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Showing papers in "Nature in 2007"


Journal ArticleDOI
Paul Burton1, David Clayton2, Lon R. Cardon, Nicholas John Craddock3  +192 moreInstitutions (4)
07 Jun 2007-Nature
TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

9,244 citations


Journal ArticleDOI
26 Jul 2007-Nature
TL;DR: Graphene oxide paper is reported, a free-standing carbon-based membrane material made by flow-directed assembly of individual graphene oxide sheets that outperforms many other paper-like materials in stiffness and strength.
Abstract: Free-standing paper-like or foil-like materials are an integral part of our technological society. Their uses include protective layers, chemical filters, components of electrical batteries or supercapacitors, adhesive layers, electronic or optoelectronic components, and molecular storage. Inorganic 'paper-like' materials based on nanoscale components such as exfoliated vermiculite or mica platelets have been intensively studied and commercialized as protective coatings, high-temperature binders, dielectric barriers and gas-impermeable membranes. Carbon-based flexible graphite foils composed of stacked platelets of expanded graphite have long been used in packing and gasketing applications because of their chemical resistivity against most media, superior sealability over a wide temperature range, and impermeability to fluids. The discovery of carbon nanotubes brought about bucky paper, which displays excellent mechanical and electrical properties that make it potentially suitable for fuel cell and structural composite applications. Here we report the preparation and characterization of graphene oxide paper, a free-standing carbon-based membrane material made by flow-directed assembly of individual graphene oxide sheets. This new material outperforms many other paper-like materials in stiffness and strength. Its combination of macroscopic flexibility and stiffness is a result of a unique interlocking-tile arrangement of the nanoscale graphene oxide sheets.

5,117 citations


Journal ArticleDOI
14 Jun 2007-Nature
TL;DR: Functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project are reported, providing convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts.
Abstract: We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

5,091 citations


Journal ArticleDOI
Ed S. Lein1, Michael Hawrylycz1, Nancy Ao2, Mikael Ayres1, Amy Bensinger1, Amy Bernard1, Andrew F. Boe1, Mark S. Boguski3, Mark S. Boguski1, Kevin S. Brockway1, Emi J. Byrnes1, Lin Chen1, Li Chen2, Tsuey-Ming Chen2, Mei Chi Chin1, Jimmy Chong1, Brian E. Crook1, Aneta Czaplinska2, Chinh Dang1, Suvro Datta1, Nick Dee1, Aimee L. Desaki1, Tsega Desta1, Ellen Diep1, Tim A. Dolbeare1, Matthew J. Donelan1, Hong-Wei Dong1, Jennifer G. Dougherty1, Ben J. Duncan1, Amanda Ebbert1, Gregor Eichele4, Lili K. Estin1, Casey Faber1, Benjamin A.C. Facer1, Rick Fields2, Shanna R. Fischer1, Tim P. Fliss1, Cliff Frensley1, Sabrina N. Gates1, Katie J. Glattfelder1, Kevin R. Halverson1, Matthew R. Hart1, John G. Hohmann1, Maureen P. Howell1, Darren P. Jeung1, Rebecca A. Johnson1, Patrick T. Karr1, Reena Kawal1, Jolene Kidney1, Rachel H. Knapik1, Chihchau L. Kuan1, James H. Lake1, Annabel R. Laramee1, Kirk D. Larsen1, Christopher Lau1, Tracy Lemon1, Agnes J. Liang2, Ying Liu2, Lon T. Luong1, Jesse Michaels1, Judith J. Morgan1, Rebecca J. Morgan1, Marty Mortrud1, Nerick Mosqueda1, Lydia Ng1, Randy Ng1, Geralyn J. Orta1, Caroline C. Overly1, Tu H. Pak1, Sheana Parry1, Sayan Dev Pathak1, Owen C. Pearson1, Ralph B. Puchalski1, Zackery L. Riley1, Hannah R. Rockett1, Stephen A. Rowland1, Joshua J. Royall1, Marcos J. Ruiz2, Nadia R. Sarno1, Katherine Schaffnit1, Nadiya V. Shapovalova1, Taz Sivisay1, Clifford R. Slaughterbeck1, Simon Smith1, Kimberly A. Smith1, Bryan I. Smith1, Andy J. Sodt1, Nick N. Stewart1, Kenda-Ruth Stumpf1, Susan M. Sunkin1, Madhavi Sutram1, Angelene Tam2, Carey D. Teemer1, Christina Thaller2, Carol L. Thompson1, Lee R. Varnam1, Axel Visel5, Axel Visel4, Ray M. Whitlock1, Paul Wohnoutka1, Crissa K. Wolkey1, Victoria Y. Wong1, Matthew J.A. Wood2, Murat B. Yaylaoglu2, Rob Young1, Brian L. Youngstrom1, Xu Feng Yuan1, Bin Zhang2, Theresa A. Zwingman1, Allan R. Jones1 
11 Jan 2007-Nature
TL;DR: An anatomically comprehensive digital atlas containing the expression patterns of ∼20,000 genes in the adult mouse brain is described, providing an open, primary data resource for a wide variety of further studies concerning brain organization and function.
Abstract: Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.

