IL17E) have been implicated in inducing T(H)2 cell-dependent inflammation at mucosal sites, but how these cytokines influence innate immune responses remains poorly defined. Here we show that IL25, a member of the IL17 cytokine family, promotes the accumulation of a lineage-negative (Lin(-)) multipotent progenitor (MPP) cell population in the gut-associated lymphoid tissue that promotes T(H)2 cytokine responses. The IL25-elicited cell population, termed MPP(type2) cells, was defined by the expression of Sca-1 (also known as Ly6a) and intermediate expression of c-Kit (c-Kit(int)), and exhibited multipotent capacity, giving rise to cells of monocyte/macrophage and granulocyte lineages both in vitro and in vivo. Progeny of MPP(type2) cells were competent antigen presenting cells, and adoptive transfer of MPP(type2) cells could promote T(H)2 cytokine responses and confer protective immunity to helminth infection in normally susceptible Il25(-/-) mice. The ability of IL25 to induce the emergence of an MPP(type2) cell population identifies a link between the IL17 cytokine family and extramedullary haematopoiesis, and suggests a previously unrecognized innate immune pathway that promotes T(H)2 cytokine responses at mucosal sites.

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Transcriptional control of preadipocyte determination by Zfp423.

Publication Date: 2010 Mar 3 PMID: 20200519
Authors: Gupta, R. K. - Arany, Z. - Seale, P. - Mepani, R. J. - Ye, L. - Conroe, H. M. - Roby, Y. A. - Kulaga, H. - Reed, R. R. - Spiegelman, B. M.
Journal: Nature

The worldwide epidemic of obesity has increased the urgency to develop a deeper understanding of physiological systems related to energy balance and energy storage, including the mechanisms controlling the development of fat cells (adipocytes). The differentiation of committed preadipocytes to adipocytes is controlled by PPARgamma and several other transcription factors, but the molecular basis for preadipocyte determination is not understood. Using a new method for the quantitative analysis of transcriptional components, we identified the zinc-finger protein Zfp423 as a factor enriched in preadipose versus non-preadipose fibroblasts. Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate. Furthermore, both brown and white adipocyte differentiation is markedly impaired in Zfp423-deficient mouse embryos. Zfp423 regulates Pparg expression, in part, through amplification of the BMP signalling pathway, an effect dependent on the SMAD-binding capacity of Zfp423. This study identifies Zfp423 as a transcriptional regulator of preadipocyte determination.

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Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.

Publication Date: 2010 Mar 3 PMID: 20200518
Authors: Neill, D. R. - Wong, S. H. - Bellosi, A. - Flynn, R. J. - Daly, M. - Langford, T. K. - Bucks, C. - Kane, C. M. - Fallon, P. G. - Pannell, R. - Jolin, H. E. - McKenzie, A. N.
Journal: Nature

Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity-responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma-consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively determined. Here, through the use of novel Il13-eGFP reporter mice, we present the identification and functional characterization of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL25 and IL33, and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25 and IL33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity.

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Systems survey of endocytosis by multiparametric image analysis.

Publication Date: 2010 Feb 28 PMID: 20190736
Authors: Collinet, C. - Stoter, M. - Bradshaw, C. R. - Samusik, N. - Rink, J. C. - Kenski, D. - Habermann, B. - Buchholz, F. - Henschel, R. - Mueller, M. S. - Nagel, W. E. - Fava, E. - Kalaidzidis, Y. - Zerial, M.
Journal: Nature

Endocytosis is a complex process fulfilling many cellular and developmental functions. Understanding how it is regulated and integrated with other cellular processes requires a comprehensive analysis of its molecular constituents and general design principles. Here, we developed a new strategy to phenotypically profile the human genome with respect to transferrin (TF) and epidermal growth factor (EGF) endocytosis by combining RNA interference, automated high-resolution confocal microscopy, quantitative multiparametric image analysis and high-performance computing. We identified several novel components of endocytic trafficking, including genes implicated in human diseases. We found that signalling pathways such as Wnt, integrin/cell adhesion, transforming growth factor (TGF)-beta and Notch regulate the endocytic system, and identified new genes involved in cargo sorting to a subset of signalling endosomes. A systems analysis by Bayesian networks further showed that the number, size, concentration of cargo and intracellular position of endosomes are not determined randomly but are subject to specific regulation, thus uncovering novel properties of the endocytic system.

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Control of Arabidopsis apical-basal embryo polarity by antagonistic transcription factors.

Publication Date: 2010 Feb 28 PMID: 20190735
Authors: Smith, Z. R. - Long, J. A.
Journal: Nature

Plants, similarly to animals, form polarized axes during embryogenesis on which cell differentiation and organ patterning programs are orchestrated. During Arabidopsis embryogenesis, establishment of the shoot and root stem cell populations occurs at opposite ends of an apical-basal axis. Recent work has identified the PLETHORA (PLT) genes as master regulators of basal/root fate, whereas the master regulators of apical/shoot fate have remained elusive. Here we show that the PLT1 and PLT2 genes are direct targets of the transcriptional co-repressor TOPLESS (TPL) and that PLT1/2 are necessary for the homeotic conversion of shoots to roots in tpl-1 mutants. Using tpl-1 as a genetic tool, we identify the CLASS III HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIP III) transcription factors as master regulators of embryonic apical fate, and show they are sufficient to drive the conversion of the embryonic root pole into a second shoot pole. Furthermore, genetic and misexpression studies show an antagonistic relationship between the PLT and HD-ZIP III genes in specifying the root and shoot poles.

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An essential role for XBP-1 in host protection against immune activation in C. elegans.

Publication Date: 2010 Feb 25 PMID: 20182512
Authors: Richardson, C. E. - Kooistra, T. - Kim, D. H.
Journal: Nature

The detection and compensatory response to the accumulation of unfolded proteins in the endoplasmic reticulum (ER), termed the unfolded protein response (UPR), represents a conserved cellular homeostatic mechanism with important roles in normal development and in the pathogenesis of disease. The IRE1-XBP1/Hac1 pathway is a major branch of the UPR that has been conserved from yeast to human. X-box binding protein 1 (XBP1) is required for the differentiation of the highly secretory plasma cells of the mammalian adaptive immune system, but recent work also points to reciprocal interactions between the UPR and other aspects of immunity and inflammation. We have been studying innate immunity in the nematode Caenorhabditis elegans, having established a principal role for a conserved PMK-1 p38 mitogen-activated protein kinase (MAPK) pathway in mediating resistance to microbial pathogens. Here we show that during C. elegans development, XBP-1 has an essential role in protecting the host during activation of innate immunity. Activation of the PMK-1-mediated response to infection with Pseudomonas aeruginosa induces the XBP-1-dependent UPR. Whereas a loss-of-function xbp-1 mutant develops normally in the presence of relatively non-pathogenic bacteria, infection of the xbp-1 mutant with P. aeruginosa leads to disruption of ER morphology and larval lethality. Unexpectedly, the larval lethality phenotype on pathogenic P. aeruginosa is suppressed by loss of PMK-1-mediated immunity. Furthermore, hyperactivation of PMK-1 causes larval lethality in the xbp-1 mutant even in the absence of pathogenic bacteria. Our data establish innate immunity as a physiologically relevant inducer of ER stress during C. elegans development and indicate that an ancient, conserved role for XBP-1 may be to protect the host organism from the detrimental effects of mounting an innate immune response to microbes.

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Neural evidence for inequality-averse social preferences.

Publication Date: 2010 Feb 25 PMID: 20182511
Authors: Tricomi, E. - Rangel, A. - Camerer, C. F. - O'Doherty, J. P.
Journal: Nature

A popular hypothesis in the social sciences is that humans have social preferences to reduce inequality in outcome distributions because it has a negative impact on their experienced reward. Although there is a large body of behavioural and anthropological evidence consistent with the predictions of these theories, there is no direct neural evidence for the existence of inequality-averse preferences. Such evidence would be especially useful because some behaviours that are consistent with a dislike for unequal outcomes could also be explained by concerns for social image or reciprocity, which do not require a direct aversion towards inequality. Here we use functional MRI to test directly for the existence of inequality-averse social preferences in the human brain. Inequality was created by recruiting pairs of subjects and giving one of them a large monetary endowment. While both subjects evaluated further monetary transfers from the experimenter to themselves and to the other participant, we measured neural responses in the ventral striatum and ventromedial prefrontal cortex, two areas that have been shown to be involved in the valuation of monetary and primary rewards in both social and non-social contexts. Consistent with inequality-averse models of social preferences, we find that activity in these areas was more responsive to transfers to others than to self in the 'high-pay' subject, whereas the activity of the 'low-pay' subject showed the opposite pattern. These results provide direct evidence for the validity of this class of models, and also show that the brain's reward circuitry is sensitive to both advantageous and disadvantageous inequality.

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Electric currents couple spatially separated biogeochemical processes in marine sediment.

Publication Date: 2010 Feb 25 PMID: 20182510
Authors: Nielsen, L. P. - Risgaard-Petersen, N. - Fossing, H. - Christensen, P. B. - Sayama, M.
Journal: Nature

Some bacteria are capable of extracellular electron transfer, thereby enabling them to use electron acceptors and donors without direct cell contact. Beyond the micrometre scale, however, no firm evidence has previously existed that spatially segregated biogeochemical processes can be coupled by electric currents in nature. Here we provide evidence that electric currents running through defaunated sediment couple oxygen consumption at the sediment surface to oxidation of hydrogen sulphide and organic carbon deep within the sediment. Altering the oxygen concentration in the sea water overlying the sediment resulted in a rapid (<1-h) change in the hydrogen sulphide concentration within the sediment more than 12 mm below the oxic zone, a change explicable by transmission of electrons but not by diffusion of molecules. Mass balances indicated that more than 40% of total oxygen consumption in the sediment was driven by electrons conducted from the anoxic zone. A distinct pH peak in the oxic zone could be explained by electrochemical oxygen reduction, but not by any conventional sets of aerobic sediment processes. We suggest that the electric current was conducted by bacterial nanowires combined with pyrite, soluble electron shuttles and outer-membrane cytochromes. Electrical communication between distant chemical and biological processes in nature adds a new dimension to our understanding of biogeochemistry and microbial ecology.

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Tropical cyclones and permanent El Nino in the early Pliocene epoch.

Publication Date: 2010 Feb 25 PMID: 20182509
Authors: Fedorov, A. V. - Brierley, C. M. - Emanuel, K.
Journal: Nature

Tropical cyclones (also known as hurricanes and typhoons) are now believed to be an important component of the Earth's climate system. In particular, by vigorously mixing the upper ocean, they can affect the ocean's heat uptake, poleward heat transport, and hence global temperatures. Changes in the distribution and frequency of tropical cyclones could therefore become an important element of the climate response to global warming. A potential analogue to modern greenhouse conditions, the climate of the early Pliocene epoch (approximately 5 to 3 million years ago) can provide important clues to this response. Here we describe a positive feedback between hurricanes and the upper-ocean circulation in the tropical Pacific Ocean that may have been essential for maintaining warm, El Nino-like conditions during the early Pliocene. This feedback is based on the ability of hurricanes to warm water parcels that travel towards the Equator at shallow depths and then resurface in the eastern equatorial Pacific as part of the ocean's wind-driven circulation. In the present climate, very few hurricane tracks intersect the parcel trajectories; consequently, there is little heat exchange between waters at such depths and the surface. More frequent and/or stronger hurricanes in the central Pacific imply greater heating of the parcels, warmer temperatures in the eastern equatorial Pacific, warmer tropics and, in turn, even more hurricanes. Using a downscaling hurricane model, we show dramatic shifts in the tropical cyclone distribution for the early Pliocene that favour this feedback. Further calculations with a coupled climate model support our conclusions. The proposed feedback should be relevant to past equable climates and potentially to contemporary climate change.

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Simultaneous phase and size control of upconversion nanocrystals through lanthanide doping.

Publication Date: 2010 Feb 25 PMID: 20182508
Authors: Wang, F. - Han, Y. - Lim, C. S. - Lu, Y. - Wang, J. - Xu, J. - Chen, H. - Zhang, C. - Hong, M. - Liu, X.
Journal: Nature

Doping is a widely applied technological process in materials science that involves incorporating atoms or ions of appropriate elements into host lattices to yield hybrid materials with desirable properties and functions. For nanocrystalline materials, doping is of fundamental importance in stabilizing a specific crystallographic phase, modifying electronic properties, modulating magnetism as well as tuning emission properties. Here we describe a material system in which doping influences the growth process to give simultaneous control over the crystallographic phase, size and optical emission properties of the resulting nanocrystals. We show that NaYF(4) nanocrystals can be rationally tuned in size (down to ten nanometres), phase (cubic or hexagonal) and upconversion emission colour (green to blue) through use of trivalent lanthanide dopant ions introduced at precisely defined concentrations. We use first-principles calculations to confirm that the influence of lanthanide doping on crystal phase and size arises from a strong dependence on the size and dipole polarizability of the substitutional dopant ion. Our results suggest that the doping-induced structural and size transition, demonstrated here in NaYF(4) upconversion nanocrystals, could be extended to other lanthanide-doped nanocrystal systems for applications ranging from luminescent biological labels to volumetric three-dimensional displays.

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Exploring the thermodynamics of a universal Fermi gas.

Publication Date: 2010 Feb 25 PMID: 20182507
Authors: Nascimbene, S. - Navon, N. - Jiang, K. J. - Chevy, F. - Salomon, C.
Journal: Nature

One of the greatest challenges in modern physics is to understand the behaviour of an ensemble of strongly interacting particles. A class of quantum many-body systems (such as neutron star matter and cold Fermi gases) share the same universal thermodynamic properties when interactions reach the maximum effective value allowed by quantum mechanics, the so-called unitary limit. This makes it possible in principle to simulate some astrophysical phenomena inside the highly controlled environment of an atomic physics laboratory. Previous work on the thermodynamics of a two-component Fermi gas led to thermodynamic quantities averaged over the trap, making comparisons with many-body theories developed for uniform gases difficult. Here we develop a general experimental method that yields the equation of state of a uniform gas, as well as enabling a detailed comparison with existing theories. The precision of our equation of state leads to new physical insights into the unitary gas. For the unpolarized gas, we show that the low-temperature thermodynamics of the strongly interacting normal phase is well described by Fermi liquid theory, and we localize the superfluid transition. For a spin-polarized system, our equation of state at zero temperature has a 2 per cent accuracy and extends work on the phase diagram to a new regime of precision. We show in particular that, despite strong interactions, the normal phase behaves as a mixture of two ideal gases: a Fermi gas of bare majority atoms and a non-interacting gas of dressed quasi-particles, the fermionic polarons.

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WASP-12b as a prolate, inflated and disrupting planet from tidal dissipation.

Publication Date: 2010 Feb 25 PMID: 20182506
Authors: Li, S. L. - Miller, N. - Lin, D. N. - Fortney, J. J.
Journal: Nature

The class of exotic Jupiter-mass planets that orbit very close to their parent stars were not explicitly expected before their discovery. The recently discovered transiting planet WASP-12b has a mass M = 1.4 +/- 0.1 Jupiter masses (M(J)), a mean orbital distance of only 3.1 stellar radii (meaning it is subject to intense tidal forces), and a period of 1.1 days. Its radius 1.79 +/- 0.09R(J) is unexpectedly large and its orbital eccentricity 0.049 +/- 0.015 is even more surprising because such close orbits are usually quickly circularized. Here we report an analysis of its properties, which reveals that the planet is losing mass to its host star at a rate of about 10(-7)M(J) per year. The planet's surface is distorted by the star's gravity and the light curve produced by its prolate shape will differ by about ten per cent from that of a spherical planet. We conclude that dissipation of the star's tidal perturbation in the planet's convective envelope provides the energy source for its large volume. We predict up to 10 mJy CO band-head (2.292 mum) emission from a tenuous disk around the host star, made up of tidally stripped planetary gas. It may also contain a detectable resonant super-Earth, as a hypothetical perturber that continually stirs up WASP-12b's eccentricity.

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Orm family proteins mediate sphingolipid homeostasis.

Publication Date: 2010 Feb 25 PMID: 20182505
Authors: Breslow, D. K. - Collins, S. R. - Bodenmiller, B. - Aebersold, R. - Simons, K. - Shevchenko, A. - Ejsing, C. S. - Weissman, J. S.
Journal: Nature

Despite the essential roles of sphingolipids both as structural components of membranes and critical signalling molecules, we have a limited understanding of how cells sense and regulate their levels. Here we reveal the function in sphingolipid metabolism of the ORM genes (known as ORMDL genes in humans)-a conserved gene family that includes ORMDL3, which has recently been identified as a potential risk factor for childhood asthma. Starting from an unbiased functional genomic approach in Saccharomyces cerevisiae, we identify Orm proteins as negative regulators of sphingolipid synthesis that form a conserved complex with serine palmitoyltransferase, the first and rate-limiting enzyme in sphingolipid production. We also define a regulatory pathway in which phosphorylation of Orm proteins relieves their inhibitory activity when sphingolipid production is disrupted. Changes in ORM gene expression or mutations to their phosphorylation sites cause dysregulation of sphingolipid metabolism. Our work identifies the Orm proteins as critical mediators of sphingolipid homeostasis and raises the possibility that sphingolipid misregulation contributes to the development of childhood asthma.

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Geomicrobiology: Sediment reactions defy dogma.

Publication Date: 2010 Feb 25 PMID: 20182504
Authors: Nealson, K. H.
Journal: Nature

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Climate change: Tropical cyclones in the mix.

Publication Date: 2010 Feb 25 PMID: 20182503
Authors: Sriver, R. L.
Journal: Nature

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Regenerative medicine: Cell reprogramming gets direct.

Publication Date: 2010 Feb 25 PMID: 20182502
Authors: Nicholas, C. R. - Kriegstein, A. R.
Journal: Nature

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Low-temperature physics: Surprise in the strong regime.

Publication Date: 2010 Feb 25 PMID: 20182500
Authors: Shin, Y. I.
Journal: Nature

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Cell biology: A brake on lipid synthesis.

Publication Date: 2010 Feb 25 PMID: 20182499
Authors: Tafesse, F. G. - Holthuis, J. C.
Journal: Nature

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Applied mathematics: The statistics of style.

Publication Date: 2010 Feb 25 PMID: 20182498
Authors: Olshausen, B. A. - Deweese, M. R.
Journal: Nature

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Q&A: Georgina Ferry on writing biography. Interview by Nicola Jones.

Publication Date: 2010 Feb 25 PMID: 20182497
Authors: Ferry, G.
Journal: Nature

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Globe still in grip of addiction.

Publication Date: 2010 Feb 25 PMID: 20182492
Authors: Samet, J. M. - Wipfli, H. L.
Journal: Nature

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Research thrives on integration of natural and social sciences.

Publication Date: 2010 Feb 25 PMID: 20182491
Authors: Fisher, E. - Biggs, S. - Lindsay, S. - Zhao, J.
Journal: Nature

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Rigid animal-rights views not useful to ethics debate.

Publication Date: 2010 Feb 25 PMID: 20182490
Authors: Campbell, R.
Journal: Nature

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New NMR machines are set to boost biomedical potential.

Publication Date: 2010 Feb 25 PMID: 20182489
Authors: Hoch, J. C.
Journal: Nature

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Skewed assessment values have stifled textbook-writing.

Publication Date: 2010 Feb 25 PMID: 20182488
Authors: Wyatt, T. D.
Journal: Nature

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Futures perfect - food for thought and welcome light relief.

Publication Date: 2010 Feb 25 PMID: 20182487
Authors: Thompson, R.
Journal: Nature

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Earth science: The climate machine.

Publication Date: 2010 Feb 25 PMID: 20182486
Authors: Heffernan, O.
Journal: Nature

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A land without Google?

Publication Date: 2010 Feb 25 PMID: 20182485
Authors: Qiu, J.
Journal: Nature

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Cosmic-ray theory unravels.

Publication Date: 2010 Feb 25 PMID: 20182484
Authors: Hand, E.
Journal: Nature

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German paper chase to end.

Publication Date: 2010 Feb 25 PMID: 20182483
Authors: Schiermeier, Q.
Journal: Nature

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Did design flaws doom the LHC?

Publication Date: 2010 Feb 25 PMID: 20182482
Authors: Brumfiel, G.
Journal: Nature

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Pebble-bed nuclear reactor gets pulled.

Publication Date: 2010 Feb 25 PMID: 20182481
Authors: Nordling, L.
Journal: Nature

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Reserves 'win-win' for fish and fishermen.

Publication Date: 2010 Feb 25 PMID: 20182480
Authors: Dalton, R.
Journal: Nature

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'Seek, test and treat' slows HIV.

Publication Date: 2010 Feb 25 PMID: 20182479
Authors: Check Hayden, E.
Journal: Nature

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Journal club. An evolutionary biologist ponders the pace of evolution.

Publication Date: 2010 Feb 25 PMID: 20182473
Authors: Harmon, L.
Journal: Nature

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An absurd law.

Publication Date: 2010 Feb 25 PMID: 20182466
Authors:
Journal: Nature

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Bridges, not barriers.

Publication Date: 2010 Feb 25 PMID: 20182465
Authors:
Journal: Nature

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Simplification is essential.

Publication Date: 2010 Feb 25 PMID: 20182464
Authors:
Journal: Nature

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Location of corneal epithelial stem cells.

Publication Date: 2010 Feb 25 PMID: 20182462
Authors: Sun, T. T. - Tseng, S. C. - Lavker, R. M.
Journal: Nature

The longstanding concept that corneal epithelial stem cells reside mainly in the limbus is supported by the absence of major corneal epithelial differentiation markers, that is, K3 and K12 keratins, in limbal basal cells (these markers are expressed, however, in corneal basal cells, thus distinguishing the mode of keratin expression in corneal epithelium from that of all other stratified epithelia), the centripetal migration of corneal epithelial cells, the exclusive location of slow-cycling cells in the limbal basal layer, the superior in vitro proliferative potential of limbal epithelial cells, and the transplanted limbal cells' ability to reconstitute corneal epithelium in vivo (reviewed in refs 1-4). Moreover, previous data indicate that corneal and conjunctival epithelia represent two separate cell lineages (reviewed in refs 1-4). Majo et al. suggested, however, that corneal and conjunctival epithelia are equipotent, and that identical oligopotent stem cells are present throughout the corneal, limbal and conjunctival epithelia. We point out here that these suggestions are inconsistent with many known growth, differentiation and cell migration properties of the anterior ocular epithelia.

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Compensatory evolution in mitochondrial tRNAs navigates valleys of low fitness.

Publication Date: 2010 Feb 24 PMID: 20182427
Authors: Meer, M. V. - Kondrashov, A. S. - Artzy-Randrup, Y. - Kondrashov, F. A.
Journal: Nature

A long-standing controversy in evolutionary biology is whether or not evolving lineages can cross valleys on the fitness landscape that correspond to low-fitness genotypes, which can eventually enable them to reach isolated fitness peaks. Here we study the fitness landscapes traversed by switches between different AU and GC Watson-Crick nucleotide pairs at complementary sites of mitochondrial transfer RNA stem regions in 83 mammalian species. We find that such Watson-Crick switches occur 30-40 times more slowly than pairs of neutral substitutions, and that alleles corresponding to GU and AC non-Watson-Crick intermediate states segregate within human populations at low frequencies, similar to those of non-synonymous alleles. Substitutions leading to a Watson-Crick switch are strongly correlated, especially in mitochondrial tRNAs encoded on the GT-nucleotide-rich strand of the mitochondrial genome. Using these data we estimate that a typical Watson-Crick switch involves crossing a fitness valley of a depth of about 10(-3) or even about 10(-2), with AC intermediates being slightly more deleterious than GU intermediates. This compensatory evolution must proceed through rare intermediate variants that never reach fixation. The ubiquitous nature of compensatory evolution in mammalian mitochondrial tRNAs and other molecules implies that simultaneous fixation of two alleles that are individually deleterious may be a common phenomenon at the molecular level.

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An intrinsic vasopressin system in the olfactory bulb is involved in social recognition.

Publication Date: 2010 Feb 24 PMID: 20182426
Authors: Tobin, V. A. - Hashimoto, H. - Wacker, D. W. - Takayanagi, Y. - Langnaese, K. - Caquineau, C. - Noack, J. - Landgraf, R. - Onaka, T. - Leng, G. - Meddle, S. L. - Engelmann, M. - Ludwig, M.
Journal: Nature

Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader-Willi syndrome, affective disorders and obsessive-compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism. Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.

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Antagonistic coevolution accelerates molecular evolution.

Publication Date: 2010 Feb 24 PMID: 20182425
Authors: Paterson, S. - Vogwill, T. - Buckling, A. - Benmayor, R. - Spiers, A. J. - Thomson, N. R. - Quail, M. - Smith, F. - Walker, D. - Libberton, B. - Fenton, A. - Hall, N. - Brockhurst, M. A.
Journal: Nature

The Red Queen hypothesis proposes that coevolution of interacting species (such as hosts and parasites) should drive molecular evolution through continual natural selection for adaptation and counter-adaptation. Although the divergence observed at some host-resistance and parasite-infectivity genes is consistent with this, the long time periods typically required to study coevolution have so far prevented any direct empirical test. Here we show, using experimental populations of the bacterium Pseudomonas fluorescens SBW25 and its viral parasite, phage Phi2 (refs 10, 11), that the rate of molecular evolution in the phage was far higher when both bacterium and phage coevolved with each other than when phage evolved against a constant host genotype. Coevolution also resulted in far greater genetic divergence between replicate populations, which was correlated with the range of hosts that coevolved phage were able to infect. Consistent with this, the most rapidly evolving phage genes under coevolution were those involved in host infection. These results demonstrate, at both the genomic and phenotypic level, that antagonistic coevolution is a cause of rapid and divergent evolution, and is likely to be a major driver of evolutionary change within species.

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RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF.

Publication Date: 2010 Feb 23 PMID: 20179705
Authors: Poulikakos, P. I. - Zhang, C. - Bollag, G. - Shokat, K. M. - Rosen, N.
Journal: Nature

Tumours with mutant BRAF are dependent on the RAF-MEK-ERK signalling pathway for their growth. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one protomer, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation of wild-type RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS.

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Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal.

Publication Date: 2010 Feb 21 PMID: 20173739
Authors: Sotillo, R. - Schvartzman, J. M. - Socci, N. D. - Benezra, R.
Journal: Nature

Inhibition of an initiating oncogene often leads to extensive tumour cell death, a phenomenon known as oncogene addiction. This has led to the search for compounds that specifically target and inhibit oncogenes as anticancer agents. However, there has been no systematic exploration of whether chromosomal instability generated as a result of deregulation of the mitotic checkpoint pathway, a frequent characteristic of solid tumours, has any effect on oncogene addiction. Here we show that induction of chromosome instability by overexpression of the mitotic checkpoint gene Mad2 in mice does not affect the regression of Kras-driven lung tumours when Kras is inhibited. However, tumours that experience transient Mad2 overexpression and consequent chromosome instability recur at markedly elevated rates. The recurrent tumours are highly aneuploid and have varied activation of pro-proliferative pathways. Thus, early chromosomal instability may be responsible for tumour relapse after seemingly effective anticancer treatments.

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Sister chromosome pairing maintains heterozygosity in parthenogenetic lizards.

Publication Date: 2010 Feb 21 PMID: 20173738
Authors: Lutes, A. A. - Neaves, W. B. - Baumann, D. P. - Wiegraebe, W. - Baumann, P.
Journal: Nature

Although bisexual reproduction has proven to be highly successful, parthenogenetic all-female populations occur frequently in certain taxa, including the whiptail lizards of the genus Aspidoscelis. Allozyme analysis revealed a high degree of fixed heterozygosity in these parthenogenetic species, supporting the view that they originated from hybridization events between related sexual species. It has remained unclear how the meiotic program is altered to produce diploid eggs while maintaining heterozygosity. Here we show that meiosis commences with twice the number of chromosomes in parthenogenetic versus sexual species, a mechanism that provides the basis for generating gametes with unreduced chromosome content without fundamental deviation from the classic meiotic program. Our observation of synaptonemal complexes and chiasmata demonstrate that a typical meiotic program occurs and that heterozygosity is not maintained by bypassing recombination. Instead, fluorescent in situ hybridization probes that distinguish between homologues reveal that bivalents form between sister chromosomes, the genetically identical products of the first of two premeiotic replication cycles. Sister chromosome pairing provides a mechanism for the maintenance of heterozygosity, which is critical for offsetting the reduced fitness associated with the lack of genetic diversity in parthenogenetic species.

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Metabolic streamlining in an open-ocean nitrogen-fixing cyanobacterium.

