Showing papers in "Nature in 2011"
Debra A. Bell1, Andrew Berchuck2, Michael J. Birrer3, Jeremy Chien1 +282 more•Institutions (35)
TL;DR: It is reported that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1,BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes.
Abstract: A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.
TL;DR: It is shown that tremendous progress could be made by halting agricultural expansion, closing ‘yield gaps’ on underperforming lands, increasing cropping efficiency, shifting diets and reducing waste, which could double food production while greatly reducing the environmental impacts of agriculture.
Abstract: Increasing population and consumption are placing unprecedented demands on agriculture and natural resources. Today, approximately a billion people are chronically malnourished while our agricultural systems are concurrently degrading land, water, biodiversity and climate on a global scale. To meet the world's future food security and sustainability needs, food production must grow substantially while, at the same time, agriculture's environmental footprint must shrink dramatically. Here we analyse solutions to this dilemma, showing that tremendous progress could be made by halting agricultural expansion, closing 'yield gaps' on underperforming lands, increasing cropping efficiency, shifting diets and reducing waste. Together, these strategies could double food production while greatly reducing the environmental impacts of agriculture.
TL;DR: Using a quantitative model, the first genome-scale prediction of synthesis rates of mRNAs and proteins is obtained and it is found that the cellular abundance of proteins is predominantly controlled at the level of translation.
Abstract: Gene expression is a multistep process that involves the transcription, translation and turnover of messenger RNAs and proteins. Although it is one of the most fundamental processes of life, the entire cascade has never been quantified on a genome-wide scale. Here we simultaneously measured absolute mRNA and protein abundance and turnover by parallel metabolic pulse labelling for more than 5,000 genes in mammalian cells. Whereas mRNA and protein levels correlated better than previously thought, corresponding half-lives showed no correlation. Using a quantitative model we have obtained the first genome-scale prediction of synthesis rates of mRNAs and proteins. We find that the cellular abundance of proteins is predominantly controlled at the level of translation. Genes with similar combinations of mRNA and protein stability shared functional properties, indicating that half-lives evolved under energetic and dynamic constraints. Quantitative information about all stages of gene expression provides a rich resource and helps to provide a greater understanding of the underlying design principles.
University of Évry Val d'Essonne1, Institut national de la recherche agronomique2, Technical University of Denmark3, Barcelona Supercomputing Center4, University of Copenhagen5, University of Tokyo6, University of Miyazaki7, Wageningen University and Research Centre8, Tokyo Institute of Technology9, French Alternative Energies and Atomic Energy Commission10
TL;DR: Three robust clusters (referred to as enterotypes hereafter) are identified that are not nation or continent specific and confirmed in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous.
Abstract: Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.
TL;DR: Preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.
Abstract: Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.
University of Zurich1, University of California, Berkeley2, Lawrence Berkeley National Laboratory3, University of Oldenburg4, Max Planck Society5, Leibniz University of Hanover6, University of Antwerp7, Oregon State University8, Technische Universität München9, Cornell University10, Newcastle University11, University of Florence12, Weizmann Institute of Science13
TL;DR: In this article, a new generation of experiments and soil carbon models were proposed to predict the SOM response to global warming, and they showed that molecular structure alone alone does not control SOM stability.
Abstract: Globally, soil organic matter (SOM) contains more than three times as much carbon as either the atmosphere or terrestrial vegetation. Yet it remains largely unknown why some SOM persists for millennia whereas other SOM decomposes readily—and this limits our ability to predict how soils will respond to climate change. Recent analytical and experimental advances have demonstrated that molecular structure alone does not control SOM stability: in fact, environmental and biological controls predominate. Here we propose ways to include this understanding in a new generation of experiments and soil carbon models, thereby improving predictions of the SOM response to global warming.
TL;DR: Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.
Abstract: Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N-oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.
TL;DR: YAP/TAZ are identified as sensors and mediators of mechanical cues instructed by the cellular microenvironment and are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry.
Abstract: Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.
TL;DR: It is shown that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome, and may explain the frequent association of mitochondrial damage with inflammatory diseases.
Abstract: An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
TL;DR: The crystal structure of photosystem II is reported, finding that five oxygen atoms served as oxo bridges linking the five metal atoms, and that four water molecules were bound to the Mn4CaO5 cluster; some of them may therefore serve as substrates for dioxygen formation.
