Showing papers by "University of Copenhagen published in 2011"
TL;DR: The Cochrane Collaboration’s tool for assessing risk of bias aims to make the process clearer and more accurate.
Abstract: Flaws in the design, conduct, analysis, and reporting of randomised trials can cause the effect of an intervention to be underestimated or overestimated. The Cochrane Collaboration’s tool for assessing risk of bias aims to make the process clearer and more accurate
22,227 citations
TL;DR: SignalP 4.0 was the best signal-peptide predictor for all three organism types but was not in all cases as good as SignalP 3.0 according to cleavage-site sensitivity or signal- peptide correlation when there are no transmembrane proteins present.
Abstract: We benchmarked SignalP 4.0 against SignalP 3.0 and ten other signal peptide prediction algorithms (Fig. 1). We compared prediction performance using the Matthews correlation coefficient16, for which each sequence was counted as a true or false positive or negative. To test SignalP 4.0 performance, we did not use data that had been used in training the networks or selecting the optimal architecture, and the test data did not contain homologs to the training and optimization data (Supplementary Methods). The test set for SignalP 3.0 was also independent of the training set because we removed sequences used to construct SignalP 3.0 and their homologs from the benchmark data. For other algorithms more recent than SignalP 3.0, the benchmark data may include data used to train the methods, possibly leading to slight overestimations of their performance. Our results show that SignalP 4.0 was the best signal-peptide predictor for all three organism types (Fig. 1). This comes at a price, however, because SignalP 4.0 was not in all cases as good as SignalP 3.0 according to cleavage-site sensitivity or signal-peptide correlation when there are no transmembrane proteins present (Supplementary Results). An ideal method would have the best SignalP 4.0: discriminating signal peptides from transmembrane regions
8,370 citations
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.
5,566 citations
TL;DR: In this article, exact dynamic programming algorithms can be used to compute ground states, base pairing probabilities, as well as thermodynamic properties of nucleic acids based on carefully measured thermodynamic parameters.
Abstract: Background
Secondary structure forms an important intermediate level of description of nucleic acids that encapsulates the dominating part of the folding energy, is often well conserved in evolution, and is routinely used as a basis to explain experimental findings. Based on carefully measured thermodynamic parameters, exact dynamic programming algorithms can be used to compute ground states, base pairing probabilities, as well as thermodynamic properties.
3,620 citations
TL;DR: Although the NPR is overall a sound data source, both the content and the definitions of single variables have changed over time and researchers using the data should carefully consider potential fallacies in the data before drawing conclusions.
Abstract: Introduction: The Danish National Patient Register (NPR) was established in 1977, and it is considered to be the finest of its kind internationally. Content: At the onset the register included information on inpatient in somatic wards. The content of the register has gradually been expanded, and since 2007 the register has included information on all patients in Danish hospitals. Validity and coverage: Although the NPR is overall a sound data source, both the content and the definitions of single variables have changed over time. Changes in the organisation and provision of health services may affect both the type and the completeness of registrations. Conclusion: The NPR is a unique data source. Researchers using the data should carefully consider potential fallacies in the data before drawing conclusions.
3,275 citations
TL;DR: An update on the online database resource Search Tool for the Retrieval of Interacting Genes (STRING), which provides uniquely comprehensive coverage and ease of access to both experimental as well as predicted interaction information.
Abstract: An essential prerequisite for any systems-level understanding of cellular functions is to correctly uncover and annotate all functional interactions among proteins in the cell. Toward this goal, remarkable progress has been made in recent years, both in terms of experimental measurements and computational prediction techniques. However, public efforts to collect and present protein interaction information have struggled to keep up with the pace of interaction discovery, partly because protein-protein interaction information can be error-prone and require considerable effort to annotate. Here, we present an update on the online database resource Search Tool for the Retrieval of Interacting Genes (STRING); it provides uniquely comprehensive coverage and ease of access to both experimental as well as predicted interaction information. Interactions in STRING are provided with a confidence score, and accessory information such as protein domains and 3D structures is made available, all within a stable and consistent identifier space. New features in STRING include an interactive network viewer that can cluster networks on demand, updated on-screen previews of structural information including homology models, extensive data updates and strongly improved connectivity and integration with third-party resources. Version 9.0 of STRING covers more than 1100 completely sequenced organisms; the resource can be reached at http://string-db.org.
