Showing papers by "University of Bonn published in 2012"
TL;DR: In this article, a search for the Standard Model Higgs boson in proton-proton collisions with the ATLAS detector at the LHC is presented, which has a significance of 5.9 standard deviations, corresponding to a background fluctuation probability of 1.7×10−9.
9,282 citations
TL;DR: An overview of the current possibilities of ORCA is provided and its efficiency is documents.
Abstract: ORCA is a general-purpose quantum chemistry program package that features virtually all modern electronic structure methods (density functional theory, many-body perturbation and coupled cluster theories, and multireference and semiempirical methods). It is designed with the aim of generality, extendibility, efficiency, and user friendliness. Its main field of application is larger molecules, transition metal complexes, and their spectroscopic properties. ORCA uses standard Gaussian basis functions and is fully parallelized. The article provides an overview of its current possibilities and documents its efficiency. © 2011 John Wiley & Sons, Ltd.
8,821 citations
Daniel J. Klionsky1, Fábio Camargo Abdalla2, Hagai Abeliovich3, Robert T. Abraham4 +1284 more•Institutions (463)
TL;DR: These guidelines are presented for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
4,316 citations
Wellcome Trust Sanger Institute1, Broad Institute2, University of Groningen3, University of Pittsburgh4, Cedars-Sinai Medical Center5, Yale University6, University of Cambridge7, University of Chicago8, Harvard University9, Katholieke Universiteit Leuven10, University of Liège11, King's College London12, Université de Montréal13, New Jersey Institute of Technology14, Cleveland Clinic15, Peninsula College of Medicine and Dentistry16, Université libre de Bruxelles17, Aarhus University18, University of Adelaide19, University of Kiel20, Flinders University21, McGill University22, Ludwig Maximilian University of Munich23, Charité24, Icahn School of Medicine at Mount Sinai25, University of Bonn26, Karolinska Institutet27, Torbay Hospital28, University of Auckland29, Christchurch Hospital30, Imperial College London31, Queen's University32, University of Oslo33, Lithuanian University of Health Sciences34, Emory University35, Casa Sollievo della Sofferenza36, Ghent University37, University of Western Australia38, University of Edinburgh39, Queensland Health40, Newcastle University41, University of Dundee42, University of Manchester43, University of Amsterdam44, University of Maribor45, Royal Hospital for Sick Children46, Guy's and St Thomas' NHS Foundation Trust47, QIMR Berghofer Medical Research Institute48, Norfolk and Norwich University Hospital49, Leiden University50, Technische Universität München51, University of Toronto52, University of Pennsylvania53, Johns Hopkins University54, University of Queensland55
TL;DR: A meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans is undertaken, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls.
Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
4,094 citations
TL;DR: A high-quality genome sequence of domesticated tomato is presented, a draft sequence of its closest wild relative, Solanum pimpinellifolium, is compared, and the two tomato genomes are compared to each other and to the potato genome.
Abstract: Tomato (Solanum lycopersicum) is a major crop plant and a model system for fruit development. Solanum is one of the largest angiosperm genera1 and includes annual and perennial plants from diverse habitats. Here we present a high-quality genome sequence of domesticated tomato, a draft sequence of its closest wild relative, Solanum pimpinellifolium2, and compare them to each other and to the potato genome (Solanum tuberosum). The two tomato genomes show only 0.6% nucleotide divergence and signs of recent admixture, but show more than 8% divergence from potato, with nine large and several smaller inversions. In contrast to Arabidopsis, but similar to soybean, tomato and potato small RNAs map predominantly to gene-rich chromosomal regions, including gene promoters. The Solanum lineage has experienced two consecutive genome triplications: one that is ancient and shared with rosids, and a more recent one. These triplications set the stage for the neofunctionalization of genes controlling fruit characteristics, such as colour and fleshiness.
2,687 citations
Andrew P. Morris1, Benjamin F. Voight2, Benjamin F. Voight3, Tanya M. Teslovich4 +229 more•Institutions (53)
TL;DR: This article conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent, and identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association.
Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.