Abstract: Photosystem II is the site of photosynthetic water oxidation and contains 20 subunits with a total molecular mass of 350 kDa. The structure of photosystem II has been reported at resolutions from 3.8 to 2.9 angstrom. These resolutions have provided much information on the arrangement of protein subunits and cofactors but are insufficient to reveal the detailed structure of the catalytic centre of water splitting. Here we report the crystal structure of photosystem II at a resolution of 1.9 angstrom. From our electron density map, we located all of the metal atoms of the Mn(4)CaO(5) cluster, together with all of their ligands. We found that five oxygen atoms served as oxo bridges linking the five metal atoms, and that four water molecules were bound to the Mn(4)CaO(5) cluster; some of them may therefore serve as substrates for dioxygen formation. We identified more than 1,300 water molecules in each photosystem II monomer. Some of them formed extensive hydrogen-bonding networks that may serve as channels for protons, water or oxygen molecules. The determination of the high-resolution structure of photosystem II will allow us to analyse and understand its functions in great detail.
TL;DR: Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.
Abstract: Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.
TL;DR: Graphene-based optical modulation mechanism, with combined advantages of compact footprint, low operation voltage and ultrafast modulation speed across a broad range of wavelengths, can enable novel architectures for on-chip optical communications.
Abstract: Graphene, the single-atom-thick form of carbon, holds promise for many applications, notably in electronics where it can complement or be integrated with silicon-based devices. Intense efforts have been devoted to develop a key enabling device, a broadband, fast optical modulator with a small device footprint. Now Liu et al. demonstrate an exciting new possibility for graphene in the area of on-chip optical communication: a graphene-based optical modulator integrated with a silicon chip. This new device relies on the electrical tuning of the Fermi level of the graphene sheet, and achieves modulation of guided light at frequencies over 1 gigahertz, together with a broad operating spectrum. At just 25 square micrometres in area, it is one of the smallest of its type. Integrated optical modulators with high modulation speed, small footprint and large optical bandwidth are poised to be the enabling devices for on-chip optical interconnects1,2. Semiconductor modulators have therefore been heavily researched over the past few years. However, the device footprint of silicon-based modulators is of the order of millimetres, owing to its weak electro-optical properties3. Germanium and compound semiconductors, on the other hand, face the major challenge of integration with existing silicon electronics and photonics platforms4,5,6. Integrating silicon modulators with high-quality-factor optical resonators increases the modulation strength, but these devices suffer from intrinsic narrow bandwidth and require sophisticated optical design; they also have stringent fabrication requirements and limited temperature tolerances7. Finding a complementary metal-oxide-semiconductor (CMOS)-compatible material with adequate modulation speed and strength has therefore become a task of not only scientific interest, but also industrial importance. Here we experimentally demonstrate a broadband, high-speed, waveguide-integrated electroabsorption modulator based on monolayer graphene. By electrically tuning the Fermi level of the graphene sheet, we demonstrate modulation of the guided light at frequencies over 1 GHz, together with a broad operation spectrum that ranges from 1.35 to 1.6 µm under ambient conditions. The high modulation efficiency of graphene results in an active device area of merely 25 µm2, which is among the smallest to date. This graphene-based optical modulation mechanism, with combined advantages of compact footprint, low operation voltage and ultrafast modulation speed across a broad range of wavelengths, can enable novel architectures for on-chip optical communications.
TL;DR: In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses, these successes suggest that active immunotherapy represents a path to obtain a durable and long-lasting response in cancer patients.
Abstract: Activating the immune system for therapeutic benefit in cancer has long been a goal in immunology and oncology. After decades of disappointment, the tide has finally changed due to the success of recent proof-of-concept clinical trials. Most notable has been the ability of the anti-CTLA4 antibody, ipilimumab, to achieve a significant increase in survival for patients with metastatic melanoma, for which conventional therapies have failed. In the context of advances in the understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses together with the advent of targeted therapies, these successes suggest that active immunotherapy represents a path to obtain a durable and long-lasting response in cancer patients.
TL;DR: In this article, the authors developed analytical tools to study the controllability of an arbitrary complex directed network, identifying the set of driver nodes with time-dependent control that can guide the system's entire dynamics.
Abstract: The ultimate proof of our understanding of natural or technological systems is reflected in our ability to control them. Although control theory offers mathematical tools for steering engineered and natural systems towards a desired state, a framework to control complex self-organized systems is lacking. Here we develop analytical tools to study the controllability of an arbitrary complex directed network, identifying the set of driver nodes with time-dependent control that can guide the system's entire dynamics. We apply these tools to several real networks, finding that the number of driver nodes is determined mainly by the network's degree distribution. We show that sparse inhomogeneous networks, which emerge in many real complex systems, are the most difficult to control, but that dense and homogeneous networks can be controlled using a few driver nodes. Counterintuitively, we find that in both model and real systems the driver nodes tend to avoid the high-degree nodes.
