Showing papers in "Nature in 2009"
TL;DR: The direct synthesis of large-scale graphene films using chemical vapour deposition on thin nickel layers is reported, and two different methods of patterning the films and transferring them to arbitrary substrates are presented, implying that the quality of graphene grown by chemical vapours is as high as mechanically cleaved graphene.
Abstract: Problems associated with large-scale pattern growth of graphene constitute one of the main obstacles to using this material in device applications. Recently, macroscopic-scale graphene films were prepared by two-dimensional assembly of graphene sheets chemically derived from graphite crystals and graphene oxides. However, the sheet resistance of these films was found to be much larger than theoretically expected values. Here we report the direct synthesis of large-scale graphene films using chemical vapour deposition on thin nickel layers, and present two different methods of patterning the films and transferring them to arbitrary substrates. The transferred graphene films show very low sheet resistance of approximately 280 Omega per square, with approximately 80 per cent optical transparency. At low temperatures, the monolayers transferred to silicon dioxide substrates show electron mobility greater than 3,700 cm(2) V(-1) s(-1) and exhibit the half-integer quantum Hall effect, implying that the quality of graphene grown by chemical vapour deposition is as high as mechanically cleaved graphene. Employing the outstanding mechanical properties of graphene, we also demonstrate the macroscopic use of these highly conducting and transparent electrodes in flexible, stretchable, foldable electronics.
10,033 citations
Stockholm Environment Institute1, Stockholm University2, Australian National University3, University of Alaska Fairbanks4, Université catholique de Louvain5, University of East Anglia6, Wageningen University and Research Centre7, Royal Swedish Academy of Sciences8, Potsdam Institute for Climate Impact Research9, University of Oxford10, James Cook University11, Arizona State University12, Royal Institute of Technology13, University of Minnesota14, University of Vermont15, Stockholm International Water Institute16, California State University San Marcos17, Goddard Institute for Space Studies18, Commonwealth Scientific and Industrial Research Organisation19, University of Arizona20, Max Planck Society21
TL;DR: Identifying and quantifying planetary boundaries that must not be transgressed could help prevent human activities from causing unacceptable environmental change, argue Johan Rockstrom and colleagues.
Abstract: Identifying and quantifying planetary boundaries that must not be transgressed could help prevent human activities from causing unacceptable environmental change, argue Johan Rockstrom and colleagues.
8,837 citations
National Institutes of Health1, University of Chicago2, Duke University3, Harvard University4, University of Oxford5, GlaxoSmithKline6, Johns Hopkins University7, Yale University8, deCODE genetics9, Howard Hughes Medical Institute10, Princeton University11, Washington University in St. Louis12, University of California, Berkeley13, Stanford University14, University of Michigan15, Cornell University16, University of Washington17, University of Queensland18, Vanderbilt University19, North Carolina State University20, QIMR Berghofer Medical Research Institute21
TL;DR: This paper examined potential sources of missing heritability and proposed research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Abstract: Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
7,797 citations
TL;DR: The faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers are characterized to address how host genotype, environmental exposure and host adiposity influence the gut microbiome.
Abstract: The human distal gut harbours a vast ensemble of microbes (the microbiota) that provide important metabolic capabilities, including the ability to extract energy from otherwise indigestible dietary polysaccharides. Studies of a few unrelated, healthy adults have revealed substantial diversity in their gut communities, as measured by sequencing 16S rRNA genes, yet how this diversity relates to function and to the rest of the genes in the collective genomes of the microbiota (the gut microbiome) remains obscure. Studies of lean and obese mice suggest that the gut microbiota affects energy balance by influencing the efficiency of calorie harvest from the diet, and how this harvested energy is used and stored. Here we characterize the faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers, to address how host genotype, environmental exposure and host adiposity influence the gut microbiome. Analysis of 154 individuals yielded 9,920 near full-length and 1,937,461 partial bacterial 16S rRNA sequences, plus 2.14 gigabases from their microbiomes. The results reveal that the human gut microbiome is shared among family members, but that each person's gut microbial community varies in the specific bacterial lineages present, with a comparable degree of co-variation between adult monozygotic and dizygotic twin pairs. However, there was a wide array of shared microbial genes among sampled individuals, comprising an extensive, identifiable 'core microbiome' at the gene, rather than at the organismal lineage, level. Obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathways. These results demonstrate that a diversity of organismal assemblages can nonetheless yield a core microbiome at a functional level, and that deviations from this core are associated with different physiological states (obese compared with lean).