3,239 citations
Dresden University of Technology1, Centre for Addiction and Mental Health2, Karlstad University3, Stockholm School of Economics4, University of Copenhagen5, Karolinska Institutet6, University of Florence7, University of Basel8, University of Zurich9, Maastricht University10, University of Lausanne11, European Monitoring Centre for Drugs and Drug Addiction12, Aarhus University Hospital13
TL;DR: The true size and burden of disorders of the brain in the EU was significantly underestimated in the past, and Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research and policy decisions.
3,079 citations
TL;DR: The rules and parameters for one of the most commonly used empirical pKa predictors, PROPKA, are revised based on better physical description of the desolvation and dielectric response for the protein, and a new and consistent approach to interpolate the description between the previously distinct classifications into internal and surface residues is introduced.
Abstract: In this study, we have revised the rules and parameters for one of the most commonly used empirical pKa predictors, PROPKA, based on better physical description of the desolvation and dielectric response for the protein. We have introduced a new and consistent approach to interpolate the description between the previously distinct classifications into internal and surface residues, which otherwise is found to give rise to an erratic and discontinuous behavior. Since the goal of this study is to lay out the framework and validate the concept, it focuses on Asp and Glu residues where the protein pKa values and structures are assumed to be more reliable. The new and improved implementation is evaluated and discussed; it is found to agree better with experiment than the previous implementation (in parentheses): rmsd = 0.79 (0.91) for Asp and Glu, 0.75 (0.97) for Tyr, 0.65 (0.72) for Lys, and 1.00 (1.37) for His residues. The most significant advance, however, is in reducing the number of outliers and removing...
2,833 citations
TL;DR: Iolite is a non-commercial software package developed to aid in the processing of inorganic mass spectrometric data, with a strong emphasis on visualisation versus time of acquisition, to provide a powerful framework for data processing and interpretation, while giving users the ability to implement their own data reduction protocols.
Abstract: Iolite is a non-commercial software package developed to aid in the processing of inorganic mass spectrometric data, with a strong emphasis on visualisation versus time of acquisition. The goal of the software is to provide a powerful framework for data processing and interpretation, while giving users the ability to implement their own data reduction protocols. It is intended to be highly interactive, providing the user with a complete overview of the data at all stages of processing, and allowing the freedom to change parameters and reprocess data at any point. The program presents a variety of windows for the selection and viewing of data versus time, as well as features for the generation of X-Y plots, summary reports and export of data. In addition, it is capable of generating X-Y images from laser ablation rasters, and combining information from up to four separate elemental concentrations (intensities of red, green and blue, and the z-axis) in a false-colour three-dimensional image. By virtue of its underlying computing environment—Igor Pro—Iolite is capable of processing very large datasets (i.e., millions of timeslices) rapidly, and is thus ideal for the interrogation of multi-hour sessions of laser ablation data that can not be easily manipulated in conventional spreadsheet applications, for example. It is also well suited to multi-day sessions of solution-mode inductively-coupled plasma mass spectrometer (ICPMS) or thermal ionisation mass spectrometer (TIMS) data. A strong emphasis is placed on the interpolation of parameters that vary with time by a variety of user selectable methods including smoothed cubic splines. Data are processed on a timeslice-by-timeslice basis, allowing outlier rejection and calculation of statistics to be employed directly on calculated results. This approach can reduce the risk of processing biases associated with the manipulation of integrated datasets, while also allowing the implementation of more complex data reduction methods.
2,512 citations
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.
