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Showing papers in "Nature in 2010"


Journal ArticleDOI
04 Mar 2010-Nature
TL;DR: 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 are described, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species.
Abstract: 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, ~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

9,268 citations


Journal ArticleDOI
28 Oct 2010-Nature
TL;DR: The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype as mentioned in this paper, and the results of the pilot phase of the project, designed to develop and compare different strategies for genomewide sequencing with high-throughput platforms.
Abstract: The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.

7,538 citations


Journal ArticleDOI
11 Feb 2010-Nature
TL;DR: A new process for creating plausible scenarios to investigate some of the most challenging and important questions about climate change confronting the global community is described.
Abstract: 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.

5,670 citations


Journal ArticleDOI
30 Sep 2010-Nature
TL;DR: The first worldwide synthesis to jointly consider human and biodiversity perspectives on water security using a spatial framework that quantifies multiple stressors and accounts for downstream impacts is presented.
Abstract: Protecting the world’s freshwater resources requires diagnosing threats over a broad range of scales, from global to local. Here we present the first worldwide synthesis to jointly consider human and biodiversity perspectives on water security using a spatial framework that quantifies multiple stressors and accounts for downstream impacts. We find that nearly 80% of the world’s population is exposed to high levels of threat to water security. Massive investment in water technology enables rich nations to offset high stressor levels without remedying their underlying causes, whereas less wealthy nations remain vulnerable. A similar lack of precautionary investment jeopardizes biodiversity, with habitats associated with 65% of continental discharge classified as moderately to highly threatened. The cumulative threat framework offers a tool for prioritizing policy and management responses to this crisis, and underscores the necessity of limiting threats at their source instead of through costly remediation of symptoms in order to assure global water security for both humans and freshwater biodiversity.

5,401 citations


Journal ArticleDOI
15 Apr 2010-Nature
TL;DR: It is shown that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression, indicating that l incRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
Abstract: Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.

4,605 citations


Journal ArticleDOI
14 Jan 2010-Nature
TL;DR: An accurate soybean genome sequence will facilitate the identification of the genetic basis of many soybean traits, and accelerate the creation of improved soybean varieties.
Abstract: Soybean (Glycine max) is one of the most important crop plants for seed protein and oil content, and for its capacity to fix atmospheric nitrogen through symbioses with soil-borne microorganisms. We sequenced the 1.1-gigabase genome by a whole-genome shotgun approach and integrated it with physical and high-density genetic maps to create a chromosome-scale draft sequence assembly. We predict 46,430 protein-coding genes, 70% more than Arabidopsis and similar to the poplar genome which, like soybean, is an ancient polyploid (palaeopolyploid). About 78% of the predicted genes occur in chromosome ends, which comprise less than one-half of the genome but account for nearly all of the genetic recombination. Genome duplications occurred at approximately 59 and 13 million years ago, resulting in a highly duplicated genome with nearly 75% of the genes present in multiple copies. The two duplication events were followed by gene diversification and loss, and numerous chromosome rearrangements. An accurate soybean genome sequence will facilitate the identification of the genetic basis of many soybean traits, and accelerate the creation of improved soybean varieties.

3,743 citations


Journal ArticleDOI
15 Apr 2010-Nature
TL;DR: In this paper, the authors develop a framework for understanding the robustness of interacting networks subject to cascading failures and present exact analytical solutions for the critical fraction of nodes that, on removal, will lead to a failure cascade and to a complete fragmentation of two interdependent networks.
Abstract: Complex networks have been studied intensively for a decade, but research still focuses on the limited case of a single, non-interacting network. Modern systems are coupled together and therefore should be modelled as interdependent networks. A fundamental property of interdependent networks is that failure of nodes in one network may lead to failure of dependent nodes in other networks. This may happen recursively and can lead to a cascade of failures. In fact, a failure of a very small fraction of nodes in one network may lead to the complete fragmentation of a system of several interdependent networks. A dramatic real-world example of a cascade of failures ('concurrent malfunction') is the electrical blackout that affected much of Italy on 28 September 2003: the shutdown of power stations directly led to the failure of nodes in the Internet communication network, which in turn caused further breakdown of power stations. Here we develop a framework for understanding the robustness of interacting networks subject to such cascading failures. We present exact analytical solutions for the critical fraction of nodes that, on removal, will lead to a failure cascade and to a complete fragmentation of two interdependent networks. Surprisingly, a broader degree distribution increases the vulnerability of interdependent networks to random failure, which is opposite to how a single network behaves. Our findings highlight the need to consider interdependent network properties in designing robust networks.