4,944 citations


Journal ArticleDOI
25 Oct 2007-Nature
TL;DR: The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers, suggesting that it represents the stem cell of the small intestine and colon.
Abstract: The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.

4,918 citations


Journal ArticleDOI
02 Aug 2007-Nature
TL;DR: It is shown that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells.
Abstract: Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

4,826 citations


Journal ArticleDOI
17 Oct 2007-Nature
TL;DR: A strategy to understand the microbial components of the human genetic and metabolic landscape and how they contribute to normal physiology and predisposition to disease.
Abstract: A strategy to understand the microbial components of the human genetic and metabolic landscape and how they contribute to normal physiology and predisposition to disease.

4,730 citations


Journal ArticleDOI
01 Mar 2007-Nature
TL;DR: These studies by transmission electron microscopy reveal that individual graphene sheets freely suspended on a microfabricated scaffold in vacuum or air are not perfectly flat: they exhibit intrinsic microscopic roughening such that the surface normal varies by several degrees and out-of-plane deformations reach 1 nm.
Abstract: Graphene — a recently isolated one-atom-thick layered form of graphite — is a hot topic in the materials science and condensed matter physics communities, where it is proving to be a popular model system for investigation. An experiment involving individual graphene sheets suspended over a microscale scaffold has allowed structure determination using transmission electron microscopy and diffraction, perhaps paving the way towards an answer to the question of why graphene can exist at all. The 'two-dimensional' sheets, it seems, are not flat, but wavy. The undulations are less pronounced in a two-layer system, and disappear in multilayer samples. Learning more about this 'waviness' may reveal what makes these extremely thin carbon membranes so stable. Investigations of individual graphene sheets freely suspended on a microfabricated scaffold in vacuum or in air reveal that the membranes are not perfectly flat, but exhibit an intrinsic waviness, such that the surface normal varies by several degrees, and out-of-plane deformations reach 1 nm. The recent discovery of graphene has sparked much interest, thus far focused on the peculiar electronic structure of this material, in which charge carriers mimic massless relativistic particles1,2,3. However, the physical structure of graphene—a single layer of carbon atoms densely packed in a honeycomb crystal lattice—is also puzzling. On the one hand, graphene appears to be a strictly two-dimensional material, exhibiting such a high crystal quality that electrons can travel submicrometre distances without scattering. On the other hand, perfect two-dimensional crystals cannot exist in the free state, according to both theory and experiment4,5,6,7,8,9. This incompatibility can be avoided by arguing that all the graphene structures studied so far were an integral part of larger three-dimensional structures, either supported by a bulk substrate or embedded in a three-dimensional matrix1,2,3,9,10,11,12. Here we report on individual graphene sheets freely suspended on a microfabricated scaffold in vacuum or air. These membranes are only one atom thick, yet they still display long-range crystalline order. However, our studies by transmission electron microscopy also reveal that these suspended graphene sheets are not perfectly flat: they exhibit intrinsic microscopic roughening such that the surface normal varies by several degrees and out-of-plane deformations reach 1 nm. The atomically thin single-crystal membranes offer ample scope for fundamental research and new technologies, whereas the observed corrugations in the third dimension may provide subtle reasons for the stability of two-dimensional crystals13,14,15.