2,511 citations
Clinical Trial Service Unit1, University College London2, North Bristol NHS Trust3, University of Würzburg4, The George Institute for Global Health5, Children's Hospital at Westmead6, Peking Union Medical College7, Sultanah Aminah Hospital8, University of British Columbia9, National Institutes of Health10, Brigham and Women's Hospital11, University of Minnesota12, University of Otago13, University of Picardie Jules Verne14, University of Copenhagen15, Chiang Mai University16, Oslo University Hospital17, Charles University in Prague18, Medical University of Silesia19, Utrecht University20, University Medical Center Groningen21, University of Helsinki22, John Radcliffe Hospital23
TL;DR: Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
Kessler Institute for Rehabilitation1, University of Washington2, University of Copenhagen3, University of Texas Health Science Center at Houston4, University of Kentucky5, Geron Corporation6, Vancouver General Hospital7, Shriners Hospitals for Children8, Magee Rehabilitation Hospital9, Medical College of Wisconsin10
TL;DR: The booklet describes the recommended International Standards examination, including both sensory and motor components, and describes the ASIA (American Spinal Injury Association) Impairment Scale (AIS) to classify the severity (i.e. completeness) of injury.
Abstract: This article represents the content of the booklet, International Standards for Neurological Classification of Spinal Cord Injury, revised 2011, published by the American Spinal Injury Association (ASIA). For further explanation of the clarifications and changes in this revision, see the accompanying article (Kirshblum S., et al. J Spinal Cord Med. 2011:doi 10.1179/107902611X13186000420242
The spinal cord is the major conduit through which motor and sensory information travels between the brain and body. The spinal cord contains longitudinally oriented spinal tracts (white matter) surrounding central areas (gray matter) where most spinal neuronal cell bodies are located. The gray matter is organized into segments comprising sensory and motor neurons. Axons from spinal sensory neurons enter and axons from motor neurons leave the spinal cord via segmental nerves or roots.
In the cervical spine, there are 8 nerve roots. Cervical roots of C1-C7 are named according to the vertebra above which they exit (i.e. C1 exits above the C1 vertebra, just below the skull and C6 nerve roots pass between the C5 and C6 vertebrae) whereas C8 exists between the C7 and T1 vertebra; as there is no C8 vertebra. The C1 nerve root does not have a sensory component that is tested on the International Standards Examination.
The thoracic spine has 12 distinct nerve roots and the lumbar spine consists of 5 distinct nerve roots that are each named accordingly as they exit below the level of the respective vertebrae. The sacrum consists of 5 embryonic sections that have fused into one bony structure with 5 distinct nerve roots that exit via the sacral foramina. The spinal cord itself ends at approximately the L1-2 vertebral level. The distal most part of the spinal cord is called the conus medullaris. The cauda equina is a cluster of paired (right and left) lumbosacral nerve roots that originate in the region of the conus medullaris and travel down through the thecal sac and exit via the intervertebral foramen below their respective vertebral levels. There may be 0, 1, or 2 coccygeal nerves but they do not have a role with the International Standards examination in accordance with the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI).
Each root receives sensory information from skin areas called dermatomes. Similarly each root innervates a group of muscles called a myotome. While a dermatome usually represents a discrete and contiguous skin area, most roots innervate more than one muscle, and most muscles are innervated by more than one root.
Spinal cord injury (SCI) affects conduction of sensory and motor signals across the site(s) of lesion(s), as well as the autonomic nervous system. By systematically examining the dermatomes and myotomes, as described within this booklet, one can determine the cord segments affected by the SCI. From the International Standards examination several measures of neurological damage are generated, e.g., Sensory and Motor Levels (on right and left sides), NLI, Sensory Scores (Pin Prick and Light Touch), Motor Scores (upper and lower limb), and ZPP. This booklet also describes the ASIA (American Spinal Injury Association) Impairment Scale (AIS) to classify the severity (i.e. completeness) of injury.
This booklet begins with basic definitions of common terms used herein. The section that follows describes the recommended International Standards examination, including both sensory and motor components. Subsequent sections cover sensory and motor scores, the AIS classification, and clinical syndromes associated with SCI. For ease of reference, a worksheet (Appendix 1) of the recommended examination is included, with a summary of steps used to classify the injury (Appendix 2). A full-size version for photocopying and use in patient records has been included as an enclosure and may also be downloaded from the ASIA website (www.asia-spinalinjury.org). Additional details regarding the examination and e-Learning training materials can also be obtained from the website15.