3,651 citations


Journal ArticleDOI
23 Dec 2010-Nature
TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Abstract: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

3,489 citations


Journal ArticleDOI
05 Aug 2010-Nature
TL;DR: The results identify several novel loci associated with plasma lipids that are also associated with CAD and provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Abstract: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

3,469 citations


Journal ArticleDOI
12 Aug 2010-Nature
TL;DR: In this paper, the authors used ribosome profiling to measure the overall effects on protein production and compare these to simultaneously measured effects on mRNA levels, showing that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output.
Abstract: MicroRNAs (miRNAs) are endogenous approximately 22-nucleotide RNAs that mediate important gene-regulatory events by pairing to the mRNAs of protein-coding genes to direct their repression. Repression of these regulatory targets leads to decreased translational efficiency and/or decreased mRNA levels, but the relative contributions of these two outcomes have been largely unknown, particularly for endogenous targets expressed at low-to-moderate levels. Here, we use ribosome profiling to measure the overall effects on protein production and compare these to simultaneously measured effects on mRNA levels. For both ectopic and endogenous miRNA regulatory interactions, lowered mRNA levels account for most (>/=84%) of the decreased protein production. These results show that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output.

3,401 citations


Journal ArticleDOI
Rameen Beroukhim, Craig H. Mermel1, Craig H. Mermel2, Dale Porter3, Guo Wei2, Soumya Raychaudhuri2, Soumya Raychaudhuri4, Jerry Donovan3, Jordi Barretina1, Jordi Barretina2, Jesse S. Boehm2, Jennifer Dobson1, Jennifer Dobson2, Mitsuyoshi Urashima5, Kevin T. Mc Henry3, Reid M. Pinchback2, Azra H. Ligon4, Yoon Jae Cho6, Leila Haery1, Leila Haery2, Heidi Greulich, Michael R. Reich2, Wendy Winckler2, Michael S. Lawrence2, Barbara A. Weir1, Barbara A. Weir2, Kumiko E. Tanaka1, Kumiko E. Tanaka2, Derek Y. Chiang7, Derek Y. Chiang1, Derek Y. Chiang2, Adam J. Bass2, Adam J. Bass1, Adam J. Bass4, Alice Loo3, Carter Hoffman1, Carter Hoffman2, John R. Prensner2, John R. Prensner1, Ted Liefeld2, Qing Gao2, Derek Yecies1, Sabina Signoretti1, Sabina Signoretti4, Elizabeth A. Maher8, Frederic J. Kaye, Hidefumi Sasaki9, Joel E. Tepper7, Jonathan A. Fletcher4, Josep Tabernero10, José Baselga10, Ming-Sound Tsao11, Francesca Demichelis12, Mark A. Rubin12, Pasi A. Jänne4, Pasi A. Jänne1, Mark J. Daly2, Mark J. Daly1, Carmelo Nucera13, Ross L. Levine14, Benjamin L. Ebert4, Benjamin L. Ebert2, Benjamin L. Ebert1, Stacey Gabriel2, Anil K. Rustgi15, Cristina R. Antonescu14, Marc Ladanyi14, Anthony Letai1, Levi A. Garraway1, Levi A. Garraway2, Massimo Loda1, Massimo Loda4, David G. Beer16, Lawrence D. True17, Aikou Okamoto5, Scott L. Pomeroy6, Samuel Singer14, Todd R. Golub18, Todd R. Golub2, Todd R. Golub1, Eric S. Lander1, Eric S. Lander2, Eric S. Lander19, Gad Getz2, William R. Sellers3, Matthew Meyerson2, Matthew Meyerson1 
18 Feb 2010-Nature
TL;DR: It is demonstrated that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival, and a large majority of SCNAs identified in individual cancer types are present in several cancer types.
Abstract: 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.