6,970 citations
TL;DR: It is concluded that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
Abstract: The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
5,193 citations
TL;DR: The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases.
Abstract: The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
4,871 citations
Broad Institute1, Harvard University2, QIMR Berghofer Medical Research Institute3, Cardiff University4, North Carolina State University5, Trinity College, Dublin6, University of Edinburgh7, Karolinska Institutet8, Uppsala University9, University of Southern California10, University of North Carolina at Chapel Hill11, University College London12, National Health Service13, University of Oxford14, University of Aberdeen15, Strathclyde Institute of Pharmacy and Biomedical Sciences16, State University of New York Upstate Medical University17, University of Coimbra18
TL;DR: The extent to which common genetic variation underlies the risk of schizophrenia is shown, using two analytic approaches, and the major histocompatibility complex is implicate, which is shown to involve thousands of common alleles of very small effect.
Abstract: Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
4,573 citations
TL;DR: The first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors were presented in this article.
Abstract: DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.
4,266 citations
TL;DR: A method of analysing large numbers of Google search queries to track influenza-like illness in a population and accurately estimate the current level of weekly influenza activity in each region of the United States with a reporting lag of about one day is presented.
Abstract: This paper - first published on-line in November 2008 - draws on data from an early version of the Google Flu Trends search engine to estimate the levels of flu in a population. It introduces a computational model that converts raw search query data into a region-by-region real-time surveillance system that accurately estimates influenza activity with a lag of about one day - one to two weeks faster than the conventional reports published by the Centers for Disease Prevention and Control. This report introduces a computational model based on internet search queries for real-time surveillance of influenza-like illness (ILI), which reproduces the patterns observed in ILI data from the Centers for Disease Control and Prevention. Seasonal influenza epidemics are a major public health concern, causing tens of millions of respiratory illnesses and 250,000 to 500,000 deaths worldwide each year1. In addition to seasonal influenza, a new strain of influenza virus against which no previous immunity exists and that demonstrates human-to-human transmission could result in a pandemic with millions of fatalities2. Early detection of disease activity, when followed by a rapid response, can reduce the impact of both seasonal and pandemic influenza3,4. One way to improve early detection is to monitor health-seeking behaviour in the form of queries to online search engines, which are submitted by millions of users around the world each day. Here we present a method of analysing large numbers of Google search queries to track influenza-like illness in a population. Because the relative frequency of certain queries is highly correlated with the percentage of physician visits in which a patient presents with influenza-like symptoms, we can accurately estimate the current level of weekly influenza activity in each region of the United States, with a reporting lag of about one day. This approach may make it possible to use search queries to detect influenza epidemics in areas with a large population of web search users.
3,984 citations
TL;DR: It is demonstrated that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NFκB, Sox2, Oct4 (also known as Pou5f1) and Nanog, defining a unique collection of functional linc RNAs that are highly conserved and implicated in diverse biological processes.
Abstract: There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts. However, the functional significance of these transcripts has been particularly controversial. Although there are some well-characterized examples, most (>95%) show little evidence of evolutionary conservation and have been suggested to represent transcriptional noise. Here we report a new approach to identifying large non-coding RNAs using chromatin-state maps to discover discrete transcriptional units intervening known protein-coding loci. Our approach identified ~1,600 large multi-exonic RNAs across four mouse cell types. In sharp contrast to previous collections, these large intervening non-coding RNAs (lincRNAs) show strong purifying selection in their genomic loci, exonic sequences and promoter regions, with greater than 95% showing clear evolutionary conservation. We also developed a functional genomics approach that assigns putative functions to each lincRNA, demonstrating a diverse range of roles for lincRNAs in processes from embryonic stem cell pluripotency to cell proliferation. We obtained independent functional validation for the predictions for over 100 lincRNAs, using cell-based assays. In particular, we demonstrate that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NFκB, Sox2, Oct4 (also known as Pou5f1) and Nanog. Together, these results define a unique collection of functional lincRNAs that are highly conserved and implicated in diverse biological processes.