TL;DR: The possibility of linkage with many other nationwide individual-level data sources renders the DNPR a very powerful pharmacoepidemiological tool.
Abstract: Introduction: Individual-level data on all prescription drugs sold in Danish community pharmacies has since 1994 been recorded in the Register of Medicinal Products Statistics of the Danish Medicines Agency. Content: The register subset, termed the Danish National Prescription Registry (DNPR), contains information on dispensed prescriptions, including variables at the level of the drug user, the prescriber, and the pharmacy. Validity and coverage: Reimbursement-driven record keeping, with automated bar-code-based data entry provides data of high quality, including detailed information on the dispensed drug. Conclusion: The possibility of linkage with many other nationwide individual-level data sources renders the DNPR a very powerful pharmacoepidemiological tool.
Civil Aviation Authority of Singapore1, Beijing Institute of Genomics2, Rothamsted Research3, University of Copenhagen4, Rural Development Administration5, John Innes Centre6, University of Georgia7, North China University of Science and Technology8, University of California, Berkeley9, University of Missouri10, University of Queensland11, Australian Research Council12, National Research Council13, Bielefeld University14, Australian Centre for Plant Functional Genomics15, University of Rennes16, Wageningen University and Research Centre17, Agriculture and Agri-Food Canada18, Huazhong Agricultural University19, French Alternative Energies and Atomic Energy Commission20, Chungnam National University21, Norwich Research Park22
TL;DR: The annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage, and used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution.
Abstract: We report the annotation and analysis of the draft genome sequence of Brassica rapa accession Chiifu-401-42, a Chinese cabbage. We modeled 41,174 protein coding genes in the B. rapa genome, which has undergone genome triplication. We used Arabidopsis thaliana as an outgroup for investigating the consequences of genome triplication, such as structural and functional evolution. The extent of gene loss (fractionation) among triplicated genome segments varies, with one of the three copies consistently retaining a disproportionately large fraction of the genes expected to have been present in its ancestor. Variation in the number of members of gene families present in the genome may contribute to the remarkable morphological plasticity of Brassica species. The B. rapa genome sequence provides an important resource for studying the evolution of polyploid genomes and underpins the genetic improvement of Brassica oil and vegetable crops.
07 May 2011
TL;DR: This workshop brings together practitioners and researchers to develop a shared understanding of existing approaches and findings around the gamification of information systems, and identify key synergies, opportunities, and questions for future research.
Abstract: "Gamification" is an informal umbrella term for the use of video game elements in non-gaming systems to improve user experience (UX) and user engagement. The recent introduction of 'gamified' applications to large audiences promises new additions to the existing rich and diverse research on the heuristics, design patterns and dynamics of games and the positive UX they provide. However, what is lacking for a next step forward is the integration of this precise diversity of research endeavors. Therefore, this workshop brings together practitioners and researchers to develop a shared understanding of existing approaches and findings around the gamification of information systems, and identify key synergies, opportunities, and questions for future research.
St James's University Hospital1, University College London2, Paris Descartes University3, Oslo University Hospital4, University of British Columbia5, University of Valencia6, Charité7, University of Duisburg-Essen8, Edinburgh Cancer Research Centre9, University of Copenhagen10, University of Helsinki11, Laval University12, University of Leeds13, Medical Research Council14, Cambridge University Hospitals NHS Foundation Trust15, Princess Margaret Cancer Centre16
TL;DR: In patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months, higher than the average for women with ovarian cancer.
Abstract: A B S T R AC T Background Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. Methods We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 addi tional cycles or until progression of disease. Outcome measures included progressionfree survival, first analyzed per protocol and then updated, and interim overall survival. Results
Stephan Ripke1, Alan R. Sanders2, Kenneth S. Kendler3, Douglas F. Levinson4 +207 more•Institutions (71)
TL;DR: The authors examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects.
Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).
TL;DR: Recently developed statistical methods both improve and quantify the considerable uncertainty associated with genotype calling, and will especially benefit the growing number of studies using low- to medium-coverage data.
Abstract: Meaningful analysis of next-generation sequencing (NGS) data, which are produced extensively by genetics and genomics studies, relies crucially on the accurate calling of SNPs and genotypes. Recently developed statistical methods both improve and quantify the considerable uncertainty associated with genotype calling, and will especially benefit the growing number of studies using low- to medium-coverage data. We review these methods and provide a guide for their use in NGS studies.
TL;DR: In this paper, a novel definition for the hydrogen bond is proposed, which takes into account the theoretical and experimental knowledge acquired over the past century, and six criteria are listed that could be used as evidence for the presence of a hydrogen bond.
Abstract: A novel definition for the hydrogen bond is recommended here. It takes into account the theoretical and experimental knowledge acquired over the past century. This def- inition insists on some evidence. Six criteria are listed that could be used as evidence for the presence of a hydrogen bond.
TL;DR: A novel algorithm is presented that identifies noncovalently coupled ionizable groups, where pKa prediction may be especially difficult, which is a general improvement to PROPKA and is applied to proteins with and without ligands.
Abstract: The new empirical rules for protein pKa predictions implemented in the PROPKA3.0 software package (Olsson et al. J. Chem. Theory Comput.2010, 7, 525–537) have been extended to the prediction of pKa shifts of active site residues and ionizable ligand groups in protein–ligand complexes. We present new algorithms that allow pKa shifts due to inductive (i.e., covalently coupled) intraligand interactions, as well as noncovalently coupled interligand interactions in multiligand complexes, to be included in the prediction. The number of different ligand chemical groups that are automatically recognized has been increased to 18, and the general implementation has been changed so that new functional groups can be added easily by the user, aided by a new and more general protonation scheme. Except for a few cases, the new algorithms in PROPKA3.1 are found to yield results similar to or better than those obtained with PROPKA2.0 (Bas et al. Proteins: Struct., Funct., Bioinf.2008, 73, 765–783). Finally, we present a n...
Journal Article•
TL;DR: The epidemiological distinction between the generic term "physical activity" and the specific category of "exercise", which implies activity for a specific purpose such as improvement of physical condition or competition is recognised.
Abstract: An ever-growing volume of peer-reviewed publications speaks to the recent and rapid growth in both scope and understanding of exercise immunology. Indeed, more than 95% of all peer-reviewed publications in exercise immunology (currently >2, 200 publications using search terms "exercise" and "immune") have been published since the formation of the International Society of Exercise and Immunology (ISEI) in 1989 (ISI Web of Knowledge). We recognise the epidemiological distinction between the generic term "physical activity" and the specific category of "exercise", which implies activity for a specific purpose such as improvement of physical condition or competition. Extreme physical activity of any type may have implications for the immune system. However, because of its emotive component, exercise is likely to have a larger effect, and to date the great majority of our knowledge on this subject comes from exercise studies.
Australian National University1, Stockholm Resilience Centre2, Stockholm Environment Institute3, Stockholm University4, University of Leicester5, University of Copenhagen6, Max Planck Society7, Royal Swedish Academy of Sciences8, Massachusetts Institute of Technology9, University of California, San Diego10, Wageningen University and Research Centre11, Potsdam Institute for Climate Impact Research12
TL;DR: The Anthropocene is a reminder that the Holocene, during which complex human societies have developed, has been a stable, accommodating environment and is the only state of the Earth System that the authors know for sure can support contemporary society.