Journal ArticleDOI
28 Oct 2010-Nature
TL;DR: Radio timing observations of the binary millisecond pulsar J1614-2230 that show a strong Shapiro delay signature are presented and the pulsar mass is calculated to be (1.97 ± 0.04)M⊙, which rules out almost all currently proposed hyperon or boson condensate equations of state.
Abstract: Neutron stars comprise the densest form of matter known to exist in our Universe, but their composition and properties are uncertain. Measurements of their masses and radii can constrain theoretical predictions of their composition, but so far it has not been possible to rule out many predictions of 'exotic' non-nucleonic components. Here, radio timing observations of the binary millisecond pulsar J1614-2230 are presented, allowing almost all currently proposed hyperon or boson condensate equations of state to be ruled out.

Journal ArticleDOI
10 Mar 2010-Nature
TL;DR: This exotic behaviour of frustrated magnets is now being uncovered in the laboratory, providing insight into the properties of spin liquids and challenges to the theoretical description of these materials.
Abstract: Frustrated magnets are materials in which localized magnetic moments, or spins, interact through competing exchange interactions that cannot be simultaneously satisfied, giving rise to a large degeneracy of the system ground state. Under certain conditions, this can lead to the formation of fluid-like states of matter, so-called spin liquids, in which the constituent spins are highly correlated but still fluctuate strongly down to a temperature of absolute zero. The fluctuations of the spins in a spin liquid can be classical or quantum and show remarkable collective phenomena such as emergent gauge fields and fractional particle excitations. This exotic behaviour is now being uncovered in the laboratory, providing insight into the properties of spin liquids and challenges to the theoretical description of these materials.

Journal ArticleDOI
12 Aug 2010-Nature
TL;DR: It is demonstrated that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
Abstract: The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.

Journal ArticleDOI
18 Mar 2010-Nature
TL;DR: Shell-isolated nanoparticle-enhanced Raman spectroscopy is reported, in which the Raman signal amplification is provided by gold nanoparticles with an ultrathin silica or alumina shell, which significantly expands the flexibility of SERS for useful applications in the materials and life sciences, as well as for the inspection of food safety, drugs, explosives and environment pollutants.
Abstract: Surface-enhanced Raman scattering (SERS) is a powerful spectroscopy technique that can provide non-destructive and ultra-sensitive characterization down to single molecular level, comparable to single-molecule fluorescence spectroscopy. However, generally substrates based on metals such as Ag, Au and Cu, either with roughened surfaces or in the form of nanoparticles, are required to realise a substantial SERS effect, and this has severely limited the breadth of practical applications of SERS. A number of approaches have extended the technique to non-traditional substrates, most notably tip-enhanced Raman spectroscopy (TERS) where the probed substance (molecule or material surface) can be on a generic substrate and where a nanoscale gold tip above the substrate acts as the Raman signal amplifier. The drawback is that the total Raman scattering signal from the tip area is rather weak, thus limiting TERS studies to molecules with large Raman cross-sections. Here, we report an approach, which we name shell-isolated nanoparticle-enhanced Raman spectroscopy, in which the Raman signal amplification is provided by gold nanoparticles with an ultrathin silica or alumina shell. A monolayer of such nanoparticles is spread as 'smart dust' over the surface that is to be probed. The ultrathin coating keeps the nanoparticles from agglomerating, separates them from direct contact with the probed material and allows the nanoparticles to conform to different contours of substrates. High-quality Raman spectra were obtained on various molecules adsorbed at Pt and Au single-crystal surfaces and from Si surfaces with hydrogen monolayers. These measurements and our studies on yeast cells and citrus fruits with pesticide residues illustrate that our method significantly expands the flexibility of SERS for useful applications in the materials and life sciences, as well as for the inspection of food safety, drugs, explosives and environment pollutants.

Journal ArticleDOI
04 Mar 2010-Nature
TL;DR: It is shown that injury releases mitochondrial DAMPs into the circulation with functionally important immune consequences, including formyl peptides and mitochondrial DNA, which promote PMN Ca2+ flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo.
Abstract: 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.