1,899 citations
Lawrence Berkeley National Laboratory1, University of California, Berkeley2, Australian Astronomical Observatory3, Pontifical Catholic University of Chile4, Harvard University5, Hamilton College6, University of Utah7, University of Tokyo8, Michigan State University9, Space Telescope Science Institute10, California Institute of Technology11, University of Colorado Boulder12, University of California, Santa Cruz13, University of Waterloo14, University of Chicago15, University of Florida16, Stockholm University17, University of Minnesota18, National Institutes of Natural Sciences, Japan19, Leiden University20, Northwestern University21, University of Bonn22, University of California, Davis23, University of Washington24, Kyoto University25, Pennsylvania State University26, European Southern Observatory27, Lawrence Livermore National Laboratory28, University of Lisbon29, Texas A&M University30, University of Toronto31
TL;DR: In this article, Advanced Camera for Surveys, NICMOS and Keck adaptive-optics-assisted photometry of 20 Type Ia supernovae (SNe Ia) from the Hubble Space Telescope (HST) Cluster Supernova Survey was presented.
Abstract: We present Advanced Camera for Surveys, NICMOS, and Keck adaptive-optics-assisted photometry of 20 Type Ia supernovae (SNe Ia) from the Hubble Space Telescope (HST) Cluster Supernova Survey. The SNe Ia were discovered over the redshift interval 0.623 1 SNe Ia. We describe how such a sample could be efficiently obtained by targeting cluster fields with WFC3 on board HST. The updated supernova Union2.1 compilation of 580 SNe is available at http://supernova.lbl.gov/Union.
1,784 citations
TL;DR: More than 70% of all massive stars will exchange mass with a companion, leading to a binary merger in one-third of the cases, greatly exceed previous estimates and imply that binary interaction dominates the evolution of massive stars, with implications for populations ofmassive stars and their supernovae.
Abstract: The presence of a nearby companion alters the evolution of massive stars in binary systems, leading to phenomena such as stellar mergers, x-ray binaries, and gamma-ray bursts. Unambiguous constraints on the fraction of massive stars affected by binary interaction were lacking. We simultaneously measured all relevant binary characteristics in a sample of Galactic massive O stars and quantified the frequency and nature of binary interactions. More than 70% of all massive stars will exchange mass with a companion, leading to a binary merger in one-third of the cases. These numbers greatly exceed previous estimates and imply that binary interaction dominates the evolution of massive stars, with implications for populations of massive stars and their supernovae.
1,779 citations
TL;DR: This critical review on the associations between the intake of vegetables and fruit and the risk of several chronic diseases shows that a high daily intake of these foods promotes health.
Abstract: Vegetables and fruit provide a significant part of human nutrition, as they are important sources of nutrients, dietary fibre, and phytochemicals. However, it is uncertain whether the risk of certain chronic diseases can be reduced by increased consumption of vegetables or fruit by the general public, and what strength of evidence has to be allocated to such an association. Therefore, a comprehensive analysis of the studies available in the literature and the respective study results has been performed and evaluated regarding obesity, type 2 diabetes mellitus, hypertension, coronary heart disease (CHD), stroke, cancer, chronic inflammatory bowel disease (IBD), rheumatoid arthritis (RA), chronic obstructive pulmonary disease (COPD), asthma, osteoporosis, eye diseases, and dementia. For judgement, the strength of evidence for a risk association, the level of evidence, and the number of studies were considered, the quality of the studies and their estimated relevance based on study design and size. For hypertension, CHD, and stroke, there is convincing evidence that increasing the consumption of vegetables and fruit reduces the risk of disease. There is probable evidence that the risk of cancer in general is inversely associated with the consumption of vegetables and fruit. In addition, there is possible evidence that an increased consumption of vegetables and fruit may prevent body weight gain. As overweight is the most important risk factor for type 2 diabetes mellitus, an increased consumption of vegetables and fruit therefore might indirectly reduces the incidence of type 2 diabetes mellitus. Independent of overweight, there is probable evidence that there is no influence of increased consumption on the risk of type 2 diabetes mellitus. There is possible evidence that increasing the consumption of vegetables and fruit lowers the risk of certain eye diseases, dementia and the risk of osteoporosis. Likewise, current data on asthma, COPD, and RA indicate that an increase in vegetable and fruit consumption may contribute to the prevention of these diseases. For IBD, glaucoma, and diabetic retinopathy, there was insufficient evidence regarding an association with the consumption of vegetables and fruit. This critical review on the associations between the intake of vegetables and fruit and the risk of several chronic diseases shows that a high daily intake of these foods promotes health. Therefore, from a scientific point of view, national campaigns to increase vegetable and fruit consumption are justified. The promotion of vegetable and fruit consumption by nutrition and health policies is a preferable strategy to decrease the burden of several chronic diseases in Western societies.
1,461 citations
TL;DR: The theoretical approach employs a (nondynamic) single-structure model, but computes the various energy terms accurately without any special empirical adjustments, and provides unprecedented accuracy for ΔG(a) values with errors of only 2 kcal mol(-1) on average.
Abstract: The equilibrium association free enthalpies ΔG(a) for typical supramolecular complexes in solution are calculated by ab initio quantum chemical methods. Ten neutral and three positively charged complexes with experimental ΔG(a) values in the range 0 to -21 kcal mol(-1) (on average -6 kcal mol(-1)) are investigated. The theoretical approach employs a (nondynamic) single-structure model, but computes the various energy terms accurately without any special empirical adjustments. Dispersion corrected density functional theory (DFT-D3) with extended basis sets (triple-ζ and quadruple-ζ quality) is used to determine structures and gas-phase interaction energies (ΔE), the COSMO-RS continuum solvation model (based on DFT data) provides solvation free enthalpies and the remaining ro-vibrational enthalpic/entropic contributions are obtained from harmonic frequency calculations. Low-lying vibrational modes are treated by a free-rotor approximation. The accurate account of London dispersion interactions is mandatory with contributions in the range -5 to -60 kcal mol(-1) (up to 200% of ΔE). Inclusion of three-body dispersion effects improves the results considerably. A semilocal (TPSS) and a hybrid density functional (PW6B95) have been tested. Although the ΔG(a) values result as a sum of individually large terms with opposite sign (ΔE vs. solvation and entropy change), the approach provides unprecedented accuracy for ΔG(a) values with errors of only 2 kcal mol(-1) on average. Relative affinities for different guests inside the same host are always obtained correctly. The procedure is suggested as a predictive tool in supramolecular chemistry and can be applied routinely to semirigid systems with 300-400 atoms. The various contributions to binding and enthalpy-entropy compensations are discussed.
1,202 citations
University of Cologne1, Max Planck Society2, University of Bonn3, Ghent University4, Broad Institute5, Stanford University6, Technical University of Dortmund7, Columbia University8, University of Melbourne9, St. Vincent's Health System10, University of Jena11, Casa Sollievo della Sofferenza12, University of Groningen13, VU University Amsterdam14, University of Bologna15, University of Liverpool16, University of Oslo17, University of Zurich18, Peter MacCallum Cancer Centre19, Institut Gustave Roussy20, University of Grenoble21, Vanderbilt University22, Harvard University23, University of Washington24, University of Strasbourg25
TL;DR: This study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
Abstract: Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice(4). Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
TL;DR: Emerging evidence to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontococcal inflammation, andperiodontal inflammation negatively affecting glycaemic control is supported.
Abstract: Periodontitis is a common chronic inflammatory disease characterised by destruction of the supporting structures of the teeth (the periodontal ligament and alveolar bone). It is highly prevalent (severe periodontitis affects 10–15% of adults) and has multiple negative impacts on quality of life. Epidemiological data confirm that diabetes is a major risk factor for periodontitis; susceptibility to periodontitis is increased by approximately threefold in people with diabetes. There is a clear relationship between degree of hyperglycaemia and severity of periodontitis. The mechanisms that underpin the links between these two conditions are not completely understood, but involve aspects of immune functioning, neutrophil activity, and cytokine biology. There is emerging evidence to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting glycaemic control. Incidences of macroalbuminuria and end-stage renal disease are increased twofold and threefold, respectively, in diabetic individuals who also have severe periodontitis compared to diabetic individuals without severe periodontitis. Furthermore, the risk of cardiorenal mortality (ischaemic heart disease and diabetic nephropathy combined) is three times higher in diabetic people with severe periodontitis than in diabetic people without severe periodontitis. Treatment of periodontitis is associated with HbA1c reductions of approximately 0.4%. Oral and periodontal health should be promoted as integral components of diabetes management.
TL;DR: Variations in mortality between countries suggest the need for national and international strategies to improve care for patients undergoing inpatient non-cardiac surgery.
TL;DR: The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes, suggesting a strong bias in present clinical syndrome descriptions.
TL;DR: Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma and MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making.
Abstract: Summary Background Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. Methods Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m 2 temozolomide, given on days 1–7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6–7 weeks in 30 fractions of 1·8–2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. Findings Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3–10·2) in the temozolomide group versus 9·6 months (8·2–10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84–1·42, p non-inferiority =0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2–4·1] vs 4·7 [4·2–5·2]; HR 1·15, 95% CI 0·92–1·43, p non-inferiority =0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0–10·0]; HR 0·62, 95% CI 0·42–0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5–11·7] vs 4·6 [4·2–5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0–3·5] vs 4·6 months [3·7–6·3]). The most frequent grade 3–4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). Interpretation Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. Funding Merck Sharp & Dohme.
TL;DR: If the lowest loss and waste percentages achieved in any region in each step of the FSC could be reached globally, food supply losses could be halved and there would be enough food for approximately one billion extra people.
TL;DR: In this paper, the authors show that the main sequence stage offers the best opportunity to gauge the relevance of the various possible evolutionary scenarios, and sketching the post-main-sequence evolution of massive stars, for which observations of Wolf Rayet stars give essential clues.
Abstract: Understanding massive stars is essential for a variety of branches of astronomy including galaxy and star cluster evolution, nucleosynthesis and supernovae, pulsars, and black holes. It has become evident that massive star evolution is very diverse, being sensitive to metallicity, binarity, rotation, and possibly magnetic fields. Although the problem to obtain a good statistical observational database is alleviated by current large spectroscopic surveys, it remains a challenge to model these diverse paths of massive stars toward their violent end stage. I show that the main sequence stage offers the best opportunity to gauge the relevance of the various possible evolutionary scenarios. This also allows sketching the post-main-sequence evolution of massive stars, for which observations of Wolf-Rayet stars give essential clues. Recent supernova discoveries owing to the current boost in transient searches allow tentative mappings of progenitor models with supernova types, including pair-instability supernova...
German Cancer Research Center1, University Hospital Heidelberg2, University of Toronto3, Stanford University4, University of Amsterdam5, VU University Amsterdam6, Newcastle University7, University of Bonn8, University of Hamburg9, University of Cambridge10, Manchester Academic Health Science Centre11, Karolinska Institutet12, Medical University of Vienna13, Curie Institute14, Paris Descartes University15, Harvard University16
TL;DR: A meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies shows how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival.
Abstract: Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.
TL;DR: A meta-analysis of genome-wide association studies and independent data sets genotyped on the Immunochip identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals, and identified five independent signals within previously known loci.
Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
TL;DR: This Review will focus on developments over the last six years and includes discussions on the underlying technologies as well as their applications.
Abstract: Spatial and temporal control over chemical and biological processes plays a key role in life, where the whole is often much more than the sum of its parts. Quite trivially, the molecules of a cell do not form a living system if they are only arranged in a random fashion. If we want to understand these relationships and especially the problems arising from malfunction, tools are necessary that allow us to design sophisticated experiments that address these questions. Highly valuable in this respect are external triggers that enable us to precisely determine where, when, and to what extent a process is started or stopped. Light is an ideal external trigger: It is highly selective and if applied correctly also harmless. It can be generated and manipulated with well-established techniques, and many ways exist to apply light to living systems--from cells to higher organisms. This Review will focus on developments over the last six years and includes discussions on the underlying technologies as well as their applications.
TL;DR: It is shown that many of these puzzling observations are predicted by one single relation — Milgrom’s law — involving an acceleration constant a0 on the order of the square-root of the cosmological constant in natural units.
Abstract: A wealth of astronomical data indicate the presence of mass discrepancies in the Universe. The motions observed in a variety of classes of extragalactic systems exceed what can be explained by the mass visible in stars and gas. Either (i) there is a vast amount of unseen mass in some novel form — dark matter — or (ii) the data indicate a breakdown of our understanding of dynamics on the relevant scales, or (iii) both. Here, we first review a few outstanding challenges for the dark matter interpretation of mass discrepancies in galaxies, purely based on observations and independently of any alternative theoretical framework. We then show that many of these puzzling observations are predicted by one single relation — Milgrom’s law — involving an acceleration constant a0 (or a characteristic surface density Σ† = a0/G) on the order of the square-root of the cosmological constant in natural units. This relation can at present most easily be interpreted as the effect of a single universal force law resulting from a modification of Newtonian dynamics (MOND) on galactic scales. We exhaustively review the current observational successes and problems of this alternative paradigm at all astrophysical scales, and summarize the various theoretical attempts (TeVeS, GEA, BIMOND, and others) made to effectively embed this modification of Newtonian dynamics within a relativistic theory of gravity.
TL;DR: The platform presented here provides a significant advancement in the ability to understand the spatiotemporal dynamics of metabolite production in live microbial colonies and communities.
Abstract: Integrating the governing chemistry with the genomics and phenotypes of microbial colonies has been a “holy grail” in microbiology. This work describes a highly sensitive, broadly applicable, and cost-effective approach that allows metabolic profiling of live microbial colonies directly from a Petri dish without any sample preparation. Nanospray desorption electrospray ionization mass spectrometry (MS), combined with alignment of MS data and molecular networking, enabled monitoring of metabolite production from live microbial colonies from diverse bacterial genera, including Bacillus subtilis, Streptomyces coelicolor, Mycobacterium smegmatis, and Pseudomonas aeruginosa. This work demonstrates that, by using these tools to visualize small molecular changes within bacterial interactions, insights can be gained into bacterial developmental processes as a result of the improved organization of MS/MS data. To validate this experimental platform, metabolic profiling was performed on Pseudomonas sp. SH-C52, which protects sugar beet plants from infections by specific soil-borne fungi [R. Mendes et al. (2011) Science 332:1097–1100]. The antifungal effect of strain SH-C52 was attributed to thanamycin, a predicted lipopeptide encoded by a nonribosomal peptide synthetase gene cluster. Our technology, in combination with our recently developed peptidogenomics strategy, enabled the detection and partial characterization of thanamycin and showed that it is a monochlorinated lipopeptide that belongs to the syringomycin family of antifungal agents. In conclusion, the platform presented here provides a significant advancement in our ability to understand the spatiotemporal dynamics of metabolite production in live microbial colonies and communities.
University of Edinburgh1, University of British Columbia2, University of Oxford3, University of Bonn4, University of Victoria5, Leiden University6, Institut d'Astrophysique de Paris7, Institut de Ciències de l'Espai8, Academia Sinica9, Shanghai Normal University10, University of Toronto11, Perimeter Institute for Theoretical Physics12, University of Waterloo13, University College London14, California Institute of Technology15, Stanford University16
TL;DR: In this article, the Canada-France-Hawaii Telescope Lensing Survey (CFHTLenS) was used to determine a weak gravitational lensing signal from the full 154 deg^2 of deep multicolour data obtained by the CFHT Legacy Survey.
Abstract: We present the Canada–France–Hawaii Telescope Lensing Survey (CFHTLenS) that accurately determines a weak gravitational lensing signal from the full 154 deg^2 of deep multicolour data obtained by the CFHT Legacy Survey. Weak gravitational lensing by large-scale structure is widely recognized as one of the most powerful but technically challenging probes of cosmology. We outline the CFHTLenS analysis pipeline, describing how and why every step of the chain from the raw pixel data to the lensing shear and photometric redshift measurement has been revised and improved compared to previous analyses of a subset of the same data. We present a novel method to identify data which contributes a non-negligible contamination to our sample and quantify the required level of calibration for the survey. Through a series of cosmology-insensitive tests we demonstrate the robustness of the resulting cosmic shear signal, presenting a science-ready shear and photometric redshift catalogue for future exploitation.
TL;DR: A novel framework to generate and rank plausible hypotheses for the spatial extent of objects in images using bottom-up computational processes and mid-level selection cues and it is shown that the algorithm can be used, successfully, in a segmentation-based visual object category recognition pipeline.
Abstract: We present a novel framework to generate and rank plausible hypotheses for the spatial extent of objects in images using bottom-up computational processes and mid-level selection cues. The object hypotheses are represented as figure-ground segmentations, and are extracted automatically, without prior knowledge of the properties of individual object classes, by solving a sequence of Constrained Parametric Min-Cut problems (CPMC) on a regular image grid. In a subsequent step, we learn to rank the corresponding segments by training a continuous model to predict how likely they are to exhibit real-world regularities (expressed as putative overlap with ground truth) based on their mid-level region properties, then diversify the estimated overlap score using maximum marginal relevance measures. We show that this algorithm significantly outperforms the state of the art for low-level segmentation in the VOC 2009 and 2010 data sets. In our companion papers [1], [2], we show that the algorithm can be used, successfully, in a segmentation-based visual object category recognition pipeline. This architecture ranked first in the VOC2009 and VOC2010 image segmentation and labeling challenges.
Technische Universität München1, Hospital de Sant Pau2, University of Bonn3, Aarhus University Hospital4, University of Milan5, Boston Children's Hospital6, University of Modena and Reggio Emilia7, University of Vienna8, Wrocław Medical University9, Hannover Medical School10, Ludwig Maximilian University of Munich11
TL;DR: The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation as discussed by the authors.
Abstract: The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted of a nominal group process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific provocation factors. Anti-inflammatory treatment based on topical glucocorticosteroids and topical calcineurin inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in certain locations. Systemic immune-suppressive treatment is an option for severe refractory cases. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Adjuvant therapy includes UV irradiation preferably with UVA1 wavelength or UVB 311 nm. Dietary recommendations should be specific and given only in diagnosed individual food allergy. Allergen-specific immunotherapy to aeroallergens may be useful in selected cases. Stress-induced exacerbations may make psychosomatic counselling recommendable. 'Eczema school' educational programs have been proven to be helpful. Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic therapies.
University of Copenhagen1, University of Maryland, College Park2, Council for Scientific and Industrial Research3, ETH Zurich4, University of Bonn5, Centre national de la recherche scientifique6, Potsdam Institute for Climate Impact Research7, Clark University8, University of Virginia9, University of Florida10, Lund University11, Cheikh Anta Diop University12, University of Buenos Aires13, Helmholtz Centre for Environmental Research - UFZ14
TL;DR: In this paper, the authors provided an analysis of trends in vegetation greenness of semi-arid areas using AVHRR GIMMS from 1981 to 2007, and found that greenness increases are found both in semi-arsid areas where precipitation is the dominating limiting factor for plant production (0.019 NDVI units) and in semiarid regions where air temperature is the primarily growth constraint (0.,013 NDVI Units).
Jason L. Stein1, Sarah E. Medland2, Sarah E. Medland3, Alejandro Arias Vasquez4 +234 more•Institutions (61)
TL;DR: In this article, the authors report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium.
Abstract: Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).
TL;DR: A combined search for the Standard Model Higgs boson with the ATLAS experiment at the LHC using datasets corresponding to integrated luminosities from 1.04 fb(-1) to 4.9 fb(1) of pp collisions is described in this paper.
07 Oct 2012
TL;DR: This paper introduces multiplicative second-order analogues of average and max-pooling that together with appropriate non-linearities lead to state-of-the-art performance on free-form region recognition, without any type of feature coding.
Abstract: Feature extraction, coding and pooling, are important components on many contemporary object recognition paradigms. In this paper we explore novel pooling techniques that encode the second-order statistics of local descriptors inside a region. To achieve this effect, we introduce multiplicative second-order analogues of average and max-pooling that together with appropriate non-linearities lead to state-of-the-art performance on free-form region recognition, without any type of feature coding. Instead of coding, we found that enriching local descriptors with additional image information leads to large performance gains, especially in conjunction with the proposed pooling methodology. We show that second-order pooling over free-form regions produces results superior to those of the winning systems in the Pascal VOC 2011 semantic segmentation challenge, with models that are 20,000 times faster.
TL;DR: The results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism–associated TKI resistance.
Abstract: Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.