4,653 citations


Journal ArticleDOI
18 Oct 2007-Nature
TL;DR: The Phase II HapMap is described, which characterizes over 3.1 million human single nucleotide polymorphisms genotyped in 270 individuals from four geographically diverse populations and includes 25–35% of common SNP variation in the populations surveyed, and increased differentiation at non-synonymous, compared to synonymous, SNPs is demonstrated.
Abstract: We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

4,565 citations


Journal ArticleDOI
19 Jul 2007-Nature
TL;DR: iPS cells competent for germline chimaeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application.
Abstract: We have previously shown that pluripotent stem cells can be induced from mouse fibroblasts by retroviral introduction of Oct3/4 (also called Pou5f1), Sox2, c-Myc and Klf4, and subsequent selection for Fbx15 (also called Fbxo15) expression These induced pluripotent stem (iPS) cells (hereafter called Fbx15 iPS cells) are similar to embryonic stem (ES) cells in morphology, proliferation and teratoma formation; however, they are different with regards to gene expression and DNA methylation patterns, and fail to produce adult chimaeras Here we show that selection for Nanog expression results in germline-competent iPS cells with increased ES-cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells The four transgenes (Oct3/4, Sox2, c-myc and Klf4) were strongly silenced in Nanog iPS cells We obtained adult chimaeras from seven Nanog iPS cell clones, with one clone being transmitted through the germ line to the next generation Approximately 20% of the offspring developed tumours attributable to reactivation of the c-myc transgene Thus, iPS cells competent for germline chimaeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application

4,371 citations


Journal ArticleDOI
02 Aug 2007-Nature
TL;DR: The application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells is reported and it is shown that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms.
Abstract: We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences Lysine 4 and lysine 9 trimethylation marks imprinting control regions Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations

Journal ArticleDOI
04 Jan 2007-Nature
TL;DR: The identification of colon cancer stem cells that are distinct from the bulk tumour cells provides strong support for the hierarchical organization of human colon cancer, and their existence suggests that for therapeutic strategies to be effective, they must target the cancer stem Cells.
Abstract: Colon cancer is one of the best-understood neoplasms from a genetic perspective, yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies. What has yet to be established is whether every colon cancer cell possesses the potential to initiate and sustain tumour growth, or whether the tumour is hierarchically organized so that only a subset of cells--cancer stem cells--possess such potential. Here we use renal capsule transplantation in immunodeficient NOD/SCID mice to identify a human colon cancer-initiating cell (CC-IC). Purification experiments established that all CC-ICs were CD133+; the CD133- cells that comprised the majority of the tumour were unable to initiate tumour growth. We calculated by limiting dilution analysis that there was one CC-IC in 5.7 x 10(4) unfractionated tumour cells, whereas there was one CC-IC in 262 CD133+ cells, representing >200-fold enrichment. CC-ICs within the CD133+ population were able to maintain themselves as well as differentiate and re-establish tumour heterogeneity upon serial transplantation. The identification of colon cancer stem cells that are distinct from the bulk tumour cells provides strong support for the hierarchical organization of human colon cancer, and their existence suggests that for therapeutic strategies to be effective, they must target the cancer stem cells.

Journal ArticleDOI
04 Jan 2007-Nature
TL;DR: It is concluded that colorectal cancer is created and propagated by a small number of undifferentiated tumorigenic CD133+ cells, which should therefore be the target of future therapies.
Abstract: Colon carcinoma is the second most common cause of death from cancer. The isolation and characterization of tumorigenic colon cancer cells may help to devise novel diagnostic and therapeutic procedures. Although there is increasing evidence that a rare population of undifferentiated cells is responsible for tumour formation and maintenance, this has not been explored for colorectal cancer. Here, we show that tumorigenic cells in colon cancer are included in the high-density CD133+ population, which accounts for about 2.5% of the tumour cells. Subcutaneous injection of colon cancer CD133+ cells readily reproduced the original tumour in immunodeficient mice, whereas CD133- cells did not form tumours. Such tumours were serially transplanted for several generations, in each of which we observed progressively faster tumour growth without significant phenotypic alterations. Unlike CD133- cells, CD133+ colon cancer cells grew exponentially for more than one year in vitro as undifferentiated tumour spheres in serum-free medium, maintaining the ability to engraft and reproduce the same morphological and antigenic pattern of the original tumour. We conclude that colorectal cancer is created and propagated by a small number of undifferentiated tumorigenic CD133+ cells, which should therefore be the target of future therapies.

Journal ArticleDOI
26 Jul 2007-Nature
TL;DR: Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation as mentioned in this paper, which have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis.
Abstract: Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and these have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis. Second, efforts directed towards the identification of environmental factors implicate commensal bacteria (or their products), rather than conventional pathogens, as drivers of dysregulated immunity and IBD. Third, murine models, which exhibit many of the features of ulcerative colitis and seem to be bacteria-driven, have helped unravel the pathogenesis/mucosal immunopathology of IBD.

Journal ArticleDOI
20 Dec 2007-Nature
TL;DR: The CTC-chip successfully identified CTCs in the peripheral blood of patients with metastatic lung, prostate, pancreatic, breast and colon cancer in 115 of 116 samples, with a range of 5–1,281CTCs per ml and approximately 50% purity.
Abstract: Viable tumour-derived epithelial cells (circulating tumour cells or CTCs) have been identified in peripheral blood from cancer patients and are probably the origin of intractable metastatic disease. Although extremely rare, CTCs represent a potential alternative to invasive biopsies as a source of tumour tissue for the detection, characterization and monitoring of non-haematologic cancers. The ability to identify, isolate, propagate and molecularly characterize CTC subpopulations could further the discovery of cancer stem cell biomarkers and expand the understanding of the biology of metastasis. Current strategies for isolating CTCs are limited to complex analytic approaches that generate very low yield and purity. Here we describe the development of a unique microfluidic platform (the 'CTC-chip') capable of efficient and selective separation of viable CTCs from peripheral whole blood samples, mediated by the interaction of target CTCs with antibody (EpCAM)-coated microposts under precisely controlled laminar flow conditions, and without requisite pre-labelling or processing of samples. The CTC-chip successfully identified CTCs in the peripheral blood of patients with metastatic lung, prostate, pancreatic, breast and colon cancer in 115 of 116 (99%) samples, with a range of 5-1,281 CTCs per ml and approximately 50% purity. In addition, CTCs were isolated in 7/7 patients with early-stage prostate cancer. Given the high sensitivity and specificity of the CTC-chip, we tested its potential utility in monitoring response to anti-cancer therapy. In a small cohort of patients with metastatic cancer undergoing systemic treatment, temporal changes in CTC numbers correlated reasonably well with the clinical course of disease as measured by standard radiographic methods. Thus, the CTC-chip provides a new and effective tool for accurate identification and measurement of CTCs in patients with cancer. It has broad implications in advancing both cancer biology research and clinical cancer management, including the detection, diagnosis and monitoring of cancer.

Journal ArticleDOI
26 Aug 2007-Nature
TL;DR: A high-quality draft of the genome sequence of grapevine is obtained from a highly homozygous genotype, revealing the contribution of three ancestral genomes to the grapevine haploid content and explaining the chronology of previously described whole-genome duplication events in the evolution of flowering plants.
Abstract: The analysis of the first plant genomes provided unexpected evidence for genome duplication events in species that had previously been considered as true diploids on the basis of their genetics. These polyploidization events may have had important consequences in plant evolution, in particular for species radiation and adaptation and for the modulation of functional capacities. Here we report a high-quality draft of the genome sequence of grapevine (Vitis vinifera) obtained from a highly homozygous genotype. The draft sequence of the grapevine genome is the fourth one produced so far for flowering plants, the second for a woody species and the first for a fruit crop (cultivated for both fruit and beverage). Grapevine was selected because of its important place in the cultural heritage of humanity beginning during the Neolithic period. Several large expansions of gene families with roles in aromatic features are observed. The grapevine genome has not undergone recent genome duplication, thus enabling the discovery of ancestral traits and features of the genetic organization of flowering plants. This analysis reveals the contribution of three ancestral genomes to the grapevine haploid content. This ancestral arrangement is common to many dicotyledonous plants but is absent from the genome of rice, which is a monocotyledon. Furthermore, we explain the chronology of previously described whole-genome duplication events in the evolution of flowering plants.

Journal ArticleDOI
04 Oct 2007-Nature
TL;DR: It is demonstrated that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft.
Abstract: Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.

Journal ArticleDOI
12 Apr 2007-Nature
TL;DR: Previous two-dimensional electronic spectroscopy investigations of the FMO bacteriochlorophyll complex are extended, and direct evidence is obtained for remarkably long-lived electronic quantum coherence playing an important part in energy transfer processes within this system is obtained.
Abstract: Photosynthesis provides the primary energy source for almost all life on Earth. One of its remarkable features is the efficiency with which energy is transferred within the light harvesting complexes comprising the photosynthetic apparatus. Suspicions that quantum trickery might be involved in the energy transfer processes at the core of photosynthesis are now confirmed by a new spectroscopic study. The study reveals electronic quantum beats characteristic of wavelike energy motion within the bacteriochlorophyll complex from the green sulphur bacterium Chlorobium tepidum. This wavelike characteristic of the energy transfer process can explain the extreme efficiency of photosynthesis, in that vast areas of phase space can be sampled effectively to find the most efficient path for energy transfer. A spectroscopic study has directly monitored the quantum beating arising from remarkably long-lived electronic quantum coherence in a bacteriochlorophyll complex. This wavelike characteristic of the energy transfer process can explain the extreme efficiency of photosynthesis, in that vast areas of phase space can be sampled effectively to find the most efficient path for energy transfer. Photosynthetic complexes are exquisitely tuned to capture solar light efficiently, and then transmit the excitation energy to reaction centres, where long term energy storage is initiated. The energy transfer mechanism is often described by semiclassical models that invoke ‘hopping’ of excited-state populations along discrete energy levels1,2. Two-dimensional Fourier transform electronic spectroscopy3,4,5 has mapped6 these energy levels and their coupling in the Fenna–Matthews–Olson (FMO) bacteriochlorophyll complex, which is found in green sulphur bacteria and acts as an energy ‘wire’ connecting a large peripheral light-harvesting antenna, the chlorosome, to the reaction centre7,8,9. The spectroscopic data clearly document the dependence of the dominant energy transport pathways on the spatial properties of the excited-state wavefunctions of the whole bacteriochlorophyll complex6,10. But the intricate dynamics of quantum coherence, which has no classical analogue, was largely neglected in the analyses—even though electronic energy transfer involving oscillatory populations of donors and acceptors was first discussed more than 70 years ago11, and electronic quantum beats arising from quantum coherence in photosynthetic complexes have been predicted12,13 and indirectly observed14. Here we extend previous two-dimensional electronic spectroscopy investigations of the FMO bacteriochlorophyll complex, and obtain direct evidence for remarkably long-lived electronic quantum coherence playing an important part in energy transfer processes within this system. The quantum coherence manifests itself in characteristic, directly observable quantum beating signals among the excitons within the Chlorobium tepidum FMO complex at 77 K. This wavelike characteristic of the energy transfer within the photosynthetic complex can explain its extreme efficiency, in that it allows the complexes to sample vast areas of phase space to find the most efficient path.

Journal ArticleDOI
22 Feb 2007-Nature
TL;DR: Four loci containing variants that confer type 2 diabetes risk are identified and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
Abstract: Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants wa ...

Journal ArticleDOI
18 Oct 2007-Nature
TL;DR: These coaxial silicon nanowire photovoltaic elements provide a new nanoscale test bed for studies of photoinduced energy/charge transport and artificial photosynthesis, and might find general usage as elements for powering ultralow-power electronics and diverse nanosystems.
Abstract: Solar cells are attractive candidates for clean and renewable power; with miniaturization, they might also serve as integrated power sources for nanoelectronic systems. The use of nanostructures or nanostructured materials represents a general approach to reduce both cost and size and to improve efficiency in photovoltaics. Nanoparticles, nanorods and nanowires have been used to improve charge collection efficiency in polymer-blend and dye-sensitized solar cells, to demonstrate carrier multiplication, and to enable low-temperature processing of photovoltaic devices. Moreover, recent theoretical studies have indicated that coaxial nanowire structures could improve carrier collection and overall efficiency with respect to single-crystal bulk semiconductors of the same materials. However, solar cells based on hybrid nanoarchitectures suffer from relatively low efficiencies and poor stabilities. In addition, previous studies have not yet addressed their use as photovoltaic power elements in nanoelectronics. Here we report the realization of p-type/intrinsic/n-type (p-i-n) coaxial silicon nanowire solar cells. Under one solar equivalent (1-sun) illumination, the p-i-n silicon nanowire elements yield a maximum power output of up to 200 pW per nanowire device and an apparent energy conversion efficiency of up to 3.4 per cent, with stable and improved efficiencies achievable at high-flux illuminations. Furthermore, we show that individual and interconnected silicon nanowire photovoltaic elements can serve as robust power sources to drive functional nanoelectronic sensors and logic gates. These coaxial silicon nanowire photovoltaic elements provide a new nanoscale test bed for studies of photoinduced energy/charge transport and artificial photosynthesis, and might find general usage as elements for powering ultralow-power electronics and diverse nanosystems.

Journal ArticleDOI
19 Jul 2007-Nature
TL;DR: The results show that the biological potency and epigenetic state of in-vitro-reprogrammed induced pluripotent stem cells are indistinguishable from those of ES cells.
Abstract: Nuclear transplantation can reprogramme a somatic genome back into an embryonic epigenetic state, and the reprogrammed nucleus can create a cloned animal or produce pluripotent embryonic stem cells. One potential use of the nuclear cloning approach is the derivation of 'customized' embryonic stem (ES) cells for patient-specific cell treatment, but technical and ethical considerations impede the therapeutic application of this technology. Reprogramming of fibroblasts to a pluripotent state can be induced in vitro through ectopic expression of the four transcription factors Oct4 (also called Oct3/4 or Pou5f1), Sox2, c-Myc and Klf4. Here we show that DNA methylation, gene expression and chromatin state of such induced reprogrammed stem cells are similar to those of ES cells. Notably, the cells-derived from mouse fibroblasts-can form viable chimaeras, can contribute to the germ line and can generate live late-term embryos when injected into tetraploid blastocysts. Our results show that the biological potency and epigenetic state of in-vitro-reprogrammed induced pluripotent stem cells are indistinguishable from those of ES cells.

Journal ArticleDOI
08 Mar 2007-Nature
TL;DR: More than 1,000 somatic mutations found in 274 megabases of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers reveal the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
Abstract: Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.

Journal ArticleDOI
12 Jul 2007-Nature
TL;DR: The generation and validation of a genome-wide library of Drosophila melanogaster RNAi transgenes, enabling the conditional inactivation of gene function in specific tissues of the intact organism and opening up the prospect of systematically analysing gene functions in any tissue and at any stage of the Drosophile lifespan.
Abstract: Forward genetic screens in model organisms have provided important insights into numerous aspects of development, physiology and pathology. With the availability of complete genome sequences and the introduction of RNA-mediated gene interference (RNAi), systematic reverse genetic screens are now also possible. Until now, such genome-wide RNAi screens have mostly been restricted to cultured cells and ubiquitous gene inactivation in Caenorhabditis elegans. This powerful approach has not yet been applied in a tissue-specific manner. Here we report the generation and validation of a genome-wide library of Drosophila melanogaster RNAi transgenes, enabling the conditional inactivation of gene function in specific tissues of the intact organism. Our RNAi transgenes consist of short gene fragments cloned as inverted repeats and expressed using the binary GAL4/UAS system. We generated 22,270 transgenic lines, covering 88% of the predicted protein-coding genes in the Drosophila genome. Molecular and phenotypic assays indicate that the majority of these transgenes are functional. Our transgenic RNAi library thus opens up the prospect of systematically analysing gene functions in any tissue and at any stage of the Drosophila lifespan.

Journal ArticleDOI
24 May 2007-Nature
TL;DR: This work has shown that transcription occurs against a backdrop of mixtures of complex modifications, which probably have several roles, and suggests that a more likely model is of a sophisticated, nuanced chromatin 'language' in which different combinations of basic building blocks yield dynamic functional outcomes.
Abstract: An important development in understanding the influence of chromatin on gene regulation has been the finding that DNA methylation and histone post-translational modifications lead to the recruitment of protein complexes that regulate transcription. Early interpretations of this phenomenon involved gene regulation reflecting predictive activating or repressing types of modification. However, further exploration reveals that transcription occurs against a backdrop of mixtures of complex modifications, which probably have several roles. Although such modifications were initially thought to be a simple code, a more likely model is of a sophisticated, nuanced chromatin 'language' in which different combinations of basic building blocks yield dynamic functional outcomes.

Journal ArticleDOI
28 Jun 2007-Nature
TL;DR: A family of miRNAs, miR-34a–c, whose expression reflected p53 status is described, whose encoded genes are direct transcriptional targets of p53, whose induction by DNA damage and oncogenic stress depends on p53 both in vitro and in vivo.
Abstract: A global decrease in microRNA (miRNA) levels is often observed in human cancers, indicating that small RNAs may have an intrinsic function in tumour suppression. To identify miRNA components of tumour suppressor pathways, we compared miRNA expression profiles of wild-type and p53-deficient cells. Here we describe a family of miRNAs, miR-34a-c, whose expression reflected p53 status. Genes encoding miRNAs in the miR-34 family are direct transcriptional targets of p53, whose induction by DNA damage and oncogenic stress depends on p53 both in vitro and in vivo. Ectopic expression of miR-34 induces cell cycle arrest in both primary and tumour-derived cell lines, which is consistent with the observed ability of miR-34 to downregulate a programme of genes promoting cell cycle progression. The p53 network suppresses tumour formation through the coordinated activation of multiple transcriptional targets, and miR-34 may act in concert with other effectors to inhibit inappropriate cell proliferation.

Journal ArticleDOI
Ruslan Medzhitov1
17 Oct 2007-Nature
TL;DR: The mammalian immune system has innate and adaptive components, which cooperate to protect the host against microbial infections, and recent progress brings us closer to an integrated view of the immune system and its function in host defence.
Abstract: The mammalian immune system has innate and adaptive components, which cooperate to protect the host against microbial infections. The innate immune system consists of functionally distinct 'modules' that evolved to provide different forms of protection against pathogens. It senses pathogens through pattern-recognition receptors, which trigger the activation of antimicrobial defences and stimulate the adaptive immune response. The adaptive immune system, in turn, activates innate effector mechanisms in an antigen-specific manner. The connections between the various immune components are not fully understood, but recent progress brings us closer to an integrated view of the immune system and its function in host defence.

Journal ArticleDOI
23 May 2007-Nature
TL;DR: During the past year, more than 2,500 articles, numerous scientific meetings and a new journal were devoted to the subject of epigenetics, portrayed by the popular press as a revolutionary new science — an antidote to the idea that the authors are hard-wired by their genes.
Abstract: Geneticists study the gene; however, for epigeneticists, there is no obvious 'epigene'. Nevertheless, during the past year, more than 2,500 articles, numerous scientific meetings and a new journal were devoted to the subject of epigenetics. It encompasses some of the most exciting contemporary biology and is portrayed by the popular press as a revolutionary new science--an antidote to the idea that we are hard-wired by our genes. So what is epigenetics?

Journal ArticleDOI
11 Oct 2007-Nature
TL;DR: It is shown that miR-10b is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion, and the workings of an undescribed regulatory pathway, in which a pleiotropic transcription factor induces expression of a specific microRNA, which suppresses its direct target and in turn activates another pro-metastatic gene, leading to tumour cell invasion and metastasis.
Abstract: MicroRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumour suppressors, the role of microRNAs in mediating cancer metastasis remains unexplored. Here we show, using a combination of mouse and human cells, that microRNA-10b (miR-10b) is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion. Overexpression of miR-10b in otherwise non-metastatic breast tumours initiates robust invasion and metastasis. Expression of miR-10b is induced by the transcription factor Twist, which binds directly to the putative promoter of mir-10b (MIRN10B). The miR-10b induced by Twist proceeds to inhibit translation of the messenger RNA encoding homeobox D10, resulting in increased expression of a well-characterized pro-metastatic gene, RHOC. Significantly, the level of miR-10b expression in primary breast carcinomas correlates with clinical progression. These findings suggest the workings of an undescribed regulatory pathway, in which a pleiotropic transcription factor induces expression of a specific microRNA, which suppresses its direct target and in turn activates another pro-metastatic gene, leading to tumour cell invasion and metastasis.

Journal ArticleDOI
Douglas F. Easton1, Karen A. Pooley1, Alison M. Dunning1, Paul D.P. Pharoah1, Deborah J. Thompson1, Dennis G. Ballinger, Jeffery P. Struewing2, Jonathan J. Morrison1, Helen I. Field1, Robert Luben1, Nicholas J. Wareham1, Shahana Ahmed1, Catherine S. Healey1, Richard Bowman, Kerstin B. Meyer1, Christopher A. Haiman3, Laurence K. Kolonel, Brian E. Henderson3, Loic Le Marchand, Paul Brennan4, Suleeporn Sangrajrang, Valerie Gaborieau4, Fabrice Odefrey4, Chen-Yang Shen5, Pei-Ei Wu5, Hui-Chun Wang5, Diana Eccles6, D. Gareth Evans7, Julian Peto8, Olivia Fletcher9, Nichola Johnson9, Sheila Seal, Michael R. Stratton10, Nazneen Rahman, Georgia Chenevix-Trench11, Georgia Chenevix-Trench12, Stig E. Bojesen13, Børge G. Nordestgaard13, C K Axelsson13, Montserrat Garcia-Closas2, Louise A. Brinton2, Stephen J. Chanock2, Jolanta Lissowska14, Beata Peplonska15, Heli Nevanlinna16, Rainer Fagerholm16, H Eerola16, Daehee Kang17, Keun-Young Yoo17, Dong-Young Noh17, Sei Hyun Ahn18, David J. Hunter19, Susan E. Hankinson19, David G. Cox19, Per Hall20, Sara Wedrén20, Jianjun Liu21, Yen-Ling Low21, Natalia Bogdanova22, Peter Schu¨rmann22, Do¨rk Do¨rk22, Rob A. E. M. Tollenaar23, Catharina E. Jacobi23, Peter Devilee23, Jan G. M. Klijn24, Alice J. Sigurdson2, Michele M. Doody2, Bruce H. Alexander25, Jinghui Zhang2, Angela Cox26, Ian W. Brock26, Gordon MacPherson26, Malcolm W.R. Reed26, Fergus J. Couch27, Ellen L. Goode27, Janet E. Olson27, Hanne Meijers-Heijboer24, Hanne Meijers-Heijboer28, Ans M.W. van den Ouweland24, André G. Uitterlinden24, Fernando Rivadeneira24, Roger L. Milne29, Gloria Ribas29, Anna González-Neira29, Javier Benitez29, John L. Hopper30, Margaret R. E. McCredie31, Margaret R. E. McCredie12, Margaret R. E. McCredie32, Melissa C. Southey12, Melissa C. Southey30, Graham G. Giles33, Chris Schroen30, Christina Justenhoven34, Christina Justenhoven35, Hiltrud Brauch34, Hiltrud Brauch35, Ute Hamann36, Yon-Dschun Ko, Amanda B. Spurdle11, Jonathan Beesley11, Xiaoqing Chen11, _ kConFab37, Arto Mannermaa37, Veli-Matti Kosma37, Vesa Kataja37, Jaana M. Hartikainen37, Nicholas E. Day1, David Cox, Bruce A.J. Ponder1 
28 Jun 2007-Nature
TL;DR: To identify further susceptibility alleles, a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls was conducted, followed by a third stage in which 30 single nucleotide polymorphisms were tested for confirmation.
Abstract: Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2.0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P,1027). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P,0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

Journal ArticleDOI
13 Dec 2007-Nature
TL;DR: This work reports the observation of rogue waves in an optical system, based on a microstructured optical fibre, near the threshold of soliton-fission supercontinuum generation—a noise-sensitive nonlinear process in which extremely broadband radiation is generated from a narrowband input.
Abstract: Recent observations show that the probability of encountering an extremely large rogue wave in the open ocean is much larger than expected from ordinary wave-amplitude statistics. Although considerable effort has been directed towards understanding the physics behind these mysterious and potentially destructive events, the complete picture remains uncertain. Furthermore, rogue waves have not yet been observed in other physical systems. Here, we introduce the concept of optical rogue waves, a counterpart of the infamous rare water waves. Using a new real-time detection technique, we study a system that exposes extremely steep, large waves as rare outcomes from an almost identically prepared initial population of waves. Specifically, we report the observation of rogue waves in an optical system, based on a microstructured optical fibre, near the threshold of soliton-fission supercontinuum generation--a noise-sensitive nonlinear process in which extremely broadband radiation is generated from a narrowband input. We model the generation of these rogue waves using the generalized nonlinear Schrodinger equation and demonstrate that they arise infrequently from initially smooth pulses owing to power transfer seeded by a small noise perturbation.