Journal ArticleDOI
22 Jul 2010-Nature
TL;DR: Cai et al. as discussed by the authors used a surface-assisted coupling of the precursors into linear polyphenylenes and their subsequent cyclodehydrogenation to produce GNRs of different topologies and widths.
Abstract: Graphene nanoribbons, narrow straight-edged strips of the single-atom-thick sheet form of carbon, are predicted to exhibit remarkable properties, making them suitable for future electronic applications. Before this potential can be realized, more chemically precise methods of production will be required. Cai et al. report a step towards that goal with the development of a bottom-up fabrication method that produces atomically precise graphene nanoribbons of different topologies and widths. The process involves the deposition of precursor monomers with structures that 'encode' the topology and width of the desired ribbon end-product onto a metal surface. Surface-assisted coupling of the precursors into linear polyphenylenes is then followed by cyclodehydrogenation. Given the method's versatility and precision, it could even provide a route to more unusual graphene nanoribbon structures with tuned chemical and electronic properties. Graphene nanoribbons (GNRs) have structure-dependent electronic properties that make them attractive for the fabrication of nanoscale electronic devices, but exploiting this potential has been hindered by the lack of precise production methods. Here the authors demonstrate how to reliably produce different GNRs, using precursor monomers that encode the structure of the targeted nanoribbon and are converted into GNRs by means of surface-assisted coupling. Graphene nanoribbons—narrow and straight-edged stripes of graphene, or single-layer graphite—are predicted to exhibit electronic properties that make them attractive for the fabrication of nanoscale electronic devices1,2,3. In particular, although the two-dimensional parent material graphene4,5 exhibits semimetallic behaviour, quantum confinement and edge effects2,6 should render all graphene nanoribbons with widths smaller than 10 nm semiconducting. But exploring the potential of graphene nanoribbons is hampered by their limited availability: although they have been made using chemical7,8,9, sonochemical10 and lithographic11,12 methods as well as through the unzipping of carbon nanotubes13,14,15,16, the reliable production of graphene nanoribbons smaller than 10 nm with chemical precision remains a significant challenge. Here we report a simple method for the production of atomically precise graphene nanoribbons of different topologies and widths, which uses surface-assisted coupling17,18 of molecular precursors into linear polyphenylenes and their subsequent cyclodehydrogenation19,20. The topology, width and edge periphery of the graphene nanoribbon products are defined by the structure of the precursor monomers, which can be designed to give access to a wide range of different graphene nanoribbons. We expect that our bottom-up approach to the atomically precise fabrication of graphene nanoribbons will finally enable detailed experimental investigations of the properties of this exciting class of materials. It should even provide a route to graphene nanoribbon structures with engineered chemical and electronic properties, including the theoretically predicted intraribbon quantum dots21, superlattice structures22 and magnetic devices based on specific graphene nanoribbon edge states3.

Journal ArticleDOI
29 Apr 2010-Nature
TL;DR: It is shown that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage and that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation.
Abstract: The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1alpha/beta-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.

Journal ArticleDOI
02 Sep 2010-Nature
TL;DR: An expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.
Abstract: Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called 'HapMap 3', includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of

Journal ArticleDOI
25 Feb 2010-Nature
TL;DR: The results suggest that the doping-induced structural and size transition, demonstrated here in NaYF4 upconversion nanocrystals, could be extended to other lanthanide-doped nanocrystal systems for applications ranging from luminescent biological labels to volumetric three-dimensional displays.
Abstract: 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.

Journal ArticleDOI
25 Feb 2010-Nature
TL;DR: In this paper, a combination of three transcription factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, was used to convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro.
Abstract: 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.

Journal ArticleDOI
17 Jun 2010-Nature
TL;DR: Real-space imaging of a two-dimensional skyrmion lattice in a thin film of Fe0.5Co 0.5Si using Lorentz transmission electron microscopy reveals a controlled nanometre-scale spin topology, which may be useful in observing unconventional magneto-transport effects.
Abstract: Crystal order is not restricted to the periodic atomic array, but can also be found in electronic systems such as the Wigner crystal or in the form of orbital order, stripe order and magnetic order. In the case of magnetic order, spins align parallel to each other in ferromagnets and antiparallel in antiferromagnets. In other, less conventional, cases, spins can sometimes form highly nontrivial structures called spin textures. Among them is the unusual, topologically stable skyrmion spin texture, in which the spins point in all the directions wrapping a sphere. The skyrmion configuration in a magnetic solid is anticipated to produce unconventional spin-electronic phenomena such as the topological Hall effect. The crystallization of skyrmions as driven by thermal fluctuations has recently been confirmed in a narrow region of the temperature/magnetic field (T-B) phase diagram in neutron scattering studies of the three-dimensional helical magnets MnSi (ref. 17) and Fe(1-x)Co(x)Si (ref. 22). Here we report real-space imaging of a two-dimensional skyrmion lattice in a thin film of Fe(0.5)Co(0.5)Si using Lorentz transmission electron microscopy. With a magnetic field of 50-70 mT applied normal to the film, we observe skyrmions in the form of a hexagonal arrangement of swirling spin textures, with a lattice spacing of 90 nm. The related T-B phase diagram is found to be in good agreement with Monte Carlo simulations. In this two-dimensional case, the skyrmion crystal seems very stable and appears over a wide range of the phase diagram, including near zero temperature. Such a controlled nanometre-scale spin topology in a thin film may be useful in observing unconventional magneto-transport effects.