Abstract: Over the past century, the total material wealth of humanity has been enhanced. However, in the twenty-first century, we face scarcity in critical resources, the degradation of ecosystem services, and the erosion of the planet’s capability to absorb our wastes. Equity issues remain stubbornly difficult to solve. This situation is novel in its speed, its global scale and its threat to the resilience of the Earth System. The advent of the Anthropence, the time interval in which human activities now rival global geophysical processes, suggests that we need to fundamentally alter our relationship with the planet we inhabit. Many approaches could be adopted, ranging from geo-engineering solutions that purposefully manipulate parts of the Earth System to becoming active stewards of our own life support system. The Anthropocene is a reminder that the Holocene, during which complex human societies have developed, has been a stable, accommodating environment and is the only state of the Earth System that we know for sure can support contemporary society. The need to achieve effective planetary stewardship is urgent. As we go further into the Anthropocene, we risk driving the Earth System onto a trajectory toward more hostile states from which we cannot easily return.
TL;DR: It is proposed that phosphorylation of autophagy receptors might be a general mechanism for regulation of cargo-selectiveautophagy, resulting in increased intracellular bacterial proliferation.
Abstract: Selective autophagy can be mediated via receptor molecules that link specific cargoes to the autophagosomal membranes decorated by ubiquitin-like microtubule-associated protein light chain 3 (LC3) modifiers. Although several autophagy receptors have been identified, little is known about mechanisms controlling their functions in vivo. In this work, we found that phosphorylation of an autophagy receptor, optineurin, promoted selective autophagy of ubiquitin-coated cytosolic Salmonella enterica. The protein kinase TANK binding kinase 1 (TBK1) phosphorylated optineurin on serine-177, enhancing LC3 binding affinity and autophagic clearance of cytosolic Salmonella. Conversely, ubiquitin- or LC3-binding optineurin mutants and silencing of optineurin or TBK1 impaired Salmonella autophagy, resulting in increased intracellular bacterial proliferation. We propose that phosphorylation of autophagy receptors might be a general mechanism for regulation of cargo-selective autophagy.
TL;DR: It is shown that the rate of gene expression evolution varies among organs, lineages and chromosomes, owing to differences in selective pressures: transcriptome change was slow in nervous tissues and rapid in testes, slower in rodents than in apes and monotremes, and rapid for the X chromosome right after its formation.
Abstract: Changes in gene expression are thought to underlie many of the phenotypic differences between species. However, large-scale analyses of gene expression evolution were until recently prevented by technological limitations. Here we report the sequencing of polyadenylated RNA from six organs across ten species that represent all major mammalian lineages (placentals, marsupials and monotremes) and birds (the evolutionary outgroup), with the goal of understanding the dynamics of mammalian transcriptome evolution. We show that the rate of gene expression evolution varies among organs, lineages and chromosomes, owing to differences in selective pressures: transcriptome change was slow in nervous tissues and rapid in testes, slower in rodents than in apes and monotremes, and rapid for the X chromosome right after its formation. Although gene expression evolution in mammals was strongly shaped by purifying selection, we identify numerous potentially selectively driven expression switches, which occurred at different rates across lineages and tissues and which probably contributed to the specific organ biology of various mammals.
TL;DR: A map of unbalanced SVs is constructed based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations, and serves as a resource for sequencing-based association studies.
Abstract: Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.
French Institute of Health and Medical Research1, Columbia University2, The Catholic University of America3, University of Gothenburg4, University of Milan5, New York University6, Forest Research Institute7, University of Amsterdam8, University of Copenhagen9, St George's, University of London10, Hacettepe University11, University of Western Australia12
TL;DR: Recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal, and that therapeutic targeting of elevated triglycerides, a marker of TRL and their remnants, and/or low HDL-C may provide further benefit.
Abstract: Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.
Massachusetts Institute of Technology1, Vassar College2, University of Copenhagen3, Wellcome Trust4, Howard Hughes Medical Institute5, University of California, Santa Cruz6, Stanford University7, University of California, San Francisco8, Harvard University9, Cornell University10, Research Institute of Molecular Pathology11, Human Genome Sequencing Center12, Washington University in St. Louis13, National Institutes of Health14, Aarhus University Hospital15
TL;DR: The comparison of related genomes has emerged as a powerful lens for genome interpretation and sequencing and comparative analysis of 29 eutherian genomes confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2%" of the genome.
Abstract: The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.
TL;DR: It is proposed that TET1 fine-tunes transcription, opposes aberrant DNA methylation at CpG-rich sequences and thereby contributes to the regulation ofDNA methylation fidelity.
Abstract: Enzymes catalysing the methylation of the 5-position of cytosine (mC) have essential roles in regulating gene expression and maintaining cellular identity. Recently, TET1 was found to hydroxylate the methyl group of mC, converting it to 5-hydroxymethyl cytosine (hmC). Here we show that TET1 binds throughout the genome of embryonic stem cells, with the majority of binding sites located at transcription start sites (TSSs) of CpG-rich promoters and within genes. The hmC modification is found in gene bodies and in contrast to mC is also enriched at CpG-rich TSSs. We provide evidence further that TET1 has a role in transcriptional repression. TET1 binds a significant proportion of Polycomb group target genes. Furthermore, TET1 associates and colocalizes with the SIN3A co-repressor complex. We propose that TET1 fine-tunes transcription, opposes aberrant DNA methylation at CpG-rich sequences and thereby contributes to the regulation of DNA methylation fidelity.
University of Bologna1, University of Copenhagen2, Imperial College London3, University of Bergen4, University of Trieste5, Ludwig Maximilian University of Munich6, University of Paris7, University of Verona8, Sapienza University of Rome9, University of Regensburg10, Innsbruck Medical University11, Institut Gustave Roussy12, Hai phong University Of Medicine and Pharmacy13, University of Cambridge14, The Royal Marsden NHS Foundation Trust15, Katholieke Universiteit Leuven16
TL;DR: Authors F. Piscaglia, C. Nolsøe, M. M. Gilja, and H. P. Weskott review the manuscript and suggest ways in which the manuscript could have been improved.
Abstract: Authors F. Piscaglia1, C. Nolsøe2, C. F. Dietrich3, D. O. Cosgrove4, O. H. Gilja5, M. Bachmann Nielsen6, T. Albrecht7, L. Barozzi8, M. Bertolotto9, O. Catalano10, M. Claudon11, D. A. Clevert12, J. M. Correas13, M. D’Onofrio14, F. M. Drudi15, J. Eyding16, M. Giovannini17, M. Hocke18, A. Ignee19, E. M. Jung20, A. S. Klauser21, N. Lassau22, E. Leen23, G. Mathis24, A. Saftoiu25, G. Seidel26, P. S. Sidhu27, G. ter. Haar28, D. Timmerman29, H. P. Weskott30
01 Jan 2011
TL;DR: Arnaut et al. as mentioned in this paper discuss super-diversity in the context of a translingual ontology and discuss the role of sociolinguistic shibboleths at the institutional gate.
Abstract: CONTENTS 1. Introduction Karel Arnaut , Jan Blommaert, Ben Rampton, and Massimiliano Spotti Part 1: Sketching the paradigm 2. Language and superdiversity Jan Blommaert and Ben Rampton 3. Super-diversity: Elements of an emerging perspective Karel Arnaut 4. From multilingual classification to translingual ontology: A turning point David Parkin Part II: Sociolinguistic complexity 5. Drilling down to the grain in superdiversity Ben Rampton 6. Buffalaxing the other: Superdiversity in action on YouTube Sirpa Leppanen and Ari Hakkinen 7. Polylanguaging in super-diversity Jens Normann Jorgensen, Martha Sif Karrebaek, Lian Malai Madsen, and Janus Spindler Moller 8. 'A typical gentleman': Metapragmatic stereotypes as systems of distinction Adrian Blackledge and Angela Creese 9. Mobility, voice, and symbolic restratification: An ethnography of 'elite migrants' in urban China Jie Dong Part III: Policing complexity 10. Ethnographic linguistic landscape analysis and social change: A case study Jan Blommaert and Ico Maly 11. Superdiversity on the Internet: A case from China Piia Varis and Xuan Wang 12. Translating global experience into institutional models of competency: Linguistic inequalities in the job interview Celia Roberts 13. Sociolinguistic shibboleths at the institutional gate: Language, origin and the construction of asylum seekers' identities Massimiliano Spotti