3,875 citations
TL;DR: It is reported that a genetic polymorphism near the IL28B gene, encoding interferon-λ-3 (IFN-α-2a) is associated with an approximately twofold change in response to treatment, both among patients of European ancestry and African-Americans.
Abstract: Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.
TL;DR: It is shown that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG), and that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
Abstract: Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
TL;DR: Work in different scientific fields is now suggesting the existence of generic early-warning signals that may indicate for a wide class of systems if a critical threshold is approaching.
Abstract: Complex dynamical systems, ranging from ecosystems to financial markets and the climate, can have tipping points at which a sudden shift to a contrasting dynamical regime may occur. Although predicting such critical points before they are reached is extremely difficult, work in different scientific fields is now suggesting the existence of generic early-warning signals that may indicate for a wide class of systems if a critical threshold is approaching.
TL;DR: A simple solution-based oxidative process for producing a nearly 100% yield of nanoribbon structures by lengthwise cutting and unravelling of multiwalled carbon nanotube (MWCNT) side walls is described.
Abstract: Graphene, or single-layered graphite, with its high crystallinity and interesting semimetal electronic properties, has emerged as an exciting two-dimensional material showing great promise for the fabrication of nanoscale devices. Thin, elongated strips of graphene that possess straight edges, termed graphene ribbons, gradually transform from semiconductors to semimetals as their width increases, and represent a particularly versatile variety of graphene. Several lithographic, chemical and synthetic procedures are known to produce microscopic samples of graphene nanoribbons, and one chemical vapour deposition process has successfully produced macroscopic quantities of nanoribbons at 950 degrees C. Here we describe a simple solution-based oxidative process for producing a nearly 100% yield of nanoribbon structures by lengthwise cutting and unravelling of multiwalled carbon nanotube (MWCNT) side walls. Although oxidative shortening of MWCNTs has previously been achieved, lengthwise cutting is hitherto unreported. Ribbon structures with high water solubility are obtained. Subsequent chemical reduction of the nanoribbons from MWCNTs results in restoration of electrical conductivity. These early results affording nanoribbons could eventually lead to applications in fields of electronics and composite materials where bulk quantities of nanoribbons are required.
TL;DR: This work demonstrates a gate-controlled, continuously tunable bandgap of up to 250 meV and suggests novel nanoelectronic and nanophotonic device applications based on graphene that have eluded previous attempts.
Abstract: The electronic bandgap is an intrinsic property of semiconductors and insulators that largely determines their transport and optical properties. As such, it has a central role in modern device physics and technology and governs the operation of semiconductor devices such as p-n junctions, transistors, photodiodes and lasers. A tunable bandgap would be highly desirable because it would allow great flexibility in design and optimization of such devices, in particular if it could be tuned by applying a variable external electric field. However, in conventional materials, the bandgap is fixed by their crystalline structure, preventing such bandgap control. Here we demonstrate the realization of a widely tunable electronic bandgap in electrically gated bilayer graphene. Using a dual-gate bilayer graphene field-effect transistor (FET) and infrared microspectroscopy, we demonstrate a gate-controlled, continuously tunable bandgap of up to 250 meV. Our technique avoids uncontrolled chemical doping and provides direct evidence of a widely tunable bandgap-spanning a spectral range from zero to mid-infrared-that has eluded previous attempts. Combined with the remarkable electrical transport properties of such systems, this electrostatic bandgap control suggests novel nanoelectronic and nanophotonic device applications based on graphene.
TL;DR: It is reported that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.
Abstract: Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
TL;DR: It is shown that batteries which obtain high energy density by storing charge in the bulk of a material can also achieve ultrahigh discharge rates, comparable to those of supercapacitors.
Abstract: The storage of electrical energy at high charge and discharge rate is an important technology in today's society, and can enable hybrid and plug-in hybrid electric vehicles and provide back-up for wind and solar energy. It is typically believed that in electrochemical systems very high power rates can only be achieved with supercapacitors, which trade high power for low energy density as they only store energy by surface adsorption reactions of charged species on an electrode material. Here we show that batteries which obtain high energy density by storing charge in the bulk of a material can also achieve ultrahigh discharge rates, comparable to those of supercapacitors. We realize this in LiFePO(4) (ref. 6), a material with high lithium bulk mobility, by creating a fast ion-conducting surface phase through controlled off-stoichiometry. A rate capability equivalent to full battery discharge in 10-20 s can be achieved.
[...]
TL;DR: This work has shown that the complete DNA sequence of large numbers of cancer genomes will be possible to obtain and will provide a detailed and comprehensive perspective on how individual cancers have developed.
Abstract: All cancers arise as a result of changes that have occurred in the DNA sequence of the genomes of cancer cells. Over the past quarter of a century much has been learnt about these mutations and the abnormal genes that operate in human cancers. We are now, however, moving into an era in which it will be possible to obtain the complete DNA sequence of large numbers of cancer genomes. These studies will provide us with a detailed and comprehensive perspective on how individual cancers have developed.
TL;DR: An improved OLED structure which reaches fluorescent tube efficiency and focuses on reducing energetic and ohmic losses that occur during electron–photon conversion, which could make white-light OLEDs, with their soft area light and high colour-rendering qualities, the light sources of choice for the future.
Abstract: The development of white organic light-emitting diodes (OLEDs) holds great promise for the production of highly efficient large-area light sources. High internal quantum efficiencies for the conversion of electrical energy to light have been realized. Nevertheless, the overall device power efficiencies are still considerably below the 60-70 lumens per watt of fluorescent tubes, which is the current benchmark for novel light sources. Although some reports about highly power-efficient white OLEDs exist, details about structure and the measurement conditions of these structures have not been fully disclosed: the highest power efficiency reported in the scientific literature is 44 lm W(-1) (ref. 7). Here we report an improved OLED structure which reaches fluorescent tube efficiency. By combining a carefully chosen emitter layer with high-refractive-index substrates, and using a periodic outcoupling structure, we achieve a device power efficiency of 90 lm W(-1) at 1,000 candelas per square metre. This efficiency has the potential to be raised to 124 lm W(-1) if the light outcoupling can be further improved. Besides approaching internal quantum efficiency values of one, we have also focused on reducing energetic and ohmic losses that occur during electron-photon conversion. We anticipate that our results will be a starting point for further research, leading to white OLEDs having efficiencies beyond 100 lm W(-1). This could make white-light OLEDs, with their soft area light and high colour-rendering qualities, the light sources of choice for the future.
TL;DR: A previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy) is identified that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
Abstract: The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
Journal Article•
TL;DR: Nitrous oxide emission currently is the single most important ozone-depleting emission and is expected to remain the largest throughout the 21st century, and N2O is unregulated by the Montreal Protocol, which would enhance the recovery of the ozone layer from its depleted state and reduce the anthropogenic forcing of the climate system.
University of Georgia1, Rutgers University2, United States Department of Energy3, Stanford University4, University of California, Berkeley5, North China University of Science and Technology6, University of Zurich7, Clemson University8, University of Düsseldorf9, Cold Spring Harbor Laboratory10, Purdue University11, International Crops Research Institute for the Semi-Arid Tropics12, Texas A&M University13, Cornell University14, University of Illinois at Urbana–Champaign15, Mississippi State University16, National Institute for Biotechnology and Genetic Engineering17, United States Department of Agriculture18
TL;DR: An initial analysis of the ∼730-megabase Sorghum bicolor (L.) Moench genome is presented, placing ∼98% of genes in their chromosomal context using whole-genome shotgun sequence validated by genetic, physical and syntenic information.
Abstract: Sorghum, an African grass related to sugar cane and maize, is grown for food, feed, fibre and fuel. We present an initial analysis of the approximately 730-megabase Sorghum bicolor (L.) Moench genome, placing approximately 98% of genes in their chromosomal context using whole-genome shotgun sequence validated by genetic, physical and syntenic information. Genetic recombination is largely confined to about one-third of the sorghum genome with gene order and density similar to those of rice. Retrotransposon accumulation in recombinationally recalcitrant heterochromatin explains the approximately 75% larger genome size of sorghum compared with rice. Although gene and repetitive DNA distributions have been preserved since palaeopolyploidization approximately 70 million years ago, most duplicated gene sets lost one member before the sorghum-rice divergence. Concerted evolution makes one duplicated chromosomal segment appear to be only a few million years old. About 24% of genes are grass-specific and 7% are sorghum-specific. Recent gene and microRNA duplications may contribute to sorghum's drought tolerance.
TL;DR: A highly soluble and printable n-channel polymer exhibiting unprecedented OTFT characteristics under ambient conditions in combination with Au contacts and various polymeric dielectrics is reported and all-printed polymeric complementary inverters have been demonstrated.
Abstract: Printed electronics is a revolutionary technology aimed at unconventional electronic device manufacture on plastic foils, and will probably rely on polymeric semiconductors for organic thin-film transistor (OTFT) fabrication. In addition to having excellent charge-transport characteristics in ambient conditions, such materials must meet other key requirements, such as chemical stability, large solubility in common solvents, and inexpensive solution and/or low-temperature processing. Furthermore, compatibility of both p-channel (hole-transporting) and n-channel (electron-transporting) semiconductors with a single combination of gate dielectric and contact materials is highly desirable to enable powerful complementary circuit technologies, where p- and n-channel OTFTs operate in concert. Polymeric complementary circuits operating in ambient conditions are currently difficult to realize: although excellent p-channel polymers are widely available, the achievement of high-performance n-channel polymers is more challenging. Here we report a highly soluble ( approximately 60 g l(-1)) and printable n-channel polymer exhibiting unprecedented OTFT characteristics (electron mobilities up to approximately 0.45-0.85 cm(2) V(-1) s(-1)) under ambient conditions in combination with Au contacts and various polymeric dielectrics. Several top-gate OTFTs on plastic substrates were fabricated with the semiconductor-dielectric layers deposited by spin-coating as well as by gravure, flexographic and inkjet printing, demonstrating great processing versatility. Finally, all-printed polymeric complementary inverters (with gain 25-65) have been demonstrated.
TL;DR: It is demonstrated that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1.
Abstract: AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.
TL;DR: It is shown that SCFA–GPR43 interactions profoundly affect inflammatory responses, and GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.
Abstract: The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases. One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in 'healthy' microbiota such as Bifidobacterium and Bacteriodes, and a concurrent reduction in SCFAs. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2), and here we show that SCFA-GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43(-/-)) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43(-/-) immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.
TL;DR: The timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses and provided the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.
Abstract: Corticalgammaoscillations(20280Hz)predictincreasesinfocusedattention,andfailureingammaregulationisahallmark of neurological and psychiatric disease. Current theory predicts that gamma oscillations are generated by synchronous activity of fast-spiking inhibitory interneurons, with the resulting rhythmic inhibition producing neural ensemble synchrony by generating a narrow window for effective excitation. We causally tested these hypotheses in barrel cortex in vivo by targeting optogenetic manipulation selectively to fast-spiking interneurons. Here we show that light-driven activation of fast-spiking interneurons atvariedfrequencies (82200Hz) selectivelyamplifies gamma oscillations. Incontrast, pyramidal neuron activation amplifies only lower frequency oscillations, a cell-type-specific double dissociation. We found that the timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses. Our data directly support the fast-spiking-gamma hypothesis and provide the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.
TL;DR: Observations indicate that TBK1 and NF-κB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.
Abstract: The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.
TL;DR: A comprehensive probabilistic analysis aimed at quantifying GHG emission budgets for the 2000–50 period that would limit warming throughout the twenty-first century to below 2 °C, based on a combination of published distributions of climate system properties and observational constraints is provided.