TL;DR: It is demonstrated that it is possible to direct the convergence of many valleys in a bulk material by tuning the doping and composition, leading to an extraordinary zT value of 1.8 at about 850 kelvin.
Abstract: Thermoelectric generators, which directly convert heat into electricity, have long been relegated to use in space-based or other niche applications, but are now being actively considered for a variety of practical waste heat recovery systems—such as the conversion of car exhaust heat into electricity. Although these devices can be very reliable and compact, the thermoelectric materials themselves are relatively inefficient: to facilitate widespread application, it will be desirable to identify or develop materials that have an intensive thermoelectric materials figure of merit, zT, above 1.5 (ref. 1). Many different concepts have been used in the search for new materials with high thermoelectric efficiency, such as the use of nanostructuring to reduce phonon thermal conductivity, which has led to the investigation of a variety of complex material systems. In this vein, it is well known, that a high valley degeneracy (typically ≤6 for known thermoelectrics) in the electronic bands is conducive to high zT, and this in turn has stimulated attempts to engineer such degeneracy by adopting low-dimensional nanostructures. Here we demonstrate that it is possible to direct the convergence of many valleys in a bulk material by tuning the doping and composition. By this route, we achieve a convergence of at least 12 valleys in doped PbTe_(1) − _(x)Se_(x) alloys, leading to an extraordinary zT value of 1.8 at about 850 kelvin. Band engineering to converge the valence (or conduction) bands to achieve high valley degeneracy should be a general strategy in the search for and improvement of bulk thermoelectric materials, because it simultaneously leads to a high Seebeck coefficient and high electrical conductivity.
TL;DR: Differences between fossil and modern data and the addition of recently available palaeontological information influence understanding of the current extinction crisis, and results confirm that current extinction rates are higher than would be expected from the fossil record.
Abstract: Palaeontologists characterize mass extinctions as times when the Earth loses more than three-quarters of its species in a geologically short interval, as has happened only five times in the past 540 million years or so. Biologists now suggest that a sixth mass extinction may be under way, given the known species losses over the past few centuries and millennia. Here we review how differences between fossil and modern data and the addition of recently available palaeontological information influence our understanding of the current extinction crisis. Our results confirm that current extinction rates are higher than would be expected from the fossil record, highlighting the need for effective conservation measures.
TL;DR: A crucial role is revealed for the autophagy pathway and proteins in immunity and inflammation, and they balance the beneficial and detrimental effects of immunity andinflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.
Abstract: Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy - the 'autophagy proteins' - orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases.
TL;DR: It is suggested that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease, which may spring from a detailed understanding of the pathways underlying proteome maintenance.
Abstract: Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
TL;DR: This study presents a general framework for deciphering cis-regulatory connections and their roles in disease, and maps nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions.
Abstract: Chromatin profiling has emerged as a powerful means of genome annotation and detection of regulatory activity. The approach is especially well suited to the characterization of non-coding portions of the genome, which critically contribute to cellular phenotypes yet remain largely uncharted. Here we map nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions. Focusing on cell-type-specific patterns of promoters and enhancers, we define multicell activity profiles for chromatin state, gene expression, regulatory motif enrichment and regulator expression. We use correlations between these profiles to link enhancers to putative target genes, and predict the cell-type-specific activators and repressors that modulate them. The resulting annotations and regulatory predictions have implications for the interpretation of genome-wide association studies. Top-scoring disease single nucleotide polymorphisms are frequently positioned within enhancer elements specifically active in relevant cell types, and in some cases affect a motif instance for a predicted regulator, thus suggesting a mechanism for the association. Our study presents a general framework for deciphering cis-regulatory connections and their roles in disease.
TL;DR: This work has uncovered a role for non-coding RNA in the recruitment of PRC2 to target genes, and expanded the perspectives on its function and regulation.
Abstract: Polycomb group proteins maintain the gene-expression pattern of different cells that is set during early development by regulating chromatin structure. In mammals, two main Polycomb group complexes exist — Polycomb repressive complex 1 (PRC1) and 2 (PRC2). PRC1 compacts chromatin and catalyses the monoubiquitylation of histone H2A. PRC2 also contributes to chromatin compaction, and catalyses the methylation of histone H3 at lysine 27. PRC2 is involved in various biological processes, including differentiation, maintaining cell identity and proliferation, and stem-cell plasticity. Recent studies of PRC2 have expanded our perspectives on its function and regulation, and uncovered a role for non-coding RNA in the recruitment of PRC2 to target genes.
TL;DR: This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR and the most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain.
Abstract: G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The b2 adrenergic receptor (b2AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomericb2AR and nucleotide-free Gs heterotrimer. The principal interactions between the b2AR and Gs involve the amino- and carboxy-terminal a-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The
TL;DR: A strategy to create self-healing, slippery liquid-infused porous surface(s) (SLIPS) with exceptional liquid- and ice-repellency, pressure stability and enhanced optical transparency, applicable to various inexpensive, low-surface-energy structured materials (such as porous Teflon membrane).
Abstract: Inspired by the insect-eating Nepenthes pitcher plant, which snares its prey on a surface lubricated by a remarkably slippery aqueous secretion, Joanna Aizenberg and colleagues have synthesized omniphobic surfaces that can self-repair and function at high pressures. Their 'slippery liquid-infused porous surfaces' (or SLIPS) exhibit almost perfect slipperiness towards polar, organic and complex liquids. SLIPS function under extreme conditions, are easily constructed from inexpensive materials and can be endowed with other useful characteristics, such as enhanced optical transparency, through the selection of appropriate substrates and lubricants. Ultra-slippery surfaces of this type might find application in biomedical fluid handling, fuel transport, antifouling, anti-icing, optical imaging and elsewhere. Creating a robust synthetic surface that repels various liquids would have broad technological implications for areas ranging from biomedical devices and fuel transport to architecture but has proved extremely challenging1. Inspirations from natural nonwetting structures2,3,4,5,6, particularly the leaves of the lotus, have led to the development of liquid-repellent microtextured surfaces that rely on the formation of a stable air–liquid interface7,8,9. Despite over a decade of intense research, these surfaces are, however, still plagued with problems that restrict their practical applications: limited oleophobicity with high contact angle hysteresis9, failure under pressure10,11,12 and upon physical damage1,7,11, inability to self-heal and high production cost1,11. To address these challenges, here we report a strategy to create self-healing, slippery liquid-infused porous surface(s) (SLIPS) with exceptional liquid- and ice-repellency, pressure stability and enhanced optical transparency. Our approach—inspired by Nepenthes pitcher plants13—is conceptually different from the lotus effect, because we use nano/microstructured substrates to lock in place the infused lubricating fluid. We define the requirements for which the lubricant forms a stable, defect-free and inert ‘slippery’ interface. This surface outperforms its natural counterparts2,3,4,5,6 and state-of-the-art synthetic liquid-repellent surfaces8,9,14,15,16 in its capability to repel various simple and complex liquids (water, hydrocarbons, crude oil and blood), maintain low contact angle hysteresis (<2.5°), quickly restore liquid-repellency after physical damage (within 0.1–1 s), resist ice adhesion, and function at high pressures (up to about 680 atm). We show that these properties are insensitive to the precise geometry of the underlying substrate, making our approach applicable to various inexpensive, low-surface-energy structured materials (such as porous Teflon membrane). We envision that these slippery surfaces will be useful in fluid handling and transportation, optical sensing, medicine, and as self-cleaning and anti-fouling materials operating in extreme environments.
Stephen Sawcer1, Garrett Hellenthal2, Matti Pirinen2, Chris C. A. Spencer2 +262 more•Institutions (67)
TL;DR: In this article, a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, they have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
TL;DR: Data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
Abstract: Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
TL;DR: It is shown that with flow-sorted nuclei, whole genome amplification and next generation sequencing the authors can accurately quantify genomic copy number within an individual nucleus and indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.
Abstract: Genomic analysis provides insights into the role of copy number variation in disease, but most methods are not designed to resolve mixed populations of cells. In tumours, where genetic heterogeneity is common, very important information may be lost that would be useful for reconstructing evolutionary history. Here we show that with flow-sorted nuclei, whole genome amplification and next generation sequencing we can accurately quantify genomic copy number within an individual nucleus. We apply single-nucleus sequencing to investigate tumour population structure and evolution in two human breast cancer cases. Analysis of 100 single cells from a polygenomic tumour revealed three distinct clonal subpopulations that probably represent sequential clonal expansions. Additional analysis of 100 single cells from a monogenomic primary tumour and its liver metastasis indicated that a single clonal expansion formed the primary tumour and seeded the metastasis. In both primary tumours, we also identified an unexpectedly abundant subpopulation of genetically diverse 'pseudodiploid' cells that do not travel to the metastatic site. In contrast to gradual models of tumour progression, our data indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.
TL;DR: The challenges to understand when evolution will occur and to identify potential evolutionary winners as well as losers, such as species lacking adaptive capacity living near physiological limits can be met through realistic models of evolutionary change linked to experimental data across a range of taxa.
Abstract: Evolutionary adaptation can be rapid and potentially help species counter stressful conditions or realize ecological opportunities arising from climate change. The challenges are to understand when evolution will occur and to identify potential evolutionary winners as well as losers, such as species lacking adaptive capacity living near physiological limits. Evolutionary processes also need to be incorporated into management programmes designed to minimize biodiversity loss under rapid climate change. These challenges can be met through realistic models of evolutionary change linked to experimental data across a range of taxa.
TL;DR: A DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes, showing its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.
Abstract: The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.
TL;DR: Tunnels based on ultrathin semiconducting films or nanowires could achieve a 100-fold power reduction over complementary metal–oxide–semiconductor transistors, so integrating tunnel FETs with CMOS technology could improve low-power integrated circuits.
Abstract: Power dissipation is a fundamental problem for nanoelectronic circuits. Scaling the supply voltage reduces the energy needed for switching, but the field-effect transistors (FETs) in today's integrated circuits require at least 60 mV of gate voltage to increase the current by one order of magnitude at room temperature. Tunnel FETs avoid this limit by using quantum-mechanical band-to-band tunnelling, rather than thermal injection, to inject charge carriers into the device channel. Tunnel FETs based on ultrathin semiconducting films or nanowires could achieve a 100-fold power reduction over complementary metal-oxide-semiconductor (CMOS) transistors, so integrating tunnel FETs with CMOS technology could improve low-power integrated circuits.
TL;DR: In this article, tracrRNA, a trans-encoded small RNA with 24-nucleotide complementarity to the repeat regions of crRNA precursor transcripts, is shown to direct the maturation of crRNAs by the activities of the widely conserved endogenous RNase III and the CRISPR-associated Csn1 protein.
Abstract: CRISPR/Cas systems constitute a widespread class of immunity systems that protect bacteria and archaea against phages and plasmids, and commonly use repeat/spacer-derived short crRNAs to silence foreign nucleic acids in a sequence-specific manner. Although the maturation of crRNAs represents a key event in CRISPR activation, the responsible endoribonucleases (CasE, Cas6, Csy4) are missing in many CRISPR/Cas subtypes. Here, differential RNA sequencing of the human pathogen Streptococcus pyogenes uncovered tracrRNA, a trans-encoded small RNA with 24-nucleotide complementarity to the repeat regions of crRNA precursor transcripts. We show that tracrRNA directs the maturation of crRNAs by the activities of the widely conserved endogenous RNase III and the CRISPR-associated Csn1 protein; all these components are essential to protect S. pyogenes against prophage-derived DNA. Our study reveals a novel pathway of small guide RNA maturation and the first example of a host factor (RNase III) required for bacterial RNA-mediated immunity against invaders.
TL;DR: In this article, a coupled, nanoscale optical and mechanical resonator formed in a silicon microchip is used to cool the mechanical motion down to its quantum ground state (reaching an average phonon occupancy number of 0.85±0.08).
Abstract: The simple mechanical oscillator, canonically consisting of a coupled mass–spring system, is used in a wide variety of sensitive measurements, including the detection of weak forces and small masses. On the one hand, a classical oscillator has a well-defined amplitude of motion; a quantum oscillator, on the other hand, has a lowest-energy state, or ground state, with a finite-amplitude uncertainty corresponding to zero-point motion. On the macroscopic scale of our everyday experience, owing to interactions with its highly fluctuating thermal environment a mechanical oscillator is filled with many energy quanta and its quantum nature is all but hidden. Recently, in experiments performed at temperatures of a few hundredths of a kelvin, engineered nanomechanical resonators coupled to electrical circuits have been measured to be oscillating in their quantum ground state. These experiments, in addition to providing a glimpse into the underlying quantum behaviour of mesoscopic systems consisting of billions of atoms, represent the initial steps towards the use of mechanical devices as tools for quantum metrology or as a means of coupling hybrid quantum systems. Here we report the development of a coupled, nanoscale optical and mechanical resonator formed in a silicon microchip, in which radiation pressure from a laser is used to cool the mechanical motion down to its quantum ground state (reaching an average phonon occupancy number of 0.85±0.08). This cooling is realized at an environmental temperature of 20 K, roughly one thousand times larger than in previous experiments and paves the way for optical control of mesoscale mechanical oscillators in the quantum regime.