Journal ArticleDOI
02 Sep 2010-Nature
TL;DR: It is found that notwithstanding the clear warming that has occurred in China in recent decades, current understanding does not allow a clear assessment of the impact of anthropogenic climate change on China’s water resources and agriculture and therefore China's ability to feed its people.
Abstract: China is the world's most populous country and a major emitter of greenhouse gases. Consequently, much research has focused on China's influence on climate change but somewhat less has been written about the impact of climate change on China. China experienced explosive economic growth in recent decades, but with only 7% of the world's arable land available to feed 22% of the world's population, China's economy may be vulnerable to climate change itself. We find, however, that notwithstanding the clear warming that has occurred in China in recent decades, current understanding does not allow a clear assessment of the impact of anthropogenic climate change on China's water resources and agriculture and therefore China's ability to feed its people. To reach a more definitive conclusion, future work must improve regional climate simulations-especially of precipitation-and develop a better understanding of the managed and unmanaged responses of crops to changes in climate, diseases, pests and atmospheric constituents.

Journal ArticleDOI
10 Mar 2010-Nature
TL;DR: Certain insulators have exotic metallic states on their surfaces that render the electrons travelling on such surfaces insensitive to scattering by impurities, possibly finding uses in technological applications in spintronics and quantum computing.
Abstract: Certain insulators have exotic metallic states on their surfaces. These states are formed by topological effects that also render the electrons travelling on such surfaces insensitive to scattering by impurities. Such topological insulators may provide new routes to generating novel phases and particles, possibly finding uses in technological applications in spintronics and quantum computing.

Journal ArticleDOI
24 Mar 2010-Nature
TL;DR: The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more, which means that over evolutionary time mutations have increased lifespan more than 2,000-fold.
Abstract: The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more. Assuming that the ancestor we share with nematodes aged rapidly, this means that over evolutionary time mutations have increased lifespan more than 2,000-fold. Which genes can extend lifespan? Can we augment their activities and live even longer? After centuries of wistful poetry and wild imagination, we are now getting answers, often unexpected ones, to these fundamental questions.

Journal ArticleDOI
26 Aug 2010-Nature
TL;DR: It is demonstrated that all three mouse Tet proteins (Tet1, Tet2 and Tet3) can also catalyse a similar reaction, uncover the enzymatic activity of the Tet proteins, and demonstrate a role for Tet1 in ES cell maintenance and inner cell mass cell specification.
Abstract: DNA methylation is one of the best-characterized epigenetic modifications. Although the enzymes that catalyse DNA methylation have been characterized, enzymes responsible for demethylation have been elusive. A recent study indicates that the human TET1 protein could catalyse the conversion of 5-methylcytosine (5mC) of DNA to 5-hydroxymethylcytosine (5hmC), raising the possibility that DNA demethylation may be a Tet1-mediated process. Here we extend this study by demonstrating that all three mouse Tet proteins (Tet1, Tet2 and Tet3) can also catalyse a similar reaction. Tet1 has an important role in mouse embryonic stem (ES) cell maintenance through maintaining the expression of Nanog in ES cells. Downregulation of Nanog via Tet1 knockdown correlates with methylation of the Nanog promoter, supporting a role for Tet1 in regulating DNA methylation status. Furthermore, knockdown of Tet1 in pre-implantation embryos results in a bias towards trophectoderm differentiation. Thus, our studies not only uncover the enzymatic activity of the Tet proteins, but also demonstrate a role for Tet1 in ES cell maintenance and inner cell mass cell specification.