Abstract: More than 100 countries have adopted a global warming limit of 2 degrees C or below (relative to pre-industrial levels) as a guiding principle for mitigation efforts to reduce climate change risks, impacts and damages. However, the greenhouse gas (GHG) emissions corresponding to a specified maximum warming are poorly known owing to uncertainties in the carbon cycle and the climate response. Here we provide a comprehensive probabilistic analysis aimed at quantifying GHG emission budgets for the 2000-50 period that would limit warming throughout the twenty-first century to below 2 degrees C, based on a combination of published distributions of climate system properties and observational constraints. We show that, for the chosen class of emission scenarios, both cumulative emissions up to 2050 and emission levels in 2050 are robust indicators of the probability that twenty-first century warming will not exceed 2 degrees C relative to pre-industrial temperatures. Limiting cumulative CO(2) emissions over 2000-50 to 1,000 Gt CO(2) yields a 25% probability of warming exceeding 2 degrees C-and a limit of 1,440 Gt CO(2) yields a 50% probability-given a representative estimate of the distribution of climate system properties. As known 2000-06 CO(2) emissions were approximately 234 Gt CO(2), less than half the proven economically recoverable oil, gas and coal reserves can still be emitted up to 2050 to achieve such a goal. Recent G8 Communiques envisage halved global GHG emissions by 2050, for which we estimate a 12-45% probability of exceeding 2 degrees C-assuming 1990 as emission base year and a range of published climate sensitivity distributions. Emissions levels in 2020 are a less robust indicator, but for the scenarios considered, the probability of exceeding 2 degrees C rises to 53-87% if global GHG emissions are still more than 25% above 2000 levels in 2020.
TL;DR: Optogenetics opens the door to a new kind of informational analysis of brain function, permitting quantitative delineation of the functional significance of individual elements in the emergent operation and function of intact neural circuitry.
Abstract: Synchronized oscillations and inhibitory interneurons have important and interconnected roles within cortical microcircuits. In particular, interneurons defined by the fast-spiking phenotype and expression of the calcium-binding protein parvalbumin have been suggested to be involved in gamma (30-80 Hz) oscillations, which are hypothesized to enhance information processing. However, because parvalbumin interneurons cannot be selectively controlled, definitive tests of their functional significance in gamma oscillations, and quantitative assessment of the impact of parvalbumin interneurons and gamma oscillations on cortical circuits, have been lacking despite potentially enormous significance (for example, abnormalities in parvalbumin interneurons may underlie altered gamma-frequency synchronization and cognition in schizophrenia and autism). Here we use a panel of optogenetic technologies in mice to selectively modulate multiple distinct circuit elements in neocortex, alone or in combination. We find that inhibiting parvalbumin interneurons suppresses gamma oscillations in vivo, whereas driving these interneurons (even by means of non-rhythmic principal cell activity) is sufficient to generate emergent gamma-frequency rhythmicity. Moreover, gamma-frequency modulation of excitatory input in turn was found to enhance signal transmission in neocortex by reducing circuit noise and amplifying circuit signals, including inputs to parvalbumin interneurons. As demonstrated here, optogenetics opens the door to a new kind of informational analysis of brain function, permitting quantitative delineation of the functional significance of individual elements in the emergent operation and function of intact neural circuitry.
TL;DR: It is demonstrated that, like their electronic counterparts, electromagnetic CESs can travel in only one direction and are very robust against scattering from disorder; it is found that even large metallic scatterers placed in the path of the propagating edge modes do not induce reflections.
Abstract: One of the most striking phenomena in condensed-matter physics is the quantum Hall effect, which arises in two-dimensional electron systems subject to a large magnetic field applied perpendicular to the plane in which the electrons reside. In such circumstances, current is carried by electrons along the edges of the system, in so-called chiral edge states (CESs). These are states that, as a consequence of nontrivial topological properties of the bulk electronic band structure, have a unique directionality and are robust against scattering from disorder. Recently, it was theoretically predicted that electromagnetic analogues of such electronic edge states could be observed in photonic crystals, which are materials having refractive-index variations with a periodicity comparable to the wavelength of the light passing through them. Here we report the experimental realization and observation of such electromagnetic CESs in a magneto-optical photonic crystal fabricated in the microwave regime. We demonstrate that, like their electronic counterparts, electromagnetic CESs can travel in only one direction and are very robust against scattering from disorder; we find that even large metallic scatterers placed in the path of the propagating edge modes do not induce reflections. These modes may enable the production of new classes of electromagnetic device and experiments that would be impossible using conventional reciprocal photonic states alone. Furthermore, our experimental demonstration and study of photonic CESs provides strong support for the generalization and application of topological band theories to classical and bosonic systems, and may lead to the realization and observation of topological phenomena in a generally much more controlled and customizable fashion than is typically possible with electronic systems.