Publication Date: 2010 Mar 4 PMID: 20173737
Authors: Tripp, H. J. - Bench, S. R. - Turk, K. A. - Foster, R. A. - Desany, B. A. - Niazi, F. - Affourtit, J. P. - Zehr, J. P.
Journal: Nature

Nitrogen (N(2))-fixing marine cyanobacteria are an important source of fixed inorganic nitrogen that supports oceanic primary productivity and carbon dioxide removal from the atmosphere. A globally distributed, periodically abundant N(2)-fixing marine cyanobacterium, UCYN-A, was recently found to lack the oxygen-producing photosystem II complex of the photosynthetic apparatus, indicating a novel metabolism, but remains uncultivated. Here we show, from metabolic reconstructions inferred from the assembly of the complete UCYN-A genome using massively parallel pyrosequencing of paired-end reads, that UCYN-A has a photofermentative metabolism and is dependent on other organisms for essential compounds. We found that UCYN-A lacks a number of major metabolic pathways including the tricarboxylic acid cycle, but retains sufficient electron transport capacity to generate energy and reducing power from light. Unexpectedly, UCYN-A has a reduced genome (1.44 megabases) that is structurally similar to many chloroplasts and some bacteria, in that it contains inverted repeats of ribosomal RNA operons. The lack of biosynthetic pathways for several amino acids and purines suggests that this organism depends on other organisms, either in close association or in symbiosis, for critical nutrients. However, size fractionation experiments using natural populations have so far not provided evidence of a symbiotic association with another microorganism. The UCYN-A cyanobacterium is a paradox in evolution and adaptation to the marine environment, and is an example of the tight metabolic coupling between microorganisms in oligotrophic oceanic microbial communities.

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Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice.

Publication Date: 2010 Feb 21 PMID: 20173736
Authors: Visel, A. - Zhu, Y. - May, D. - Afzal, V. - Gong, E. - Attanasio, C. - Blow, M. J. - Cohen, J. C. - Rubin, E. M. - Pennacchio, L. A.
Journal: Nature

Sequence polymorphisms in a 58-kilobase (kb) interval on chromosome 9p21 confer a markedly increased risk of coronary artery disease (CAD), the leading cause of death worldwide. The variants have a substantial effect on the epidemiology of CAD and other life-threatening vascular conditions because nearly one-quarter of Caucasians are homozygous for risk alleles. However, the risk interval is devoid of protein-coding genes and the mechanism linking the region to CAD risk has remained enigmatic. Here we show that deletion of the orthologous 70-kb non-coding interval on mouse chromosome 4 affects cardiac expression of neighbouring genes, as well as proliferation properties of vascular cells. Chr4(Delta70kb/Delta70kb) mice are viable, but show increased mortality both during development and as adults. Cardiac expression of two genes near the non-coding interval, Cdkn2a and Cdkn2b, is severely reduced in chr4(Delta70kb/Delta70kb) mice, indicating that distant-acting gene regulatory functions are located in the non-coding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of chr4(Delta70kb/Delta70kb) aortic smooth muscle cells exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Taken together, our results provide direct evidence that the CAD risk interval has a pivotal role in regulation of cardiac Cdkn2a/b expression, and suggest that this region affects CAD progression by altering the dynamics of vascular cell proliferation.

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ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C.

Publication Date: 2010 Feb 21 PMID: 20173735
Authors: Fellay, J. - Thompson, A. J. - Ge, D. - Gumbs, C. E. - Urban, T. J. - Shianna, K. V. - Little, L. D. - Qiu, P. - Bertelsen, A. H. - Watson, M. - Warner, A. - Muir, A. J. - Brass, C. - Albrecht, J. - Sulkowski, M. - McHutchison, J. G. - Goldstein, D. B.
Journal: Nature

Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.

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Whole-animal imaging: Probe progress.

Publication Date: 2010 Feb 18 PMID: 20164932
Authors:
Journal: Nature

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Whole-animal imaging: The whole picture.

Publication Date: 2010 Feb 18 PMID: 20164931
Authors: Baker, M.
Journal: Nature

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TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity.

Publication Date: 2010 Feb 18 PMID: 20164930
Authors: Huppa, J. B. - Axmann, M. - Mortelmaier, M. A. - Lillemeier, B. F. - Newell, E. W. - Brameshuber, M. - Klein, L. O. - Schutz, G. J. - Davis, M. M.
Journal: Nature

The recognition of foreign antigens by T lymphocytes is essential to most adaptive immune responses. It is driven by specific T-cell antigen receptors (TCRs) binding to antigenic peptide-major histocompatibility complex (pMHC) molecules on other cells. If productive, these interactions promote the formation of an immunological synapse. Here we show that synaptic TCR-pMHC binding dynamics differ significantly from TCR-pMHC binding in solution. We used single-molecule microscopy and fluorescence resonance energy transfer (FRET) between fluorescently tagged TCRs and their cognate pMHC ligands to measure the kinetics of TCR-pMHC binding in situ. When compared with solution measurements, the dissociation of this complex was increased significantly (4-12-fold). Disruption of actin polymers reversed this effect, indicating that cytoskeletal dynamics destabilize this interaction directly or indirectly. Nevertheless, TCR affinity for pMHC was significantly elevated as the result of a large (about 100-fold) increase in the association rate, a likely consequence of complementary molecular orientation and clustering. In helper T cells, the CD4 molecule has been proposed to bind cooperatively with the TCR to the same pMHC complex. However, CD4 blockade had no effect on the synaptic TCR affinity, nor did it destabilize TCR-pMHC complexes, indicating that the TCR binds pMHC independently of CD4.

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Rere controls retinoic acid signalling and somite bilateral symmetry.

Publication Date: 2010 Feb 18 PMID: 20164929
Authors: Vilhais-Neto, G. C. - Maruhashi, M. - Smith, K. T. - Vasseur-Cognet, M. - Peterson, A. S. - Workman, J. L. - Pourquie, O.
Journal: Nature

One of the most notable features of the vertebrate body plan organization is its bilateral symmetry, evident at the level of vertebrae and skeletal muscles. Here we show that a mutation in Rere (also known as atrophin2) leads to the formation of asymmetrical somites in mouse embryos, similar to embryos deprived of retinoic acid. Furthermore, we also demonstrate that Rere controls retinoic acid signalling, which is required to maintain somite symmetry by interacting with Fgf8 in the left-right signalling pathway. Rere forms a complex with Nr2f2, p300 (also known as Ep300) and a retinoic acid receptor, which is recruited to the retinoic acid regulatory element of retinoic acid targets, such as the Rarb promoter. Furthermore, the knockdown of Nr2f2 and/or Rere decreases retinoic acid signalling, suggesting that this complex is required to promote transcriptional activation of retinoic acid targets. The asymmetrical expression of Nr2f2 in the presomitic mesoderm overlaps with the asymmetry of the retinoic acid signalling response, supporting its implication in the control of somitic symmetry. Misregulation of this mechanism could be involved in symmetry defects of the human spine, such as those observed in patients with scoliosis.

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Rapid spine stabilization and synaptic enhancement at the onset of behavioural learning.

Publication Date: 2010 Feb 18 PMID: 20164928
Authors: Roberts, T. F. - Tschida, K. A. - Klein, M. E. - Mooney, R.
Journal: Nature

Behavioural learning depends on the brain's capacity to respond to instructive experience and is often enhanced during a juvenile sensitive period. How instructive experience acts on the juvenile brain to trigger behavioural learning remains unknown. In vitro studies show that forms of synaptic strengthening thought to underlie learning are accompanied by an increase in the stability, number and size of dendritic spines, which are the major sites of excitatory synaptic transmission in the vertebrate brain. In vivo imaging studies in sensory cortical regions reveal that these structural features can be affected by disrupting sensory experience and that spine turnover increases during sensitive periods for sensory map formation. These observations support two hypotheses: first, the increased capacity for behavioural learning during a sensitive period is associated with enhanced spine dynamics on sensorimotor neurons important for the learned behaviour; second, instructive experience rapidly stabilizes and strengthens these dynamic spines. Here we report a test of these hypotheses using two-photon in vivo imaging to measure spine dynamics in zebra finches, which learn to sing by imitating a tutor song during a juvenile sensitive period. Spine dynamics were measured in the forebrain nucleus HVC, the proximal site where auditory information merges with an explicit song motor representation, immediately before and after juvenile finches first experienced tutor song. Higher levels of spine turnover before tutoring correlated with a greater capacity for subsequent song imitation. In juveniles with high levels of spine turnover, hearing a tutor song led to the rapid ( approximately 24-h) stabilization, accumulation and enlargement of dendritic spines in HVC. Moreover, in vivo intracellular recordings made immediately before and after the first day of tutoring revealed robust enhancement of synaptic activity in HVC. These findings suggest that behavioural learning results when instructive experience is able to rapidly stabilize and strengthen synapses on sensorimotor neurons important for the control of the learned behaviour.

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Complete Khoisan and Bantu genomes from southern Africa.

Publication Date: 2010 Feb 18 PMID: 20164927
Authors: Schuster, S. C. - Miller, W. - Ratan, A. - Tomsho, L. P. - Giardine, B. - Kasson, L. R. - Harris, R. S. - Petersen, D. C. - Zhao, F. - Qi, J. - Alkan, C. - Kidd, J. M. - Sun, Y. - Drautz, D. I. - Bouffard, P. - Muzny, D. M. - Reid, J. G. - Nazareth, L. V. - Wang, Q. - Burhans, R. - Riemer, C. - Wittekindt, N. E. - Moorjani, P. - Tindall, E. A. - Danko, C. G. - Teo, W. S. - Buboltz, A. M. - Zhang, Z. - Ma, Q. - Oosthuysen, A. - Steenkamp, A. W. - Oostuisen, H. - Venter, P. - Gajewski, J. - Zhang, Y. - Pugh, B. F. - Makova, K. D. - Nekrutenko, A. - Mardis, E. R. - Patterson, N. - Pringle, T. H. - Chiaromonte, F. - Mullikin, J. C. - Eichler, E. E. - Hardison, R. C. - Gibbs, R. A. - Harkins, T. T. - Hayes, V. M.
Journal: Nature

The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.

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Upside-down differentiation and generation of a 'primordial' lower mantle.

Publication Date: 2010 Feb 18 PMID: 20164926
Authors: Lee, C. T. - Luffi, P. - Hoink, T. - Li, J. - Dasgupta, R. - Hernlund, J.
Journal: Nature

Except for the first 50-100 million years or so of the Earth's history, when most of the mantle may have been subjected to melting, the differentiation of Earth's silicate mantle has been controlled by solid-state convection. As the mantle upwells and decompresses across its solidus, it partially melts. These low-density melts rise to the surface and form the continental and oceanic crusts, driving the differentiation of the silicate part of the Earth. Because many trace elements, such as heat-producing U, Th and K, as well as the noble gases, preferentially partition into melts (here referred to as incompatible elements), melt extraction concentrates these elements into the crust (or atmosphere in the case of noble gases), where nearly half of the Earth's budget of these elements now resides. In contrast, the upper mantle, as sampled by mid-ocean ridge basalts, is highly depleted in incompatible elements, suggesting a complementary relationship with the crust. Mass balance arguments require that the other half of these incompatible elements be hidden in the Earth's interior. Hypotheses abound for the origin of this hidden reservoir. The most widely held view has been that this hidden reservoir represents primordial material never processed by melting or degassing. Here, we suggest that a necessary by-product of whole-mantle convection during the Earth's first billion years is deep and hot melting, resulting in the generation of dense liquids that crystallized and sank into the lower mantle. These sunken lithologies would have 'primordial' chemical signatures despite a non-primordial origin.

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A precision measurement of the gravitational redshift by the interference of matter waves.

Publication Date: 2010 Feb 18 PMID: 20164925
Authors: Muller, H. - Peters, A. - Chu, S.
Journal: Nature

One of the central predictions of metric theories of gravity, such as general relativity, is that a clock in a gravitational potential U will run more slowly by a factor of 1 + U/c(2), where c is the velocity of light, as compared to a similar clock outside the potential. This effect, known as gravitational redshift, is important to the operation of the global positioning system, timekeeping and future experiments with ultra-precise, space-based clocks (such as searches for variations in fundamental constants). The gravitational redshift has been measured using clocks on a tower, an aircraft and a rocket, currently reaching an accuracy of 7 x 10(-5). Here we show that laboratory experiments based on quantum interference of atoms enable a much more precise measurement, yielding an accuracy of 7 x 10(-9). Our result supports the view that gravity is a manifestation of space-time curvature, an underlying principle of general relativity that has come under scrutiny in connection with the search for a theory of quantum gravity. Improving the redshift measurement is particularly important because this test has been the least accurate among the experiments that are required to support curved space-time theories.

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An upper limit on the contribution of accreting white dwarfs to the type Ia supernova rate.

Publication Date: 2010 Feb 18 PMID: 20164924
Authors: Gilfanov, M. - Bogdan, A.
Journal: Nature

There is wide agreement that type Ia supernovae (used as standard candles for cosmology) are associated with the thermonuclear explosions of white dwarf stars. The nuclear runaway that leads to the explosion could start in a white dwarf gradually accumulating matter from a companion star until it reaches the Chandrasekhar limit, or could be triggered by the merger of two white dwarfs in a compact binary system. The X-ray signatures of these two possible paths are very different. Whereas no strong electromagnetic emission is expected in the merger scenario until shortly before the supernova, the white dwarf accreting material from the normal star becomes a source of copious X-rays for about 10(7) years before the explosion. This offers a means of determining which path dominates. Here we report that the observed X-ray flux from six nearby elliptical galaxies and galaxy bulges is a factor of approximately 30-50 less than predicted in the accretion scenario, based upon an estimate of the supernova rate from their K-band luminosities. We conclude that no more than about five per cent of type Ia supernovae in early-type galaxies can be produced by white dwarfs in accreting binary systems, unless their progenitors are much younger than the bulk of the stellar population in these galaxies, or explosions of sub-Chandrasekhar white dwarfs make a significant contribution to the supernova rate.

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A change in the optical polarization associated with a gamma-ray flare in the blazar 3C 279.

Publication Date: 2010 Feb 18 PMID: 20164923
Authors:
Journal: Nature

It is widely accepted that strong and variable radiation detected over all accessible energy bands in a number of active galaxies arises from a relativistic, Doppler-boosted jet pointing close to our line of sight. The size of the emitting zone and the location of this region relative to the central supermassive black hole are, however, poorly known, with estimates ranging from light-hours to a light-year or more. Here we report the coincidence of a gamma (gamma)-ray flare with a dramatic change of optical polarization angle. This provides evidence for co-spatiality of optical and gamma-ray emission regions and indicates a highly ordered jet magnetic field. The results also require a non-axisymmetric structure of the emission zone, implying a curved trajectory for the emitting material within the jet, with the dissipation region located at a considerable distance from the black hole, at about 10(5) gravitational radii.

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Variability in gene expression underlies incomplete penetrance.

Publication Date: 2010 Feb 18 PMID: 20164922
Authors: Raj, A. - Rifkin, S. A. - Andersen, E. - van Oudenaarden, A.
Journal: Nature

The phenotypic differences between individual organisms can often be ascribed to underlying genetic and environmental variation. However, even genetically identical organisms in homogeneous environments vary, indicating that randomness in developmental processes such as gene expression may also generate diversity. To examine the consequences of gene expression variability in multicellular organisms, we studied intestinal specification in the nematode Caenorhabditis elegans in which wild-type cell fate is invariant and controlled by a small transcriptional network. Mutations in elements of this network can have indeterminate effects: some mutant embryos fail to develop intestinal cells, whereas others produce intestinal precursors. By counting transcripts of the genes in this network in individual embryos, we show that the expression of an otherwise redundant gene becomes highly variable in the mutants and that this variation is subjected to a threshold, producing an ON/OFF expression pattern of the master regulatory gene of intestinal differentiation. Our results demonstrate that mutations in developmental networks can expose otherwise buffered stochastic variability in gene expression, leading to pronounced phenotypic variation.

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Active site remodelling accompanies thioester bond formation in the SUMO E1.

Publication Date: 2010 Feb 18 PMID: 20164921
Authors: Olsen, S. K. - Capili, A. D. - Lu, X. - Tan, D. S. - Lima, C. D.
Journal: Nature

E1 enzymes activate ubiquitin (Ub) and ubiquitin-like (Ubl) proteins in two steps by carboxy-terminal adenylation and thioester bond formation to a conserved catalytic cysteine in the E1 Cys domain. The structural basis for these intermediates remains unknown. Here we report crystal structures for human SUMO E1 in complex with SUMO adenylate and tetrahedral intermediate analogues at 2.45 and 2.6 A, respectively. These structures show that side chain contacts to ATP.Mg are released after adenylation to facilitate a 130 degree rotation of the Cys domain during thioester bond formation that is accompanied by remodelling of key structural elements including the helix that contains the E1 catalytic cysteine, the crossover and re-entry loops, and refolding of two helices that are required for adenylation. These changes displace side chains required for adenylation with side chains required for thioester bond formation. Mutational and biochemical analyses indicate these mechanisms are conserved in other E1s.

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The landscape of somatic copy-number alteration across human cancers.

Publication Date: 2010 Feb 18 PMID: 20164920
Authors: Beroukhim, R. - Mermel, C. H. - Porter, D. - Wei, G. - Raychaudhuri, S. - Donovan, J. - Barretina, J. - Boehm, J. S. - Dobson, J. - Urashima, M. - Mc Henry, K. T. - Pinchback, R. M. - Ligon, A. H. - Cho, Y. J. - Haery, L. - Greulich, H. - Reich, M. - Winckler, W. - Lawrence, M. S. - Weir, B. A. - Tanaka, K. E. - Chiang, D. Y. - Bass, A. J. - Loo, A. - Hoffman, C. - Prensner, J. - Liefeld, T. - Gao, Q. - Yecies, D. - Signoretti, S. - Maher, E. - Kaye, F. J. - Sasaki, H. - Tepper, J. E. - Fletcher, J. A. - Tabernero, J. - Baselga, J. - Tsao, M. S. - Demichelis, F. - Rubin, M. A. - Janne, P. A. - Daly, M. J. - Nucera, C. - Levine, R. L. - Ebert, B. L. - Gabriel, S. - Rustgi, A. K. - Antonescu, C. R. - Ladanyi, M. - Letai, A. - Garraway, L. A. - Loda, M. - Beer, D. G. - True, L. D. - Okamoto, A. - Pomeroy, S. L. - Singer, S. - Golub, T. R. - Lander, E. S. - Getz, G. - Sellers, W. R. - Meyerson, M.
Journal: Nature

A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.

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Signatures of mutation and selection in the cancer genome.

Publication Date: 2010 Feb 18 PMID: 20164919
Authors: Bignell, G. R. - Greenman, C. D. - Davies, H. - Butler, A. P. - Edkins, S. - Andrews, J. M. - Buck, G. - Chen, L. - Beare, D. - Latimer, C. - Widaa, S. - Hinton, J. - Fahey, C. - Fu, B. - Swamy, S. - Dalgliesh, G. L. - Teh, B. T. - Deloukas, P. - Yang, F. - Campbell, P. J. - Futreal, P. A. - Stratton, M. R.
Journal: Nature

The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.

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Genetics: Random expression goes binary.

Publication Date: 2010 Feb 18 PMID: 20164917
Authors: Streit, A. - Sommer, R. J.
Journal: Nature

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Quantum measurement: A light touch.

Publication Date: 2010 Feb 18 PMID: 20164916
Authors: Steinberg, A. M.
Journal: Nature

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Structural biology: Transformative encounters.

Publication Date: 2010 Feb 18 PMID: 20164915
Authors: Schulman, B. A. - Haas, A. L.
Journal: Nature

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Animal behaviour: An ill wind for finches.

Publication Date: 2010 Feb 18 PMID: 20164914
Authors: Lincoln, T.
Journal: Nature

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Gene regulation: A chromatin thermostat.

Publication Date: 2010 Feb 18 PMID: 20164913
Authors: Deal, R. B. - Henikoff, S.
Journal: Nature

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Astrophysics: Cosmic jet engines.

Publication Date: 2010 Feb 18 PMID: 20164912
Authors: Young, A.
Journal: Nature

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Early life: Ancient acritarchs.

Publication Date: 2010 Feb 18 PMID: 20164911
Authors: Buick, R.
Journal: Nature

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Q&A: David Brin on writing fiction. Interview by Nicola Jones.

Publication Date: 2010 Feb 18 PMID: 20164910
Authors: Brin, D.
Journal: Nature

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Lessons from the Haiti earthquake.

Publication Date: 2010 Feb 18 PMID: 20164905
Authors: Bilham, R.
Journal: Nature

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China fights fraud with tough tactics and integrity training.

Publication Date: 2010 Feb 18 PMID: 20164904
Authors: Michel, M. C.
Journal: Nature

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Outcry stopped approved pig study of avalanche survival.

Publication Date: 2010 Feb 18 PMID: 20164903
Authors: Brugger, H. - Paal, P. - Falk, M.
Journal: Nature

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University overhaul vital to end Bulgarian science's long decline.

Publication Date: 2010 Feb 18 PMID: 20164902
Authors: Yordanov, O. I.
Journal: Nature

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The Rubisco enzyme and agricultural productivity.

Publication Date: 2010 Feb 18 PMID: 20164901
Authors: Porter, J. R. - Wollenweber, B.
Journal: Nature

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Parliament needs members who are scientifically literate.

Publication Date: 2010 Feb 18 PMID: 20164900
Authors: Goldstein, S.
Journal: Nature

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Transdisciplinary EU science institute needs funds urgently.

Publication Date: 2010 Feb 18 PMID: 20164899
Authors: Vasbinder, J. W. - Andersson, B. - Arthur, W. B. - Boasson, M. - de Boer, R. - Changeux, J. P. - Domingo, E. - Eigen, M. - Fersht, A. - Frenkel, D. - Rees, M. - Groen, T. - Huber, R. - Hunt, T. - Holland, J. - May, R. - Norrby, E. - Nijkamp, P. - Lehn, J. M. - Rabbinge, R. - Scheffer, M. - Schuster, P. - Serageldin, I. - Stuip, J. - de Vries, J. - van Vierssen, W. - Willems, R.
Journal: Nature

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World view: Calling science to account.

Publication Date: 2010 Feb 18 PMID: 20164898
Authors: Macilwain, C.
Journal: Nature

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Carbon sequestration: Buried trouble.

Publication Date: 2010 Feb 18 PMID: 20164897
Authors: Van Noorden, R.
Journal: Nature

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Astronomy: The decadal dinner club.

Publication Date: 2010 Feb 18 PMID: 20164896
Authors: Hand, E.
Journal: Nature

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Evolution: Revenge of the hopeful monster.

Publication Date: 2010 Feb 18 PMID: 20164895
Authors: Chouard, T.
Journal: Nature

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General relativity tested on a tabletop.

Publication Date: 2010 Feb 18 PMID: 20164894
Authors: Hand, E.
Journal: Nature

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Trees spit out gas from soil microbes.

Publication Date: 2010 Feb 18 PMID: 20164893
Authors: Mascarelli, A.
Journal: Nature

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'Climategate' scientist speaks out.

Publication Date: 2010 Feb 18 PMID: 20164892
Authors: Heffernan, O.
Journal: Nature

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Asian pollution delays inevitable warming.

Publication Date: 2010 Feb 18 PMID: 20164891
Authors: Tollefson, J.
Journal: Nature

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Genomics firms turn to other markets.

Publication Date: 2010 Feb 18 PMID: 20164890
Authors: Hayden, E. C.
Journal: Nature

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How accurate are cancer cell lines?

Publication Date: 2010 Feb 18 PMID: 20164888
Authors: Borrell, B.
Journal: Nature

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Africa yields two full human genomes.

Publication Date: 2010 Feb 18 PMID: 20164887
Authors: Ledford, H.
Journal: Nature

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Three biologists slain on campus.

Publication Date: 2010 Feb 18 PMID: 20164886
Authors: Wadman, M.
Journal: Nature

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Journal club. A physical chemist is excited by the electronic potential of a new arrangement of carbon sheets.

Publication Date: 2010 Feb 18 PMID: 20164884
Authors: Ruoff, R. S.
Journal: Nature

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Nature's choices.

Publication Date: 2010 Feb 18 PMID: 20164873
Authors:
Journal: Nature

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Validation required.

Publication Date: 2010 Feb 18 PMID: 20164872
Authors:
Journal: Nature

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Progressive thinking.

Publication Date: 2010 Feb 18 PMID: 20164871
Authors:
Journal: Nature

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Multilevel and kin selection in a connected world.

Publication Date: 2010 Feb 18 PMID: 20164866
Authors: Wade, M. J. - Wilson, D. S. - Goodnight, C. - Taylor, D. - Bar-Yam, Y. - de Aguiar, M. A. - Stacey, B. - Werfel, J. - Hoelzer, G. A. - Brodie, E. D. 3rd - Fields, P. - Breden, F. - Linksvayer, T. A. - Fletcher, J. A. - Richerson, P. J. - Bever, J. D. - Van Dyken, J. D. - Zee, P.
Journal: Nature

Wild et al. argue that the evolution of reduced virulence can be understood from the perspective of inclusive fitness, obviating the need to evoke group selection as a contributing causal factor. Although they acknowledge the mathematical equivalence of the inclusive fitness and multilevel selection approaches, they conclude that reduced virulence can be viewed entirely as an individual-level adaptation by the parasite. Here we show that their model is a well-known special case of the more general theory of multilevel selection, and that the cause of reduced virulence resides in the opposition of two processes: within-group and among-group selection. This distinction is important in light of the current controversy among evolutionary biologists in which some continue to affirm that natural selection centres only and always at the level of the individual organism or gene, despite mathematical demonstrations that evolutionary dynamics must be described by selection at various levels in the hierarchy of biological organization.

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The primary transcriptome of the major human pathogen Helicobacter pylori.

Publication Date: 2010 Feb 17 PMID: 20164839
Authors: Sharma, C. M. - Hoffmann, S. - Darfeuille, F. - Reignier, J. - Findeiss, S. - Sittka, A. - Chabas, S. - Reiche, K. - Hackermuller, J. - Reinhardt, R. - Stadler, P. F. - Vogel, J.
Journal: Nature

Genome sequencing of Helicobacter pylori has revealed the potential proteins and genetic diversity of this prevalent human pathogen, yet little is known about its transcriptional organization and noncoding RNA output. Massively parallel cDNA sequencing (RNA-seq) has been revolutionizing global transcriptomic analysis. Here, using a novel differential approach (dRNA-seq) selective for the 5' end of primary transcripts, we present a genome-wide map of H. pylori transcriptional start sites and operons. We discovered hundreds of transcriptional start sites within operons, and opposite to annotated genes, indicating that complexity of gene expression from the small H. pylori genome is increased by uncoupling of polycistrons and by genome-wide antisense transcription. We also discovered an unexpected number of approximately 60 small RNAs including the epsilon-subdivision counterpart of the regulatory 6S RNA and associated RNA products, and potential regulators of cis- and trans-encoded target messenger RNAs. Our approach establishes a paradigm for mapping and annotating the primary transcriptomes of many living species.

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Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients.

Publication Date: 2010 Feb 17 PMID: 20164838
Authors: Agarwal, S. - Loh, Y. H. - McLoughlin, E. M. - Huang, J. - Park, I. H. - Miller, J. D. - Huo, H. - Okuka, M. - Dos Reis, R. M. - Loewer, S. - Ng, H. H. - Keefe, D. L. - Goldman, F. D. - Klingelhutz, A. J. - Liu, L. - Daley, G. Q.
Journal: Nature

Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues. Patient-specific induced pluripotent stem (iPS) cells represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT). We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3' deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.

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Remarkably ancient balanced polymorphisms in a multi-locus gene network.

Publication Date: 2010 Mar 4 PMID: 20164837
Authors: Hittinger, C. T. - Goncalves, P. - Sampaio, J. P. - Dover, J. - Johnston, M. - Rokas, A.
Journal: Nature

Local adaptations within species are often governed by several interacting genes scattered throughout the genome. Single-locus models of selection cannot explain the maintenance of such complex variation because recombination separates co-adapted alleles. Here we report a previously unrecognized type of intraspecific multi-locus genetic variation that has been maintained over a vast period. The galactose (GAL) utilization gene network of Saccharomyces kudriavzevii, a relative of brewer's yeast, exists in two distinct states: a functional gene network in Portuguese strains and, in Japanese strains, a non-functional gene network of allelic pseudogenes. Genome sequencing of all available S. kudriavzevii strains revealed that none of the functional GAL genes were acquired from other species. Rather, these polymorphisms have been maintained for nearly the entire history of the species, despite more recent gene flow genome-wide. Experimental evidence suggests that inactivation of the GAL3 and GAL80 regulatory genes facilitated the origin and long-term maintenance of the two gene network states. This striking example of a balanced unlinked gene network polymorphism introduces a remarkable type of intraspecific variation that may be widespread.

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Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET.

Publication Date: 2010 Feb 17 PMID: 20164836
Authors: Matsui, T. - Leung, D. - Miyashita, H. - Maksakova, I. A. - Miyachi, H. - Kimura, H. - Tachibana, M. - Lorincz, M. C. - Shinkai, Y.
Journal: Nature

Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising approximately 10% of the mouse genome. These parasitic elements are responsible for >10% of spontaneous mutations. Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells, an additional DNA-methylation-independent pathway also functions in embryonal carcinoma and embryonic stem (ES) cells to inhibit transcription of the exogenous gammaretrovirus murine leukaemia virus (MLV). Notably, a recent genome-wide study revealed that ERVs are also marked by histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3 in ES cells but not in mouse embryonic fibroblasts. However, the role that these marks have in proviral silencing remains unexplored. Here we show that the H3K9 methyltransferase ESET (also called SETDB1 or KMT1E) and the Kruppel-associated box (KRAB)-associated protein 1 (KAP1, also called TRIM28) are required for H3K9me3 and silencing of endogenous and introduced retroviruses specifically in mouse ES cells. Furthermore, whereas ESET enzymatic activity is crucial for HP1 binding and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 and Suv420h2 are dispensable for silencing. Notably, in DNA methyltransferase triple knockout (Dnmt1(-/-)Dnmt3a(-/-)Dnmt3b(-/-)) mouse ES cells, ESET and KAP1 binding and ESET-mediated H3K9me3 are maintained and ERVs are minimally derepressed. We propose that a DNA-methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed.

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Differential innate immune signalling via Ca(2+) sensor protein kinases.

Publication Date: 2010 Feb 17 PMID: 20164835
Authors: Boudsocq, M. - Willmann, M. R. - McCormack, M. - Lee, H. - Shan, L. - He, P. - Bush, J. - Cheng, S. H. - Sheen, J.
Journal: Nature

Innate immunity represents the first line of inducible defence against microbial infection in plants and animals. In both kingdoms, recognition of pathogen- or microbe-associated molecular patterns (PAMPs or MAMPs, respectively), such as flagellin, initiates convergent signalling pathways involving mitogen-activated protein kinase (MAPK) cascades and global transcriptional changes to boost immunity. Although Ca(2+) has long been recognized as an essential and conserved primary mediator in plant defence responses, how Ca(2+) signals are sensed and relayed into early MAMP signalling is unknown. Using a functional genomic screen and genome-wide gene expression profiling, here we show that four calcium-dependent protein kinases (CDPKs) are Ca(2+)-sensor protein kinases critical for transcriptional reprogramming in plant innate immune signalling. Unexpectedly, CDPKs and MAPK cascades act differentially in four MAMP-mediated regulatory programs to control early genes involved in the synthesis of defence peptides and metabolites, cell wall modifications and redox signalling. Transcriptome profile comparison suggests that CDPKs are the convergence point of signalling triggered by most MAMPs. Double, triple and quadruple cpk mutant plants display progressively diminished oxidative burst and gene activation induced by the 22-amino-acid peptide flg22, as well as compromised pathogen defence. In contrast to negative roles of calmodulin and a calmodulin-activated transcription factor in plant defence, the present study reveals Ca(2+) signalling complexity and demonstrates key positive roles of specific CDPKs in initial MAMP signalling.

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Haematopoietic stem cells derive directly from aortic endothelium during development.

Publication Date: 2010 Mar 4 PMID: 20154733
Authors: Bertrand, J. Y. - Chi, N. C. - Santoso, B. - Teng, S. - Stainier, D. Y. - Traver, D.
Journal: Nature

A major goal of regenerative medicine is to instruct formation of multipotent, tissue-specific stem cells from induced pluripotent stem cells (iPSCs) for cell replacement therapies. Generation of haematopoietic stem cells (HSCs) from iPSCs or embryonic stem cells (ESCs) is not currently possible, however, necessitating a better understanding of how HSCs normally arise during embryonic development. We previously showed that haematopoiesis occurs through four distinct waves during zebrafish development, with HSCs arising in the final wave in close association with the dorsal aorta. Recent reports have suggested that murine HSCs derive from haemogenic endothelial cells (ECs) lining the aortic floor. Additional in vitro studies have similarly indicated that the haematopoietic progeny of ESCs arise through intermediates with endothelial potential. Here we have used the unique strengths of the zebrafish embryo to image directly the generation of HSCs from the ventral wall of the dorsal aorta. Using combinations of fluorescent reporter transgenes, confocal time-lapse microscopy and flow cytometry, we have identified and isolated the stepwise intermediates as aortic haemogenic endothelium transitions to nascent HSCs. Finally, using a permanent lineage tracing strategy, we demonstrate that the HSCs generated from haemogenic endothelium are the lineal founders of the adult haematopoietic system.

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Blood stem cells emerge from aortic endothelium by a novel type of cell transition.

Publication Date: 2010 Mar 4 PMID: 20154732
Authors: Kissa, K. - Herbomel, P.
Journal: Nature

The ontogeny of haematopoietic stem cells (HSCs) during embryonic development is still highly debated, especially their possible lineage relationship to vascular endothelial cells. The first anatomical site from which cells with long-term HSC potential have been isolated is the aorta-gonad-mesonephros (AGM), more specifically the vicinity of the dorsal aortic floor. But although some authors have presented evidence that HSCs may arise directly from the aortic floor into the dorsal aortic lumen, others support the notion that HSCs first emerge within the underlying mesenchyme. Here we show by non-invasive, high-resolution imaging of live zebrafish embryos, that HSCs emerge directly from the aortic floor, through a stereotyped process that does not involve cell division but a strong bending then egress of single endothelial cells from the aortic ventral wall into the sub-aortic space, and their concomitant transformation into haematopoietic cells. The process is polarized not only in the dorso-ventral but also in the rostro-caudal versus medio-lateral direction, and depends on Runx1 expression: in Runx1-deficient embryos, the exit events are initially similar, but much rarer, and abort into violent death of the exiting cell. These results demonstrate that the aortic floor is haemogenic and that HSCs emerge from it into the sub-aortic space, not by asymmetric cell division but through a new type of cell behaviour, which we call an endothelial haematopoietic transition.

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Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome.

Publication Date: 2010 Feb 14 PMID: 20154731
Authors: Neumann, H. - Wang, K. - Davis, L. - Garcia-Alai, M. - Chin, J. W.
Journal: Nature

The in vivo, genetically programmed incorporation of designer amino acids allows the properties of proteins to be tailored with molecular precision. The Methanococcus jannaschii tyrosyl-transfer-RNA synthetase-tRNA(CUA) (MjTyrRS-tRNA(CUA)) and the Methanosarcina barkeri pyrrolysyl-tRNA synthetase-tRNA(CUA) (MbPylRS-tRNA(CUA)) orthogonal pairs have been evolved to incorporate a range of unnatural amino acids in response to the amber codon in Escherichia coli. However, the potential of synthetic genetic code expansion is generally limited to the low efficiency incorporation of a single type of unnatural amino acid at a time, because every triplet codon in the universal genetic code is used in encoding the synthesis of the proteome. To encode efficiently many distinct unnatural amino acids into proteins we require blank codons and mutually orthogonal aminoacyl-tRNA synthetase-tRNA pairs that recognize unnatural amino acids and decode the new codons. Here we synthetically evolve an orthogonal ribosome (ribo-Q1) that efficiently decodes a series of quadruplet codons and the amber codon, providing several blank codons on an orthogonal messenger RNA, which it specifically translates. By creating mutually orthogonal aminoacyl-tRNA synthetase-tRNA pairs and combining them with ribo-Q1 we direct the incorporation of distinct unnatural amino acids in response to two of the new blank codons on the orthogonal mRNA. Using this code, we genetically direct the formation of a specific, redox-insensitive, nanoscale protein cross-link by the bio-orthogonal cycloaddition of encoded azide- and alkyne-containing amino acids. Because the synthetase-tRNA pairs used have been evolved to incorporate numerous unnatural amino acids, it will be possible to encode more than 200 unnatural amino acid combinations using this approach. As ribo-Q1 independently decodes a series of quadruplet codons, this work provides foundational technologies for the encoded synthesis and synthetic evolution of unnatural polymers in cells.

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Neurogenic radial glia in the outer subventricular zone of human neocortex.

Publication Date: 2010 Feb 14 PMID: 20154730
Authors: Hansen, D. V. - Lui, J. H. - Parker, P. R. - Kriegstein, A. R.
Journal: Nature

Neurons in the developing rodent cortex are generated from radial glial cells that function as neural stem cells. These epithelial cells line the cerebral ventricles and generate intermediate progenitor cells that migrate into the subventricular zone (SVZ) and proliferate to increase neuronal number. The developing human SVZ has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. However, OSVZ progenitor cell types and their contribution to neurogenesis are not well understood. Here we show that large numbers of radial glia-like cells and intermediate progenitor cells populate the human OSVZ. We find that OSVZ radial glia-like cells have a long basal process but, surprisingly, are non-epithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, we demonstrate that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor cells that can proliferate further. We also show that inhibition of Notch signalling in OSVZ progenitor cells induces their neuronal differentiation. The establishment of non-ventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain.

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In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium.

Publication Date: 2010 Mar 4 PMID: 20154729
Authors: Boisset, J. C. - van Cappellen, W. - Andrieu-Soler, C. - Galjart, N. - Dzierzak, E. - Robin, C.
Journal: Nature

Haematopoietic stem cells (HSCs), responsible for blood production in the adult mouse, are first detected in the dorsal aorta starting at embryonic day 10.5 (E10.5). Immunohistological analysis of fixed embryo sections has revealed the presence of haematopoietic cell clusters attached to the aortic endothelium where HSCs might localize. The origin of HSCs has long been controversial and several candidates of the direct HSC precursors have been proposed (for review see ref. 7), including a specialized endothelial cell population with a haemogenic potential. Such cells have been described both in vitro in the embryonic stem cell (ESC) culture system and retrospectively in vivo by endothelial lineage tracing and conditional deletion experiments. Whether the transition from haemogenic endothelium to HSC actually occurs in the mouse embryonic aorta is still unclear and requires direct and real-time in vivo observation. To address this issue we used time-lapse confocal imaging and a new dissection procedure to visualize the deeply located aorta. Here we show the dynamic de novo emergence of phenotypically defined HSCs (Sca1(+), c-kit(+), CD41(+)) directly from ventral aortic haemogenic endothelial cells.

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Mical links semaphorins to F-actin disassembly.

Publication Date: 2010 Feb 11 PMID: 20148037
Authors: Hung, R. J. - Yazdani, U. - Yoon, J. - Wu, H. - Yang, T. - Gupta, N. - Huang, Z. - van Berkel, W. J. - Terman, J. R.
Journal: Nature

How instructive cues present on the cell surface have their precise effects on the actin cytoskeleton is poorly understood. Semaphorins are one of the largest families of these instructive cues and are widely studied for their effects on cell movement, navigation, angiogenesis, immunology and cancer. Semaphorins/collapsins were characterized in part on the basis of their ability to drastically alter actin cytoskeletal dynamics in neuronal processes, but despite considerable progress in the identification of semaphorin receptors and their signalling pathways, the molecules linking them to the precise control of cytoskeletal elements remain unknown. Recently, highly unusual proteins of the Mical family of enzymes have been found to associate with the cytoplasmic portion of plexins, which are large cell-surface semaphorin receptors, and to mediate axon guidance, synaptogenesis, dendritic pruning and other cell morphological changes. Mical enzymes perform reduction-oxidation (redox) enzymatic reactions and also contain domains found in proteins that regulate cell morphology. However, nothing is known of the role of Mical or its redox activity in mediating morphological changes. Here we report that Mical directly links semaphorins and their plexin receptors to the precise control of actin filament (F-actin) dynamics. We found that Mical is both necessary and sufficient for semaphorin-plexin-mediated F-actin reorganization in vivo. Likewise, we purified Mical protein and found that it directly binds F-actin and disassembles both individual and bundled actin filaments. We also found that Mical utilizes its redox activity to alter F-actin dynamics in vivo and in vitro, indicating a previously unknown role for specific redox signalling events in actin cytoskeletal regulation. Mical therefore is a novel F-actin-disassembly factor that provides a molecular conduit through which actin reorganization-a hallmark of cell morphological changes including axon navigation-can be precisely achieved spatiotemporally in response to semaphorins.

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Zonal flow formation in the Earth's core.

Publication Date: 2010 Feb 11 PMID: 20148036
Authors: Miyagoshi, T. - Kageyama, A. - Sato, T.
Journal: Nature

Zonal jets are very common in nature. Well-known examples are those in the atmospheres of giant planets and the alternating jet streams found in the Earth's world ocean. Zonal flow formation in nuclear fusion devices is also well studied. A common feature of these zonal flows is that they are spontaneously generated in turbulent systems. Because the Earth's outer core is believed to be in a turbulent state, it is possible that there is zonal flow in the liquid iron of the outer core. Here we report an investigation at the current low-viscosity limit of numerical simulations of the geodynamo. We find a previously unknown convection regime of the outer core that has a dual structure comprising inner, sheet-like radial plumes and an outer, westward cylindrical zonal flow. We numerically confirm that the dual-convection structure with such a zonal flow is stable under a strong, self-generated dipole magnetic field.

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Above-room-temperature ferroelectricity in a single-component molecular crystal.

Publication Date: 2010 Feb 11 PMID: 20148035
Authors: Horiuchi, S. - Tokunaga, Y. - Giovannetti, G. - Picozzi, S. - Itoh, H. - Shimano, R. - Kumai, R. - Tokura, Y.
Journal: Nature

Ferroelectrics are electro-active materials that can store and switch their polarity (ferroelectricity), sense temperature changes (pyroelectricity), interchange electric and mechanical functions (piezoelectricity), and manipulate light (through optical nonlinearities and the electro-optic effect): all of these functions have practical applications. Topological switching of pi-conjugation in organic molecules, such as the keto-enol transformation, has long been anticipated as a means of realizing these phenomena in molecular assemblies and crystals. Croconic acid, an ingredient of black dyes, was recently found to have a hydrogen-bonded polar structure in a crystalline state. Here we demonstrate that application of an electric field can coherently align the molecular polarities in crystalline croconic acid, as indicated by an increase of optical second harmonic generation, and produce a well-defined polarization hysteresis at room temperature. To make this simple pentagonal molecule ferroelectric, we switched the pi-bond topology using synchronized proton transfer instead of rigid-body rotation. Of the organic ferroelectrics, this molecular crystal exhibits the highest spontaneous polarization ( approximately 20 muC cm(-2)) in spite of its small molecular size, which is in accord with first-principles electronic-structure calculations. Such high polarization, which persists up to 400 K, may find application in active capacitor and nonlinear optics elements in future organic electronics.

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Direct mass measurements above uranium bridge the gap to the island of stability.

Publication Date: 2010 Feb 11 PMID: 20148034
Authors: Block, M. - Ackermann, D. - Blaum, K. - Droese, C. - Dworschak, M. - Eliseev, S. - Fleckenstein, T. - Haettner, E. - Herfurth, F. - Hessberger, F. P. - Hofmann, S. - Ketelaer, J. - Ketter, J. - Kluge, H. J. - Marx, G. - Mazzocco, M. - Novikov, Y. N. - Plass, W. R. - Popeko, A. - Rahaman, S. - Rodriguez, D. - Scheidenberger, C. - Schweikhard, L. - Thirolf, P. G. - Vorobyev, G. K. - Weber, C.
Journal: Nature

The mass of an atom incorporates all its constituents and their interactions. The difference between the mass of an atom and the sum of its building blocks (the binding energy) is a manifestation of Einstein's famous relation E = mc(2). The binding energy determines the energy available for nuclear reactions and decays (and thus the creation of elements by stellar nucleosynthesis), and holds the key to the fundamental question of how heavy the elements can be. Superheavy elements have been observed in challenging production experiments, but our present knowledge of the binding energy of these nuclides is based only on the detection of their decay products. The reconstruction from extended decay chains introduces uncertainties that render the interpretation difficult. Here we report direct mass measurements of trans-uranium nuclides. Located at the farthest tip of the actinide species on the proton number-neutron number diagram, these nuclides represent the gateway to the predicted island of stability. In particular, we have determined the mass values of (252-254)No (atomic number 102) with the Penning trap mass spectrometer SHIPTRAP. The uncertainties are of the order of 10 keV/c(2) (representing a relative precision of 0.05 p.p.m.), despite minute production rates of less than one atom per second. Our experiments advance direct mass measurements by ten atomic numbers with no loss in accuracy, and provide reliable anchor points en route to the island of stability.

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High molecular gas fractions in normal massive star-forming galaxies in the young Universe.

Publication Date: 2010 Feb 11 PMID: 20148033
Authors: Tacconi, L. J. - Genzel, R. - Neri, R. - Cox, P. - Cooper, M. C. - Shapiro, K. - Bolatto, A. - Bouche, N. - Bournaud, F. - Burkert, A. - Combes, F. - Comerford, J. - Davis, M. - Schreiber, N. M. - Garcia-Burillo, S. - Gracia-Carpio, J. - Lutz, D. - Naab, T. - Omont, A. - Shapley, A. - Sternberg, A. - Weiner, B.
Journal: Nature

Stars form from cold molecular interstellar gas. As this is relatively rare in the local Universe, galaxies like the Milky Way form only a few new stars per year. Typical massive galaxies in the distant Universe formed stars an order of magnitude more rapidly. Unless star formation was significantly more efficient, this difference suggests that young galaxies were much more molecular-gas rich. Molecular gas observations in the distant Universe have so far largely been restricted to very luminous, rare objects, including mergers and quasars, and accordingly we do not yet have a clear idea about the gas content of more normal (albeit massive) galaxies. Here we report the results of a survey of molecular gas in samples of typical massive-star-forming galaxies at mean redshifts of about 1.2 and 2.3, when the Universe was respectively 40% and 24% of its current age. Our measurements reveal that distant star forming galaxies were indeed gas rich, and that the star formation efficiency is not strongly dependent on cosmic epoch. The average fraction of cold gas relative to total galaxy baryonic mass at z = 2.3 and z = 1.2 is respectively about 44% and 34%, three to ten times higher than in today's massive spiral galaxies. The slow decrease between z approximately 2 and z approximately 1 probably requires a mechanism of semi-continuous replenishment of fresh gas to the young galaxies.

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Rfx6 directs islet formation and insulin production in mice and humans.

Publication Date: 2010 Feb 11 PMID: 20148032
Authors: Smith, S. B. - Qu, H. Q. - Taleb, N. - Kishimoto, N. Y. - Scheel, D. W. - Lu, Y. - Patch, A. M. - Grabs, R. - Wang, J. - Lynn, F. C. - Miyatsuka, T. - Mitchell, J. - Seerke, R. - Desir, J. - Eijnden, S. V. - Abramowicz, M. - Kacet, N. - Weill, J. - Renard, M. E. - Gentile, M. - Hansen, I. - Dewar, K. - Hattersley, A. T. - Wang, R. - Wilson, M. E. - Johnson, J. D. - Polychronakos, C. - German, M. S.
Journal: Nature

Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.

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Neural bases for addictive properties of benzodiazepines.

Publication Date: 2010 Feb 11 PMID: 20148031
Authors: Tan, K. R. - Brown, M. - Labouebe, G. - Yvon, C. - Creton, C. - Fritschy, J. M. - Rudolph, U. - Luscher, C.
Journal: Nature

Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.

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Genome sequencing and analysis of the model grass Brachypodium distachyon.

Publication Date: 2010 Feb 11 PMID: 20148030
Authors:
Journal: Nature

Three subfamilies of grasses, the Ehrhartoideae, Panicoideae and Pooideae, provide the bulk of human nutrition and are poised to become major sources of renewable energy. Here we describe the genome sequence of the wild grass Brachypodium distachyon (Brachypodium), which is, to our knowledge, the first member of the Pooideae subfamily to be sequenced. Comparison of the Brachypodium, rice and sorghum genomes shows a precise history of genome evolution across a broad diversity of the grasses, and establishes a template for analysis of the large genomes of economically important pooid grasses such as wheat. The high-quality genome sequence, coupled with ease of cultivation and transformation, small size and rapid life cycle, will help Brachypodium reach its potential as an important model system for developing new energy and food crops.

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Ancient human genome sequence of an extinct Palaeo-Eskimo.

Publication Date: 2010 Feb 11 PMID: 20148029
Authors: Rasmussen, M. - Li, Y. - Lindgreen, S. - Pedersen, J. S. - Albrechtsen, A. - Moltke, I. - Metspalu, M. - Metspalu, E. - Kivisild, T. - Gupta, R. - Bertalan, M. - Nielsen, K. - Gilbert, M. T. - Wang, Y. - Raghavan, M. - Campos, P. F. - Kamp, H. M. - Wilson, A. S. - Gledhill, A. - Tridico, S. - Bunce, M. - Lorenzen, E. D. - Binladen, J. - Guo, X. - Zhao, J. - Zhang, X. - Zhang, H. - Li, Z. - Chen, M. - Orlando, L. - Kristiansen, K. - Bak, M. - Tommerup, N. - Bendixen, C. - Pierre, T. L. - Gronnow, B. - Meldgaard, M. - Andreasen, C. - Fedorova, S. A. - Osipova, L. P. - Higham, T. F. - Ramsey, C. B. - Hansen, T. V. - Nielsen, F. C. - Crawford, M. H. - Brunak, S. - Sicheritz-Ponten, T. - Villems, R. - Nielsen, R. - Krogh, A. - Wang, J. - Willerslev, E.
Journal: Nature

We report here the genome sequence of an ancient human. Obtained from approximately 4,000-year-old permafrost-preserved hair, the genome represents a male individual from the first known culture to settle in Greenland. Sequenced to an average depth of 20x, we recover 79% of the diploid genome, an amount close to the practical limit of current sequencing technologies. We identify 353,151 high-confidence single-nucleotide polymorphisms (SNPs), of which 6.8% have not been reported previously. We estimate raw read contamination to be no higher than 0.8%. We use functional SNP assessment to assign possible phenotypic characteristics of the individual that belonged to a culture whose location has yielded only trace human remains. We compare the high-confidence SNPs to those of contemporary populations to find the populations most closely related to the individual. This provides evidence for a migration from Siberia into the New World some 5,500 years ago, independent of that giving rise to the modern Native Americans and Inuit.

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The next generation of scenarios for climate change research and assessment.

Publication Date: 2010 Feb 11 PMID: 20148028
Authors: Moss, R. H. - Edmonds, J. A. - Hibbard, K. A. - Manning, M. R. - Rose, S. K. - van Vuuren, D. P. - Carter, T. R. - Emori, S. - Kainuma, M. - Kram, T. - Meehl, G. A. - Mitchell, J. F. - Nakicenovic, N. - Riahi, K. - Smith, S. J. - Stouffer, R. J. - Thomson, A. M. - Weyant, J. P. - Wilbanks, T. J.
Journal: Nature

Advances in the science and observation of climate change are providing a clearer understanding of the inherent variability of Earth's climate system and its likely response to human and natural influences. The implications of climate change for the environment and society will depend not only on the response of the Earth system to changes in radiative forcings, but also on how humankind responds through changes in technology, economies, lifestyle and policy. Extensive uncertainties exist in future forcings of and responses to climate change, necessitating the use of scenarios of the future to explore the potential consequences of different response options. To date, such scenarios have not adequately examined crucial possibilities, such as climate change mitigation and adaptation, and have relied on research processes that slowed the exchange of information among physical, biological and social scientists. Here we describe a new process for creating plausible scenarios to investigate some of the most challenging and important questions about climate change confronting the global community.

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Astrophysics: Less greedy galaxies gulp gas.

Publication Date: 2010 Feb 11 PMID: 20148027
Authors: Blain, A.
Journal: Nature

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Parkinson's disease: Mitochondrial damage control.

Publication Date: 2010 Feb 11 PMID: 20148026
Authors: Abeliovich, A.
Journal: Nature

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Neuroscience: Lack of inhibition leads to abuse.

Publication Date: 2010 Feb 11 PMID: 20148025
Authors: Riegel, A. C. - Kalivas, P. W.
Journal: Nature

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Cosmology: Census at a distance.

Publication Date: 2010 Feb 11 PMID: 20148024
Authors: Lopes, A.
Journal: Nature

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Palaeontology: Decay distorts ancestry.

Publication Date: 2010 Feb 11 PMID: 20148023
Authors: Briggs, D. E.
Journal: Nature

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Nuclear physics: Weighing up the superheavies.

Publication Date: 2010 Feb 11 PMID: 20148021
Authors: Bollen, G.
Journal: Nature

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Evolutionary biology: Face of the past reconstructed.

Publication Date: 2010 Feb 11 PMID: 20148020
Authors: Lambert, D. M. - Huynen, L.
Journal: Nature

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Q&A: Carl Zimmer on writing popular-science books. Interview by Nicola Jones.

Publication Date: 2010 Feb 11 PMID: 20148019
Authors: Zimmer, C.
Journal: Nature

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AIDS research must link to local policy.

Publication Date: 2010 Feb 11 PMID: 20148015
Authors: Karim, S. S. - Karim, Q. A.
Journal: Nature

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IPCC: cherish it, tweak it or scrap it?

Publication Date: 2010 Feb 11 PMID: 20148014
Authors:
Journal: Nature

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Still a way to go for South Africa's science revolution.

Publication Date: 2010 Feb 11 PMID: 20148013
Authors: Pouris, A.
Journal: Nature

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Italy's stem-cell challenge gaining momentum.

Publication Date: 2010 Feb 11 PMID: 20148012
Authors: Cattaneo, E. - Cerbai, E. - Garagna, S.
Journal: Nature

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Iranian physics society striving to prevent misconduct.

Publication Date: 2010 Feb 11 PMID: 20148011
Authors: Akbarzadeh, H.
Journal: Nature

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Did the bunny sell or sully the story on toxicity testing?

Publication Date: 2010 Feb 11 PMID: 20148010
Authors: Backmann, J.
Journal: Nature

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South African science: black, white and grey.

Publication Date: 2010 Feb 11 PMID: 20148009
Authors: Cherry, M.
Journal: Nature

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Palaeogenetics: Icy resolve.

Publication Date: 2010 Feb 11 PMID: 20148008
Authors: Dalton, R.
Journal: Nature

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The future of European research.

Publication Date: 2010 Feb 11 PMID: 20148007
Authors: Abbott, A.
Journal: Nature

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Delays prompt reshuffle at ITER fusion project.

Publication Date: 2010 Feb 11 PMID: 20148006
Authors: Brumfiel, G.
Journal: Nature

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Testing time for stem cells.

Publication Date: 2010 Feb 11 PMID: 20148005
Authors: Baker, M.
Journal: Nature

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Still looking for that woodpecker.

Publication Date: 2010 Feb 11 PMID: 20148004
Authors: Dalton, R.
Journal: Nature

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Science lines up for seat to space.

Publication Date: 2010 Feb 11 PMID: 20148003
Authors: Sanderson, K.
Journal: Nature

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Journal club. A computational geneticist looks at mechanisms of chromosomal evolution.

Publication Date: 2010 Feb 11 PMID: 20147997
Authors: Flicek, P.
Journal: Nature

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A framework for success.

Publication Date: 2010 Feb 11 PMID: 20147991
Authors:
Journal: Nature

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Divide and conquer.

Publication Date: 2010 Feb 11 PMID: 20147990
Authors:
Journal: Nature

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South Africa's opportunity.

Publication Date: 2010 Feb 11 PMID: 20147989
Authors:
Journal: Nature

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Chronic DLL4 blockade induces vascular neoplasms.

Publication Date: 2010 Feb 11 PMID: 20147986
Authors: Yan, M. - Callahan, C. A. - Beyer, J. C. - Allamneni, K. P. - Zhang, G. - Ridgway, J. B. - Niessen, K. - Plowman, G. D.
Journal: Nature

Delta-like 4 (DLL4)-mediated Notch signalling has emerged as an attractive target for cancer therapy. However, the potential side effects of blocking this pathway remain uncertain. Here we show that chronic DLL4 blockade causes pathological activation of endothelial cells, disrupts normal organ homeostasis and induces vascular tumours, raising important safety concerns.

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Arthropod relationships revealed by phylogenomic analysis of nuclear protein-coding sequences.

Publication Date: 2010 Feb 25 PMID: 20147900
Authors: Regier, J. C. - Shultz, J. W. - Zwick, A. - Hussey, A. - Ball, B. - Wetzer, R. - Martin, J. W. - Cunningham, C. W.
Journal: Nature

The remarkable antiquity, diversity and ecological significance of arthropods have inspired numerous attempts to resolve their deep phylogenetic history, but the results of two decades of intensive molecular phylogenetics have been mixed. The discovery that terrestrial insects (Hexapoda) are more closely related to aquatic Crustacea than to the terrestrial centipedes and millipedes (Myriapoda) was an early, if exceptional, success. More typically, analyses based on limited samples of taxa and genes have generated results that are inconsistent, weakly supported and highly sensitive to analytical conditions. Here we present strongly supported results from likelihood, Bayesian and parsimony analyses of over 41 kilobases of aligned DNA sequence from 62 single-copy nuclear protein-coding genes from 75 arthropod species. These species represent every major arthropod lineage, plus five species of tardigrades and onychophorans as outgroups. Our results strongly support Pancrustacea (Hexapoda plus Crustacea) but also strongly favour the traditional morphology-based Mandibulata (Myriapoda plus Pancrustacea) over the molecule-based Paradoxopoda (Myriapoda plus Chelicerata). In addition to Hexapoda, Pancrustacea includes three major extant lineages of 'crustaceans', each spanning a significant range of morphological disparity. These are Oligostraca (ostracods, mystacocarids, branchiurans and pentastomids), Vericrustacea (malacostracans, thecostracans, copepods and branchiopods) and Xenocarida (cephalocarids and remipedes). Finally, within Pancrustacea we identify Xenocarida as the long-sought sister group to the Hexapoda, a result confirming that 'crustaceans' are not monophyletic. These results provide a statistically well-supported phylogenetic framework for the largest animal phylum and represent a step towards ending the often-heated, century-long debate on arthropod relationships.

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Tbx3 improves the germ-line competency of induced pluripotent stem cells.

Publication Date: 2010 Feb 25 PMID: 20139965
Authors: Han, J. - Yuan, P. - Yang, H. - Zhang, J. - Soh, B. S. - Li, P. - Lim, S. L. - Cao, S. - Tay, J. - Orlov, Y. L. - Lufkin, T. - Ng, H. H. - Tam, W. L. - Lim, B.
Journal: Nature

Induced pluripotent stem (iPS) cells can be obtained by the introduction of defined factors into somatic cells. The combination of Oct4 (also known as Pou5f1), Sox2 and Klf4 (which we term OSK) constitutes the minimal requirement for generating iPS cells from mouse embryonic fibroblasts. These cells are thought to resemble embryonic stem cells (ESCs) on the basis of global gene expression analyses; however, few studies have tested the ability and efficiency of iPS cells to contribute to chimaerism, colonization of germ tissues, and most importantly, germ-line transmission and live birth from iPS cells produced by tetraploid complementation. Using genomic analyses of ESC genes that have roles in pluripotency and fusion-mediated somatic cell reprogramming, here we show that the transcription factor Tbx3 significantly improves the quality of iPS cells. iPS cells generated with OSK and Tbx3 (OSKT) are superior in both germ-cell contribution to the gonads and germ-line transmission frequency. However, global gene expression profiling could not distinguish between OSK and OSKT iPS cells. Genome-wide chromatin immunoprecipitation sequencing analysis of Tbx3-binding sites in ESCs suggests that Tbx3 regulates pluripotency-associated and reprogramming factors, in addition to sharing many common downstream regulatory targets with Oct4, Sox2, Nanog and Smad1. This study underscores the intrinsic qualitative differences between iPS cells generated by different methods, and highlights the need to rigorously characterize iPS cells beyond in vitro studies.

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Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin.

Publication Date: 2010 Feb 18 PMID: 20139964
Authors: Liu, X. - Yang, P. S. - Yang, W. - Yue, D. T.
Journal: Nature

Ca(2+) channels and calmodulin (CaM) are two prominent signalling hubs that synergistically affect functions as diverse as cardiac excitability, synaptic plasticity and gene transcription. It is therefore fitting that these hubs are in some sense coordinated, as the opening of Ca(V)1-2 Ca(2+) channels are regulated by a single CaM constitutively complexed with channels. The Ca(2+)-free form of CaM (apoCaM) is already pre-associated with the isoleucine-glutamine (IQ) domain on the channel carboxy terminus, and subsequent Ca(2+) binding to this 'resident' CaM drives conformational changes that then trigger regulation of channel opening. Another potential avenue for channel-CaM coordination could arise from the absence of Ca(2+) regulation in channels lacking a pre-associated CaM. Natural fluctuations in CaM concentrations might then influence the fraction of regulable channels and, thereby, the overall strength of Ca(2+) feedback. However, the prevailing view has been that the ultrastrong affinity of channels for apoCaM ensures their saturation with CaM, yielding a significant form of concentration independence between Ca(2+) channels and CaM. Here we show that significant exceptions to this autonomy exist, by combining electrophysiology (to characterize channel regulation) with optical fluorescence resonance energy transfer (FRET) sensor determination of free-apoCaM concentration in live cells. This approach translates quantitative CaM biochemistry from the traditional test-tube context into the realm of functioning holochannels within intact cells. From this perspective, we find that long splice forms of Ca(V)1.3 and Ca(V)1.4 channels include a distal carboxy tail that resembles an enzyme competitive inhibitor that retunes channel affinity for apoCaM such that natural CaM variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels, the connection between ambient CaM levels and Ca(2+) entry through channels is broadly significant for Ca(2+) homeostasis. Strategies such as ours promise key advances for the in situ analysis of signalling molecules resistant to in vitro reconstitution, such as Ca(2+) channels.

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Organic-walled microfossils in 3.2-billion-year-old shallow-marine siliciclastic deposits.

Publication Date: 2010 Feb 18 PMID: 20139963
Authors: Javaux, E. J. - Marshall, C. P. - Bekker, A.
Journal: Nature

Although the notion of an early origin and diversification of life on Earth during the Archaean eon has received increasing support in geochemical, sedimentological and palaeontological evidence, ambiguities and controversies persist regarding the biogenicity and syngeneity of the record older than Late Archaean. Non-biological processes are known to produce morphologies similar to some microfossils, and hydrothermal fluids have the potential to produce abiotic organic compounds with depleted carbon isotope values, making it difficult to establish unambiguous traces of life. Here we report the discovery of a population of large (up to about 300 mum in diameter) carbonaceous spheroidal microstructures in Mesoarchaean shales and siltstones of the Moodies Group, South Africa, the Earth's oldest siliciclastic alluvial to tidal-estuarine deposits. These microstructures are interpreted as organic-walled microfossils on the basis of petrographic and geochemical evidence for their endogenicity and syngeneity, their carbonaceous composition, cellular morphology and ultrastructure, occurrence in populations, taphonomic features of soft wall deformation, and the geological context plausible for life, as well as a lack of abiotic explanation falsifying a biological origin. These are the oldest and largest Archaean organic-walled spheroidal microfossils reported so far. Our observations suggest that relatively large microorganisms cohabited with earlier reported benthic microbial mats in the photic zone of marginal marine siliciclastic environments 3.2 billion years ago.

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CHD7 cooperates with PBAF to control multipotent neural crest formation.

Publication Date: 2010 Feb 18 PMID: 20130577
Authors: Bajpai, R. - Chen, D. A. - Rada-Iglesias, A. - Zhang, J. - Xiong, Y. - Helms, J. - Chang, C. P. - Zhao, Y. - Swigut, T. - Wysocka, J.
Journal: Nature

Heterozygous mutations in the gene encoding the CHD (chromodomain helicase DNA-binding domain) member CHD7, an ATP-dependent chromatin remodeller homologous to the Drosophila trithorax-group protein Kismet, result in a complex constellation of congenital anomalies called CHARGE syndrome, which is a sporadic, autosomal dominant disorder characterized by malformations of the craniofacial structures, peripheral nervous system, ears, eyes and heart. Although it was postulated 25 years ago that CHARGE syndrome results from the abnormal development of the neural crest, this hypothesis remained untested. Here we show that, in both humans and Xenopus, CHD7 is essential for the formation of multipotent migratory neural crest (NC), a transient cell population that is ectodermal in origin but undergoes a major transcriptional reprogramming event to acquire a remarkably broad differentiation potential and ability to migrate throughout the body, giving rise to craniofacial bones and cartilages, the peripheral nervous system, pigmentation and cardiac structures. We demonstrate that CHD7 is essential for activation of the NC transcriptional circuitry, including Sox9, Twist and Slug. In Xenopus embryos, knockdown of Chd7 or overexpression of its catalytically inactive form recapitulates all major features of CHARGE syndrome. In human NC cells CHD7 associates with PBAF (polybromo- and BRG1-associated factor-containing complex) and both remodellers occupy a NC-specific distal SOX9 enhancer and a conserved genomic element located upstream of the TWIST1 gene. Consistently, during embryogenesis CHD7 and PBAF cooperate to promote NC gene expression and cell migration. Our work identifies an evolutionarily conserved role for CHD7 in orchestrating NC gene expression programs, provides insights into the synergistic control of distal elements by chromatin remodellers, illuminates the patho-embryology of CHARGE syndrome, and suggests a broader function for CHD7 in the regulation of cell motility.

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Odorant reception in the malaria mosquito Anopheles gambiae.

Publication Date: 2010 Mar 4 PMID: 20130575
Authors: Carey, A. F. - Wang, G. - Su, C. Y. - Zwiebel, L. J. - Carlson, J. R.
Journal: Nature

The mosquito Anopheles gambiae is the major vector of malaria in sub-Saharan Africa. It locates its human hosts primarily through olfaction, but little is known about the molecular basis of this process. Here we functionally characterize the Anopheles gambiae odorant receptor (AgOr) repertoire. We identify receptors that respond strongly to components of human odour and that may act in the process of human recognition. Some of these receptors are narrowly tuned, and some salient odorants elicit strong responses from only one or a few receptors, suggesting a central role for specific transmission channels in human host-seeking behaviour. This analysis of the Anopheles gambiae receptors permits a comparison with the corresponding Drosophila melanogaster odorant receptor repertoire. We find that odorants are differentially encoded by the two species in ways consistent with their ecological needs. Our analysis of the Anopheles gambiae repertoire identifies receptors that may be useful targets for controlling the transmission of malaria.

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Ancient animal microRNAs and the evolution of tissue identity.

Publication Date: 2010 Feb 25 PMID: 20118916
Authors: Christodoulou, F. - Raible, F. - Tomer, R. - Simakov, O. - Trachana, K. - Klaus, S. - Snyman, H. - Hannon, G. J. - Bork, P. - Arendt, D.
Journal: Nature

The spectacular escalation in complexity in early bilaterian evolution correlates with a strong increase in the number of microRNAs. To explore the link between the birth of ancient microRNAs and body plan evolution, we set out to determine the ancient sites of activity of conserved bilaterian microRNA families in a comparative approach. We reason that any specific localization shared between protostomes and deuterostomes (the two major superphyla of bilaterian animals) should probably reflect an ancient specificity of that microRNA in their last common ancestor. Here, we investigate the expression of conserved bilaterian microRNAs in Platynereis dumerilii, a protostome retaining ancestral bilaterian features, in Capitella, another marine annelid, in the sea urchin Strongylocentrotus, a deuterostome, and in sea anemone Nematostella, representing an outgroup to the bilaterians. Our comparative data indicate that the oldest known animal microRNA, miR-100, and the related miR-125 and let-7 were initially active in neurosecretory cells located around the mouth. Other sets of ancient microRNAs were first present in locomotor ciliated cells, specific brain centres, or, more broadly, one of four major organ systems: central nervous system, sensory tissue, musculature and gut. These findings reveal that microRNA evolution and the establishment of tissue identities were closely coupled in bilaterian evolution. Also, they outline a minimum set of cell types and tissues that existed in the protostome-deuterostome ancestor.

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Non-random decay of chordate characters causes bias in fossil interpretation.

Publication Date: 2010 Feb 11 PMID: 20118914
Authors: Sansom, R. S. - Gabbott, S. E. - Purnell, M. A.
Journal: Nature

Exceptional preservation of soft-bodied Cambrian chordates provides our only direct information on the origin of vertebrates. Fossil chordates from this interval offer crucial insights into how the distinctive body plan of vertebrates evolved, but reading this pre-biomineralization fossil record is fraught with difficulties, leading to controversial and contradictory interpretations. The cause of these difficulties is taphonomic: we lack data on when and how important characters change as they decompose, resulting in a lack of constraint on anatomical interpretation and a failure to distinguish phylogenetic absence of characters from loss through decay. Here we show, from experimental decay of amphioxus and ammocoetes, that loss of chordate characters during decay is non-random: the more phylogenetically informative are the most labile, whereas plesiomorphic characters are decay resistant. The taphonomic loss of synapomorphies and relatively higher preservation potential of chordate plesiomorphies will thus result in bias towards wrongly placing fossils on the chordate stem. Application of these data to Cathaymyrus (Cambrian period of China) and Metaspriggina (Cambrian period of Canada) highlights the difficulties: these fossils cannot be placed reliably in the chordate or vertebrate stem because they could represent the decayed remains of any non-biomineralized, total-group chordate. Preliminary data suggest that this decay filter also affects other groups of organisms and that 'stem-ward slippage' may be a widespread but currently unrecognized bias in our understanding of the early evolution of a number of phyla.

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Fossilized melanosomes and the colour of Cretaceous dinosaurs and birds.

Publication Date: 2010 Feb 25 PMID: 20107440
Authors: Zhang, F. - Kearns, S. L. - Orr, P. J. - Benton, M. J. - Zhou, Z. - Johnson, D. - Xu, X. - Wang, X.
Journal: Nature

Spectacular fossils from the Early Cretaceous Jehol Group of northeastern China have greatly expanded our knowledge of the diversity and palaeobiology of dinosaurs and early birds, and contributed to our understanding of the origin of birds, of flight, and of feathers. Pennaceous (vaned) feathers and integumentary filaments are preserved in birds and non-avian theropod dinosaurs, but little is known of their microstructure. Here we report that melanosomes (colour-bearing organelles) are not only preserved in the pennaceous feathers of early birds, but also in an identical manner in integumentary filaments of non-avian dinosaurs, thus refuting recent claims that the filaments are partially decayed dermal collagen fibres. Examples of both eumelanosomes and phaeomelanosomes have been identified, and they are often preserved in life position within the structure of partially degraded feathers and filaments. Furthermore, the data here provide empirical evidence for reconstructing the colours and colour patterning of these extinct birds and theropod dinosaurs: for example, the dark-coloured stripes on the tail of the theropod dinosaur Sinosauropteryx can reasonably be inferred to have exhibited chestnut to reddish-brown tones.

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Direct conversion of fibroblasts to functional neurons by defined factors.

Publication Date: 2010 Feb 25 PMID: 20107439
Authors: Vierbuchen, T. - Ostermeier, A. - Pang, Z. P. - Kokubu, Y. - Sudhof, T. C. - Wernig, M.
Journal: Nature

Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.

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Animal cryptochromes mediate magnetoreception by an unconventional photochemical mechanism.

Publication Date: 2010 Feb 11 PMID: 20098414
Authors: Gegear, R. J. - Foley, L. E. - Casselman, A. - Reppert, S. M.
Journal: Nature

Understanding the biophysical basis of animal magnetoreception has been one of the greatest challenges in sensory biology. Recently it was discovered that the light-dependent magnetic sense of Drosophila melanogaster is mediated by the ultraviolet (UV)-A/blue light photoreceptor cryptochrome (Cry). Here we show, using a transgenic approach, that the photoreceptive, Drosophila-like type 1 Cry and the transcriptionally repressive, vertebrate-like type 2 Cry of the monarch butterfly (Danaus plexippus) can both function in the magnetoreception system of Drosophila and require UV-A/blue light (wavelength below 420 nm) to do so. The lack of magnetic responses for both Cry types at wavelengths above 420 nm does not fit the widely held view that tryptophan triad-generated radical pairs mediate the ability of Cry to sense a magnetic field. We bolster this assessment by using a mutant form of Drosophila and monarch type 1 Cry and confirm that the tryptophan triad pathway is not crucial in magnetic transduction. Together, these results suggest that animal Crys mediate light-dependent magnetoreception through an unconventional photochemical mechanism. This work emphasizes the utility of Drosophila transgenesis for elucidating the precise mechanisms of Cry-mediated magnetosensitivity in insects and also in vertebrates such as migrating birds.

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A bony connection signals laryngeal echolocation in bats.

Publication Date: 2010 Feb 18 PMID: 20098413
Authors: Veselka, N. - McErlain, D. D. - Holdsworth, D. W. - Eger, J. L. - Chhem, R. K. - Mason, M. J. - Brain, K. L. - Faure, P. A. - Fenton, M. B.
Journal: Nature

Echolocation is an active form of orientation in which animals emit sounds and then listen to reflected echoes of those sounds to form images of their surroundings in their brains. Although echolocation is usually associated with bats, it is not characteristic of all bats. Most echolocating bats produce signals in the larynx, but within one family of mainly non-echolocating species (Pteropodidae), a few species use echolocation sounds produced by tongue clicks. Here we demonstrate, using data obtained from micro-computed tomography scans of 26 species (n = 35 fluid-preserved bats), that proximal articulation of the stylohyal bone (part of the mammalian hyoid apparatus) with the tympanic bone always distinguishes laryngeally echolocating bats from all other bats (that is, non-echolocating pteropodids and those that echolocate with tongue clicks). In laryngeally echolocating bats, the proximal end of the stylohyal bone directly articulates with the tympanic bone and is often fused with it. Previous research on the morphology of the stylohyal bone in the oldest known fossil bat (Onychonycteris finneyi) suggested that it did not echolocate, but our findings suggest that O. finneyi may have used laryngeal echolocation because its stylohyal bones may have articulated with its tympanic bones. The present findings reopen basic questions about the timing and the origin of flight and echolocation in the early evolution of bats. Our data also provide an independent anatomical character by which to distinguish laryngeally echolocating bats from other bats.

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Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency.

Publication Date: 2010 Feb 25 PMID: 20098412
Authors: Popp, C. - Dean, W. - Feng, S. - Cokus, S. J. - Andrews, S. - Pellegrini, M. - Jacobsen, S. E. - Reik, W.
Journal: Nature

Epigenetic reprogramming including demethylation of DNA occurs in mammalian primordial germ cells (PGCs) and in early embryos, and is important for the erasure of imprints and epimutations, and the return to pluripotency. The extent of this reprogramming and its molecular mechanisms are poorly understood. We previously showed that the cytidine deaminases AID and APOBEC1 can deaminate 5-methylcytosine in vitro and in Escherichia coli, and in the mouse are expressed in tissues in which demethylation occurs. Here we profiled DNA methylation throughout the genome by unbiased bisulphite next generation sequencing in wild-type and AID-deficient mouse PGCs at embryonic day (E)13.5. Wild-type PGCs revealed marked genome-wide erasure of methylation to a level below that of methylation deficient (Np95(-/-), also called Uhrf1(-/-)) embryonic stem cells, with female PGCs being less methylated than male ones. By contrast, AID-deficient PGCs were up to three times more methylated than wild-type ones; this substantial difference occurred throughout the genome, with introns, intergenic regions and transposons being relatively more methylated than exons. Relative hypermethylation in AID-deficient PGCs was confirmed by analysis of individual loci in the genome. Our results reveal that erasure of DNA methylation in the germ line is a global process, hence limiting the potential for transgenerational epigenetic inheritance. AID deficiency interferes with genome-wide erasure of DNA methylation patterns, indicating that AID has a critical function in epigenetic reprogramming and potentially in restricting the inheritance of epimutations in mammals.

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Competition drives cooperation among closely related sperm of deer mice.

Publication Date: 2010 Feb 11 PMID: 20090679
Authors: Fisher, H. S. - Hoekstra, H. E.
Journal: Nature

Among the extraordinary adaptations driven by sperm competition is the cooperative behaviour of spermatozoa. By forming cooperative groups, sperm can increase their swimming velocity and thereby gain an advantage in intermale sperm competition. Accordingly, selection should favour cooperation of the most closely related sperm to maximize fitness. Here we show that sperm of deer mice (genus Peromyscus) form motile aggregations, then we use this system to test predictions of sperm cooperation. We find that sperm aggregate more often with conspecific than heterospecific sperm, suggesting that individual sperm can discriminate on the basis of genetic relatedness. Next, we provide evidence that the cooperative behaviour of closely related sperm is driven by sperm competition. In a monogamous species lacking sperm competition, Peromyscus polionotus, sperm indiscriminately group with unrelated conspecific sperm. In contrast, in the highly promiscuous deer mouse, Peromyscus maniculatus, sperm are significantly more likely to aggregate with those obtained from the same male than with sperm from an unrelated conspecific donor. Even when we test sperm from sibling males, we continue to see preferential aggregations of related sperm in P. maniculatus. These results suggest that sperm from promiscuous deer mice discriminate among relatives and thereby cooperate with the most closely related sperm, an adaptation likely to have been driven by sperm competition.

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Mechanism of substrate recognition and transport by an amino acid antiporter.

Publication Date: 2010 Feb 11 PMID: 20090677
Authors: Gao, X. - Zhou, L. - Jiao, X. - Lu, F. - Yan, C. - Zeng, X. - Wang, J. - Shi, Y.
Journal: Nature

In extremely acidic environments, enteric bacteria such as Escherichia coli rely on the amino acid antiporter AdiC to expel protons by exchanging intracellular agmatine (Agm(2+)) for extracellular arginine (Arg(+)). AdiC is a representative member of the amino acid-polyamine-organocation (APC) superfamily of membrane transporters. The structure of substrate-free AdiC revealed a homodimeric assembly, with each protomer containing 12 transmembrane segments and existing in an outward-open conformation. The overall folding of AdiC is similar to that of the Na(+)-coupled symporters. Despite these advances, it remains unclear how the substrate (arginine or agmatine) is recognized and transported by AdiC. Here we report the crystal structure of an E. coli AdiC variant bound to Arg at 3.0 A resolution. The positively charged Arg is enclosed in an acidic binding chamber, with the head groups of Arg hydrogen-bonded to main chain atoms of AdiC and the aliphatic portion of Arg stacked by hydrophobic side chains of highly conserved residues. Arg binding induces pronounced structural rearrangement in transmembrane helix 6 (TM6) and, to a lesser extent, TM2 and TM10, resulting in an occluded conformation. Structural analysis identified three potential gates, involving four aromatic residues and Glu 208, which may work in concert to differentially regulate the upload and release of Arg and Agm.

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Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication.

Publication Date: 2010 Feb 11 PMID: 20081832
Authors: Karlas, A. - Machuy, N. - Shin, Y. - Pleissner, K. P. - Artarini, A. - Heuer, D. - Becker, D. - Khalil, H. - Ogilvie, L. A. - Hess, S. - Maurer, A. P. - Muller, E. - Wolff, T. - Rudel, T. - Meyer, T. F.
Journal: Nature

Influenza A virus, being responsible for seasonal epidemics and reoccurring pandemics, represents a worldwide threat to public health. High mutation rates facilitate the generation of viral escape mutants, rendering vaccines and drugs directed against virus-encoded targets potentially ineffective. In contrast, targeting host cell determinants temporarily dispensable for the host but crucial for virus replication could prevent viral escape. Here we report the discovery of 287 human host cell genes influencing influenza A virus replication in a genome-wide RNA interference (RNAi) screen. Using an independent assay we confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the current pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. Notably, a subset of these common hits was also essential for replication of a highly pathogenic avian H5N1 strain. In-depth analyses of several factors provided insights into their infection stage relevance. Notably, SON DNA binding protein (SON) was found to be important for normal trafficking of influenza virions to late endosomes early in infection. We also show that a small molecule inhibitor of CDC-like kinase 1 (CLK1) reduces influenza virus replication by more than two orders of magnitude, an effect connected with impaired splicing of the viral M2 messenger RNA. Furthermore, influenza-virus-infected p27(-/-) (cyclin-dependent kinase inhibitor 1B; Cdkn1b) mice accumulated significantly lower viral titres in the lung, providing in vivo evidence for the importance of this gene. Thus, our results highlight the potency of genome-wide RNAi screening for the dissection of virus-host interactions and the identification of drug targets for a broad range of influenza viruses.

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Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate.

Publication Date: 2010 Feb 11 PMID: 20072126
Authors: Zheng, Y. - Josefowicz, S. - Chaudhry, A. - Peng, X. P. - Forbush, K. - Rudensky, A. Y.
Journal: Nature

Immune homeostasis is dependent on tight control over the size of a population of regulatory T (T(reg)) cells capable of suppressing over-exuberant immune responses. The T(reg) cell subset is comprised of cells that commit to the T(reg) lineage by upregulating the transcription factor Foxp3 either in the thymus (tT(reg)) or in the periphery (iT(reg)). Considering a central role for Foxp3 in T(reg) cell differentiation and function, we proposed that conserved non-coding DNA sequence (CNS) elements at the Foxp3 locus encode information defining the size, composition and stability of the T(reg) cell population. Here we describe the function of three Foxp3 CNS elements (CNS1-3) in T(reg) cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of T(reg) cells generated in the thymus and the periphery, binds c-Rel in in vitro assays. In contrast, CNS1, which contains a TGF-beta-NFAT response element, is superfluous for tT(reg) cell differentiation, but has a prominent role in iT(reg) cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing T(reg) cells. Foxp3 binds to CNS2 in a Cbf-beta-Runx1 and CpG DNA demethylation-dependent manner, suggesting that Foxp3 recruitment to this 'cellular memory module' facilitates the heritable maintenance of the active state of the Foxp3 locus and, therefore, T(reg) lineage stability. Together, our studies demonstrate that the composition, size and maintenance of the T(reg) cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or -intrinsic cues.

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Human host factors required for influenza virus replication.

Publication Date: 2010 Feb 11 PMID: 20027183
Authors: Konig, R. - Stertz, S. - Zhou, Y. - Inoue, A. - Hoffmann, H. H. - Bhattacharyya, S. - Alamares, J. G. - Tscherne, D. M. - Ortigoza, M. B. - Liang, Y. - Gao, Q. - Andrews, S. E. - Bandyopadhyay, S. - De Jesus, P. - Tu, B. P. - Pache, L. - Shih, C. - Orth, A. - Bonamy, G. - Miraglia, L. - Ideker, T. - Garcia-Sastre, A. - Young, J. A. - Palese, P. - Shaw, M. L. - Chanda, S. K.
Journal: Nature

Influenza A virus is an RNA virus that encodes up to 11 proteins and this small coding capacity demands that the virus use the host cellular machinery for many aspects of its life cycle. Knowledge of these host cell requirements not only informs us of the molecular pathways exploited by the virus but also provides further targets that could be pursued for antiviral drug development. Here we use an integrative systems approach, based on genome-wide RNA interference screening, to identify 295 cellular cofactors required for early-stage influenza virus replication. Within this group, those involved in kinase-regulated signalling, ubiquitination and phosphatase activity are the most highly enriched, and 181 factors assemble into a highly significant host-pathogen interaction network. Moreover, 219 of the 295 factors were confirmed to be required for efficient wild-type influenza virus growth, and further analysis of a subset of genes showed 23 factors necessary for viral entry, including members of the vacuolar ATPase (vATPase) and COPI-protein families, fibroblast growth factor receptor (FGFR) proteins, and glycogen synthase kinase 3 (GSK3)-beta. Furthermore, 10 proteins were confirmed to be involved in post-entry steps of influenza virus replication. These include nuclear import components, proteases, and the calcium/calmodulin-dependent protein kinase (CaM kinase) IIbeta (CAMK2B). Notably, growth of swine-origin H1N1 influenza virus is also dependent on the identified host factors, and we show that small molecule inhibitors of several factors, including vATPase and CAMK2B, antagonize influenza virus replication.

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Reprogramming towards pluripotency requires AID-dependent DNA demethylation.

Publication Date: 2010 Feb 25 PMID: 20027182
Authors: Bhutani, N. - Brady, J. J. - Damian, M. - Sacco, A. - Corbel, S. Y. - Blau, H. M.
Journal: Nature

Reprogramming of somatic cell nuclei to yield induced pluripotent stem (iPS) cells makes possible derivation of patient-specific stem cells for regenerative medicine. However, iPS cell generation is asynchronous and slow (2-3 weeks), the frequency is low (<0.1%), and DNA demethylation constitutes a bottleneck. To determine regulatory mechanisms involved in reprogramming, we generated interspecies heterokaryons (fused mouse embryonic stem (ES) cells and human fibroblasts) that induce reprogramming synchronously, frequently and fast. Here we show that reprogramming towards pluripotency in single heterokaryons is initiated without cell division or DNA replication, rapidly (1 day) and efficiently (70%). Short interfering RNA (siRNA)-mediated knockdown showed that activation-induced cytidine deaminase (AID, also known as AICDA) is required for promoter demethylation and induction of OCT4 (also known as POU5F1) and NANOG gene expression. AID protein bound silent methylated OCT4 and NANOG promoters in fibroblasts, but not active demethylated promoters in ES cells. These data provide new evidence that mammalian AID is required for active DNA demethylation and initiation of nuclear reprogramming towards pluripotency in human somatic cells.

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