Journal ArticleDOI
15 Apr 2010-Nature
TL;DR: Evidence is provided of inducing an RNAi mechanism of action in a human from the delivered siRNA and the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for anRNAi mechanism from a patient who received the highest dose of the nanoparticles.
Abstract: Therapeutics that are designed to engage RNA interference (RNAi) pathways have the potential to provide new, major ways of imparting therapy to patients. Long, double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, and the potential use of RNAi for human therapy has been demonstrated by the finding that small interfering RNAs (siRNAs; approximately 21-base-pair double-stranded RNA) can elicit RNAi in mammalian cells without producing an interferon response. We are at present conducting the first in-human phase I clinical trial involving the systemic administration of siRNA to patients with solid cancers using a targeted, nanoparticle delivery system. Here we provide evidence of inducing an RNAi mechanism of action in a human from the delivered siRNA. Tumour biopsies from melanoma patients obtained after treatment show the presence of intracellularly localized nanoparticles in amounts that correlate with dose levels of the nanoparticles administered (this is, to our knowledge, a first for systemically delivered nanoparticles of any kind). Furthermore, a reduction was found in both the specific messenger RNA (M2 subunit of ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles. Together, these data demonstrate that siRNA administered systemically to a human can produce a specific gene inhibition (reduction in mRNA and protein) by an RNAi mechanism of action.

Journal ArticleDOI
28 Jan 2010-Nature
TL;DR: An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.
Abstract: The ability of a eukaryotic cell to resist deformation, to transport intracellular cargo and to change shape during movement depends on the cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins. Recent work has demonstrated that both internal and external physical forces can act through the cytoskeleton to affect local mechanical properties and cellular behaviour. Attention is now focused on how cytoskeletal networks generate, transmit and respond to mechanical signals over both short and long timescales. An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.

Journal ArticleDOI
12 Sep 2010-Nature
TL;DR: A number of physical systems, spanning much of modern physics, are being developed for this task, ranging from single particles of light to superconducting circuits, and it is not yet clear which, if any, will ultimately prove successful as discussed by the authors.
Abstract: Quantum mechanics---the theory describing the fundamental workings of nature---is famously counterintuitive: it predicts that a particle can be in two places at the same time, and that two remote particles can be inextricably and instantaneously linked These predictions have been the topic of intense metaphysical debate ever since the theory's inception early last century However, supreme predictive power combined with direct experimental observation of some of these unusual phenomena leave little doubt as to its fundamental correctness In fact, without quantum mechanics we could not explain the workings of a laser, nor indeed how a fridge magnet operates Over the last 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 these unique quantum properties? Today it is understood that the answer is yes Many research groups around the world are working towards one of the most ambitious goals humankind has ever embarked upon: a quantum computer that promises to exponentially improve computational power for particular tasks A number of physical systems, spanning much of modern physics, are being developed for this task---ranging from single particles of light to superconducting circuits---and it is not yet clear which, if any, will ultimately prove successful Here we describe the latest developments for each of the leading approaches and explain what the major challenges are for the future

Journal ArticleDOI
25 Nov 2010-Nature
TL;DR: A novel and critical role for pericytes is indicated in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the blood–brain barrier.
Abstract: The blood–brain barrier is a gatekeeper between the central nervous system and the rest of the body, and is made up of vascular endothelial cells. Previous work upheld the notion that the barrier was formed postnatally as a result of signalling from non-neuronal cells called astrocytes to endothelial cells. Now, two independent studies demonstrate that the barrier is in fact formed during embryogenesis, with the critical factor being the interaction between blood-vessel-surrounding cells called pericytes and epithelial cells. A better understanding of the tight relationship between pericytes, neuroendothelial cells and astrocytes in blood–brain barrier function will contribute to our understanding of the breakdown of the barrier during central nervous system injury and disease. The blood–brain barrier (BBB) is made up of vascular endothelial cells and was thought to have formed postnatally from astrocytes. Two independent studies demonstrate that this barrier forms during embryogenesis, with pericyte/endothelial cell interactions being critical to regulate the BBB during development. A better understanding of the relationship among pericytes, neuroendothelial cells and astrocytes in BBB function will contribute to our understanding of BBB breakdown during central nervous system injury and disease. The blood–brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS)1. The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport2. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes3, but the relative contribution of these different components to the BBB remains largely unknown1,3. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB.