Showing papers by "University of Zurich published in 2010"
TL;DR: Cai et al. as discussed by the authors used a surface-assisted coupling of the precursors into linear polyphenylenes and their subsequent cyclodehydrogenation to produce GNRs of different topologies and widths.
Abstract: Graphene nanoribbons, narrow straight-edged strips of the single-atom-thick sheet form of carbon, are predicted to exhibit remarkable properties, making them suitable for future electronic applications. Before this potential can be realized, more chemically precise methods of production will be required. Cai et al. report a step towards that goal with the development of a bottom-up fabrication method that produces atomically precise graphene nanoribbons of different topologies and widths. The process involves the deposition of precursor monomers with structures that 'encode' the topology and width of the desired ribbon end-product onto a metal surface. Surface-assisted coupling of the precursors into linear polyphenylenes is then followed by cyclodehydrogenation. Given the method's versatility and precision, it could even provide a route to more unusual graphene nanoribbon structures with tuned chemical and electronic properties. Graphene nanoribbons (GNRs) have structure-dependent electronic properties that make them attractive for the fabrication of nanoscale electronic devices, but exploiting this potential has been hindered by the lack of precise production methods. Here the authors demonstrate how to reliably produce different GNRs, using precursor monomers that encode the structure of the targeted nanoribbon and are converted into GNRs by means of surface-assisted coupling. Graphene nanoribbons—narrow and straight-edged stripes of graphene, or single-layer graphite—are predicted to exhibit electronic properties that make them attractive for the fabrication of nanoscale electronic devices1,2,3. In particular, although the two-dimensional parent material graphene4,5 exhibits semimetallic behaviour, quantum confinement and edge effects2,6 should render all graphene nanoribbons with widths smaller than 10 nm semiconducting. But exploring the potential of graphene nanoribbons is hampered by their limited availability: although they have been made using chemical7,8,9, sonochemical10 and lithographic11,12 methods as well as through the unzipping of carbon nanotubes13,14,15,16, the reliable production of graphene nanoribbons smaller than 10 nm with chemical precision remains a significant challenge. Here we report a simple method for the production of atomically precise graphene nanoribbons of different topologies and widths, which uses surface-assisted coupling17,18 of molecular precursors into linear polyphenylenes and their subsequent cyclodehydrogenation19,20. The topology, width and edge periphery of the graphene nanoribbon products are defined by the structure of the precursor monomers, which can be designed to give access to a wide range of different graphene nanoribbons. We expect that our bottom-up approach to the atomically precise fabrication of graphene nanoribbons will finally enable detailed experimental investigations of the properties of this exciting class of materials. It should even provide a route to graphene nanoribbon structures with engineered chemical and electronic properties, including the theoretically predicted intraribbon quantum dots21, superlattice structures22 and magnetic devices based on specific graphene nanoribbon edge states3.
2,905 citations
TL;DR: The current understanding of myeloid lineage development is reviewed and the developmental pathways and cues that drive differentiation are described, which are central to the development of immunologic memory and tolerance in mice.
Abstract: Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
2,832 citations
TL;DR: In this article, a biennial review summarizes much of particle physics using data from previous editions, plus 2158 new measurements from 551 papers, they list, evaluate and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons.
Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2158 new measurements from 551 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on neutrino mass, mixing, and oscillations, QCD, top quark, CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, fragmentation functions, particle detectors for accelerator and non-accelerator physics, magnetic monopoles, cosmological parameters, and big bang cosmology.
2,788 citations
University of Kiel1, Cedars-Sinai Medical Center2, Wellcome Trust Sanger Institute3, University of Pennsylvania4, QIMR Berghofer Medical Research Institute5, Peninsula College of Medicine and Dentistry6, University of Edinburgh7, University of Cambridge8, University of Otago9, University of Washington10, University of Groningen11, University of Liège12, Harvard University13, Casa Sollievo della Sofferenza14, King's College London15, University of Chicago16, Yale University17, Johns Hopkins University18, Ludwig Maximilian University of Munich19, Charité20, McGill University21, Lille University of Science and Technology22, Cincinnati Children's Hospital Medical Center23, Ghent University24, Torbay Hospital25, Mater Health Services26, Université libre de Bruxelles27, RWTH Aachen University28, University of Utah29, Örebro University30, Leiden University31, University of Paris32, Technion – Israel Institute of Technology33, University of Western Australia34, Tel Aviv University35, University of Dundee36, University of Manchester37, University of Pittsburgh38, Royal Hospital for Sick Children39, Katholieke Universiteit Leuven40, Guy's and St Thomas' NHS Foundation Trust41, University of Bern42, University of Toronto43, University of Amsterdam44, Karolinska Institutet45, University of Zurich46, Université de Montréal47, Emory University48, Newcastle University49
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.
Abstract: We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
2,482 citations
The Heart Research Institute1, University of Erlangen-Nuremberg2, Saarland University3, Barts Health NHS Trust4, John Hunter Hospital5, Université catholique de Louvain6, University of Kiel7, University of Cologne8, Leipzig University9, Medical University of Vienna10, Complutense University of Madrid11, St. Vincent's Health System12, University of Duisburg-Essen13, Canterbury Hospital14, University of Zurich15, University of Glasgow16, Auckland City Hospital17, University of Freiburg18, Jagiellonian University19, Stanford University20, Harvard University21
TL;DR: Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients and should be continued, according to the authors.
2,200 citations
University of Amsterdam1, Naturalis2, Utrecht University3, Central University of Venezuela4, Ecopetrol5, Spanish National Research Council6, Petrobras7, Smithsonian Tropical Research Institute8, Federal University of Uberlandia9, Universidade Federal do Acre10, Academy of Natural Sciences of Drexel University11, ETH Zurich12, University of Oxford13, University of Gothenburg14, University of Zurich15
TL;DR: It is shown that Andean uplift was crucial for the evolution of Amazonian landscapes and ecosystems, and that current biodiversity patterns are rooted deep in the pre-Quaternary.
Abstract: The Amazonian rainforest is arguably the most species-rich terrestrial ecosystem in the world, yet the timing of the origin and evolutionary causes of this diversity are a matter of debate. We review the geologic and phylogenetic evidence from Amazonia and compare it with uplift records from the Andes. This uplift and its effect on regional climate fundamentally changed the Amazonian landscape by reconfiguring drainage patterns and creating a vast influx of sediments into the basin. On this “Andean” substrate, a region-wide edaphic mosaic developed that became extremely rich in species, particularly in Western Amazonia. We show that Andean uplift was crucial for the evolution of Amazonian landscapes and ecosystems, and that current biodiversity patterns are rooted deep in the pre-Quaternary.
1,790 citations
Agricultural Research Service1, Oregon State University2, University of California, Berkeley3, John Innes Centre4, United States Department of Energy5, United States Department of Agriculture6, University of California, Davis7, University of Silesia in Katowice8, China Agricultural University9, Iowa State University10, Washington State University11, University of Florida12, University of Massachusetts Amherst13, University of Wisconsin-Madison14, Technische Universität München15, Cornell University16, University of Zurich17, University of Helsinki18, Universidade Federal de Pelotas19, Purdue University20, University of Texas at Arlington21, National Center for Genome Resources22, University of Delaware23, Joint BioEnergy Institute24, University of Copenhagen25, Kyung Hee University26, Ghent University27, Centre national de la recherche scientifique28, Oak Ridge National Laboratory29, Ohio State University30, Institut national de la recherche agronomique31, University of Picardie Jules Verne32, Illinois State University33, Sabancı University34, Donald Danforth Plant Science Center35
TL;DR: The high-quality genome sequence will help Brachypodium reach its potential as an important model system for developing new energy and food crops and establishes a template for analysis of the large genomes of economically important pooid grasses such as wheat.
Abstract: Three subfamilies of grasses, the Ehrhartoideae, Panicoideae and Pooideae, provide the bulk of human nutrition and are poised to become major sources of renewable energy. Here we describe the genome sequence of the wild grass Brachypodium distachyon (Brachypodium), which is, to our knowledge, the first member of the Pooideae subfamily to be sequenced. Comparison of the Brachypodium, rice and sorghum genomes shows a precise history of genome evolution across a broad diversity of the grasses, and establishes a template for analysis of the large genomes of economically important pooid grasses such as wheat. The high-quality genome sequence, coupled with ease of cultivation and transformation, small size and rapid life cycle, will help Brachypodium reach its potential as an important model system for developing new energy and food crops.
1,603 citations
TL;DR: TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease.
Abstract: Transcatheter arterial chemoembolization (TACE) offers a survival benefit to patients with intermediate hepatocellular carcinoma (HCC). A widely accepted TACE regimen includes administration of doxorubicin-oil emulsion followed by gelatine sponge—conventional TACE. Recently, a drug-eluting bead (DC Bead®) has been developed to enhance tumor drug delivery and reduce systemic availability. This randomized trial compares conventional TACE (cTACE) with TACE with DC Bead for the treatment of cirrhotic patients with HCC. Two hundred twelve patients with Child-Pugh A/B cirrhosis and large and/or multinodular, unresectable, N0, M0 HCCs were randomized to receive TACE with DC Bead loaded with doxorubicin or cTACE with doxorubicin. Randomization was stratified according to Child-Pugh status (A/B), performance status (ECOG 0/1), bilobar disease (yes/no), and prior curative treatment (yes/no). The primary endpoint was tumor response (EASL) at 6 months following independent, blinded review of MRI studies. The drug-eluting bead group showed higher rates of complete response, objective response, and disease control compared with the cTACE group (27% vs. 22%, 52% vs. 44%, and 63% vs. 52%, respectively). The hypothesis of superiority was not met (one-sided P = 0.11). However, patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease showed a significant increase in objective response (P = 0.038) compared to cTACE. DC Bead was associated with improved tolerability, with a significant reduction in serious liver toxicity (P < 0.001) and a significantly lower rate of doxorubicin-related side effects (P = 0.0001). TACE with DC Bead and doxorubicin is safe and effective in the treatment of HCC and offers a benefit to patients with more advanced disease.
1,333 citations
TL;DR: Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
Abstract: Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ∼600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
1,326 citations
23 Aug 2010
TL;DR: It is shown that both problems can be overcome by replacing the conventional point estimate of accuracy by an estimate of the posterior distribution of the balanced accuracy.
Abstract: Evaluating the performance of a classification algorithm critically requires a measure of the degree to which unseen examples have been identified with their correct class labels. In practice, generalizability is frequently estimated by averaging the accuracies obtained on individual cross-validation folds. This procedure, however, is problematic in two ways. First, it does not allow for the derivation of meaningful confidence intervals. Second, it leads to an optimistic estimate when a biased classifier is tested on an imbalanced dataset. We show that both problems can be overcome by replacing the conventional point estimate of accuracy by an estimate of the posterior distribution of the balanced accuracy.
1,216 citations
TL;DR: The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis ofHCV infection.
TL;DR: Hydrodynamical simulations in a framework assuming the presence of CDM and a cosmological constant are reported in which the inhomogeneous interstellar medium is resolved and the analogues of dwarf galaxies—bulgeless and with shallow central dark-matter profiles—arise naturally in these simulations.
Abstract: For almost two decades the properties of ‘dwarf’ galaxies have challenged the cold dark matter (CDM) model of galaxy formation^1. Most observed dwarf galaxies consist of a rotating stellar disk^2 embedded in a massive dark-matter halo with a near-constant-density core^3. Models based on the dominance of CDM, however, invariably form galaxies with dense spheroidal stellar bulges and steep central dark-matter profiles^(4,5,6,) because low-angular-momentum baryons and dark matter sink to the centres of galaxies through accretion and repeated mergers^7. Processes that decrease the central density of CDM halos^8 have been identified, but have not yet reconciled theory with observations of present-day dwarfs. This failure is potentially catastrophic for the CDM model, possibly requiring a different dark-matter particle candidate^9. Here we report hydrodynamical simulations (in a framework^(10) assuming the presence of CDM and a cosmological constant) in which the inhomogeneous interstellar medium is resolved. Strong outflows from supernovae remove low-angular-momentum gas, which inhibits the formation of bulges and decreases the dark-matter density to less than half of what it would otherwise be within the central kiloparsec. The analogues of dwarf galaxies—bulgeless and with shallow central dark-matter profiles—arise naturally in these simulations.
University of Basel1, Radboud University Nijmegen2, University of Padua3, Complutense University of Madrid4, University of Paris5, University of Zurich6, University of Bari7, Lithuanian University of Health Sciences8, University of Florence9, Russian Academy10, Rambam Health Care Campus11, University of Regensburg12, Charité13, University of the Witwatersrand14, Johns Hopkins University15, University of Coimbra16, University of Verona17, Lund University18, University of Ljubljana19, Utrecht University20, University of Pécs21, Medical University of Vienna22, University of Debrecen23, Sapienza University of Rome24, University of Geneva25, University of Silesia in Katowice26, University College London27, University of Tübingen28, Military Medical Academy29, Lille University of Science and Technology30, University of Michigan31, Iuliu Hațieganu University of Medicine and Pharmacy32, Charles University in Prague33, University of Zagreb34
TL;DR: Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.
Abstract: Objectives To determine the causes and predictors of mortality in systemic sclerosis (SSc). Methods Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. Results Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). Conclusion Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.
TL;DR: It is shown that chronic and unpredictable maternal separation induces depressive-like behaviors and alters the behavioral response to aversive environments in the separated animals when adult, highlighting the negative impact of early stress on behavioral responses across generations and on the regulation of DNA methylation in the germline.
University of British Columbia1, University of Zurich2, Northwestern University3, Washington University in St. Louis4, Uppsala University5, University of Sydney6, Medical University of Vienna7, Indiana University8, University of New South Wales9, Aarhus University10, University of Sheffield11, VU University Amsterdam12, University College London13, University of Antwerp14, Walton Centre15, Mayo Clinic16, University of Pennsylvania17, University of Manchester18
TL;DR: A system of nosology was introduced that grouped the FTLD subtypes into broad categories, based on the molecular defect that is most characteristic, according to current evidence, and provided a concise and consistent terminology that has now been widely adopted in the literature.
Abstract: Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration : an update
TL;DR: A practical guide for ecologists interested in exploring the potential to apply this quantitative genetic method in their research, by outlining key concepts in quantitative genetics and how an animal model estimates relevant quantitative genetic parameters, such as heritabilities or genetic correlations.
Abstract: 1. Efforts to understand the links between evolutionary and ecological dynamics hinge on our ability to measure and understand how genes influence phenotypes, fitness and population dynamics. Quantitative genetics provides a range of theoretical and empirical tools with which to achieve this when the relatedness between individuals within a population is known. 2. A number of recent studies have used a type of mixed-effects model, known as the animal model, to estimate the genetic component of phenotypic variation using data collected in the field. Here, we provide a practical guide for ecologists interested in exploring the potential to apply this quantitative genetic method in their research. 3. We begin by outlining, in simple terms, key concepts in quantitative genetics and how an animal model estimates relevant quantitative genetic parameters, such as heritabilities or genetic correlations. 4. We then provide three detailed example tutorials, for implementation in a variety of software packages, for some basic applications of the animal model. We discuss several important statistical issues relating to best practice when fitting different kinds of mixed models. 5. We conclude by briefly summarizing more complex applications of the animal model, and by highlighting key pitfalls and dangers for the researcher wanting to begin using quantitative genetic tools to address ecological and evolutionary questions.
TL;DR: It is suggested that flocks behave as critical systems, poised to respond maximally to environmental perturbations, through scale-free behavioral correlations, which provide each animal with an effective perception range much larger than the direct interindividual interaction range, thus enhancing global response to perturbation.
Abstract: From bird flocks to fish schools, animal groups often seem to react to environmental perturbations as if of one mind. Most studies in collective animal behavior have aimed to understand how a globally ordered state may emerge from simple behavioral rules. Less effort has been devoted to understanding the origin of collective response, namely the way the group as a whole reacts to its environment. Yet, in the presence of strong predatory pressure on the group, collective response may yield a significant adaptive advantage. Here we suggest that collective response in animal groups may be achieved through scale-free behavioral correlations. By reconstructing the 3D position and velocity of individual birds in large flocks of starlings, we measured to what extent the velocity fluctuations of different birds are correlated to each other. We found that the range of such spatial correlation does not have a constant value, but it scales with the linear size of the flock. This result indicates that behavioral correlations are scale free: The change in the behavioral state of one animal affects and is affected by that of all other animals in the group, no matter how large the group is. Scale-free correlations provide each animal with an effective perception range much larger than the direct interindividual interaction range, thus enhancing global response to perturbations. Our results suggest that flocks behave as critical systems, poised to respond maximally to environmental perturbations.
TL;DR: TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies because of the striking functional and structural similarities of these proteins, which imply that abnormal RNA metabolism is a pivotal event in neurodegeneration.
Abstract: Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies.
University of Cologne1, University of Zurich2, Cornell University3, University of Bonn4, Max Planck Society5, Peter MacCallum Cancer Centre6, St. Vincent's Health System7, Joseph Fourier University8, Oslo University Hospital9, Schiller International University10, University of Groningen11, VU University Medical Center12, Vanderbilt University13
TL;DR: F focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.
Abstract: Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases). Using cell-based screening with the FGFR inhibitor PD173074 in a large (n = 83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (FGFR1(V561M)), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally, we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Thus, focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.
University of Göttingen1, University of Minnesota2, University of Jena3, University of Zurich4, University of Bern5, University of Potsdam6, Max Planck Society7, Helmholtz Centre for Environmental Research - UFZ8, Leipzig University9, Humboldt State University10, University of Cologne11, ETH Zurich12, Lüneburg University13, Tallinn University of Technology14, Imperial College London15, University of British Columbia16, American Museum of Natural History17
TL;DR: It is shown that plant diversity effects dampen with increasing trophic level and degree of omnivory, and the results suggest that plant Diversity has strong bottom-up effects on multitrophic interaction networks, with particularly strong effects on lower trophIC levels.
Abstract: Biodiversity is rapidly declining, and this may negatively affect ecosystem processes, including economically important ecosystem services Previous studies have shown that biodiversity has positive effects on organisms and processes across trophic levels However, only a few studies have so far incorporated an explicit food-web perspective In an eight-year biodiversity experiment, we studied an unprecedented range of above- and below-ground organisms and multitrophic interactions A multitrophic data set originating from a single long-term experiment allows mechanistic insights that would not be gained from meta-analysis of different experiments Here we show that plant diversity effects dampen with increasing trophic level and degree of omnivory This was true both for abundance and species richness of organisms Furthermore, we present comprehensive above-ground/below-ground biodiversity food webs Both above ground and below ground, herbivores responded more strongly to changes in plant diversity than did carnivores or omnivores Density and richness of carnivorous taxa was independent of vegetation structure Below-ground responses to plant diversity were consistently weaker than above-ground responses Responses to increasing plant diversity were generally positive, but were negative for biological invasion, pathogen infestation and hyperparasitism Our results suggest that plant diversity has strong bottom-up effects on multitrophic interaction networks, with particularly strong effects on lower trophic levels Effects on higher trophic levels are indirectly mediated through bottom-up trophic cascades
Imperial College London1, Institut national de la recherche agronomique2, University of Exeter3, Max Planck Society4, John Innes Centre5, University of Oxford6, University of Reading7, Cornell University8, United States Department of Agriculture9, University of Copenhagen10, University of Zurich11, Technical University of Madrid12
TL;DR: A group of papers analyzes pathogen genomes to find the roots of virulence, opportunism, and life-style determinants in plant pathogens, suggesting that most effectors represent species-specific adaptations.
Abstract: Powdery mildews are phytopathogens whose growth and reproduction are entirely dependent on living plant cells. The molecular basis of this life-style, obligate biotrophy, remains unknown. We present the genome analysis of barley powdery mildew, Blumeria graminis f.sp. hordei (Blumeria), as well as a comparison with the analysis of two powdery mildews pathogenic on dicotyledonous plants. These genomes display massive retrotransposon proliferation, genome-size expansion, and gene losses. The missing genes encode enzymes of primary and secondary metabolism, carbohydrate-active enzymes, and transporters, probably reflecting their redundancy in an exclusively biotrophic life-style. Among the 248 candidate effectors of pathogenesis identified in the Blumeria genome, very few (less than 10) define a core set conserved in all three mildews, suggesting that most effectors represent species-specific adaptations.
TL;DR: A new consensus nomenclature for all ADP-ribosyltransferases (ARTs) based on the catalyzed reaction and on structural features is proposed to facilitate communication between researchers both inside and outside the ADP, ribosylation field.
TL;DR: It is shown that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI 1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.
Abstract: Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.
TL;DR: This document presents an updated version of the guideline for the management of bleeding following severe injury, which provides an evidence-based multidisciplinary approach to themanagement of critically injured bleeding trauma patients.
Abstract: Introduction: Evidence-based recommendations are needed to guide the acute management of the bleeding trauma patient, which when implemented may improve patient outcomes. Methods: The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing a guideline for the management of bleeding following severe injury. This document presents an updated version of the guideline published by the group in 2007. Recommendations were formulated using a nominal group process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature. Results: Key changes encompassed in this version of the guideline include new recommendations on coagulation support and monitoring and the appropriate use of local haemostatic measures, tourniquets, calcium and desmopressin in the bleeding trauma patient. The remaining recommendations have been reevaluated and graded based on literature published since the last edition of the guideline. Consideration was also given to changes in clinical practice that have taken place during this time period as a result of both new evidence and changes in the general availability of relevant agents and technologies. Conclusions: This guideline provides an evidence-based multidisciplinary approach to the management of critically injured bleeding trauma patients.
TL;DR: It is hypothesized that fornix/hypothalamus deep brain stimulation (DBS) could modulate neurophysiological activity in these pathological circuits and possibly produce clinical benefits in Alzheimer's disease.
Abstract: Objective: Alzheimer disease (AD) is characterized by functional impairment in the neural elements and circuits underlying cognitive and memory functions. We hypothesized that fornix/hypothalamus deep brain stimulation (DBS) could modulate neurophysiological activity in these pathological circuits and possibly produce clinical benefits. Methods: We conducted a phase I trial in 6 patients with mild AD receiving ongoing medication treatment. Patients received continuous stimulation for 12 months. Three main lines of investigation were pursued including: (1) mapping the brain areas whose physiological function was modulated by stimulation using standardized low-resolution electromagnetic tomography, (2) assessing whether DBS could correct the regional alterations in cerebral glucose metabolism in AD using positron emission tomography (PET), and 3) measuring the effects of DBS on cognitive function over time using clinical scales and instruments. Results: DBS drove neural activity in the memory circuit, including the entorhinal, and hippocampal areas and activated the brain’s default mode network. PET scans showed an early and striking reversal of the impaired glucose utilization in the temporal and parietal lobes that was maintained after 12 months of continuous stimulation. Evaluation of the Alzheimer’s Disease Assessment Scale cognitive subscale and the Mini Mental State Examination suggested possible improvements and/or slowing in the rate of cognitive decline at 6 and 12 months in some patients. There were no serious adverse events. Interpretation: There is an urgent need for novel therapeutic approaches for AD. Modulating pathological brain activity in this illness with DBS merits further investigation. ANN NEUROL 2010;00:000–000
TL;DR: It is demonstrated that a West Nile virus mutant that lacks 2′-O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling, and suggested an evolutionary explanation for 2-O methylation of cellular mRNA: to distinguish self from non-self RNA.
Abstract: Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2'-O positions of the 5' guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability, the function of 2'-O methylation has remained uncertain since its discovery 35 years ago. Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2'-O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2'-O methylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2'-O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2'-O methylation of the 5' cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2'-O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells.
Vardan Khachatryan, Albert M. Sirunyan, Armen Tumasyan, Wolfgang Adam1 +2197 more•Institutions (149)
TL;DR: The pre-print version of the Published Article can be accessed from the link below - Copyright @ 2010 Springer Verlag as discussed by the authors, which can be viewed as a preprint of the published article.
Abstract: This is the pre-print version of the Published Article, which can be accessed from the link below - Copyright @ 2010 Springer Verlag
Book•
12 Nov 2010TL;DR: In this paper, the authors transformed strongly elliptic boundary value problems of second order in domains \( \Omega \subset \mathbb{R}^3\) into boundary integral equations.
Abstract: In Chap. 3 we transformed strongly elliptic boundary value problems of second order in domains \( \Omega \subset \mathbb{R}^3\) into boundary integral equations. These integral equations were formulated as variational problems on a Hilbert space H:
TL;DR: Evidence is provided that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas and that much of the prognostic significance of patient age is due to the predominant occurrence of IDH 1 mutations in younger patients.
Abstract: WHO grading of human brain tumors extends beyond a strictly histological grading system by providing a basis predictive for the clinical behavior of the respective neoplasm. For example, patients with glioblastoma WHO grade IV usually show a less favorable clinical course and receive more aggressive first-line treatment than patients with anaplastic astrocytoma WHO grade III. Here we provide evidence that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas. We sequenced the isocitrate dehydrogenase 1 gene (IDH1) at codon 132 in 382 patients with anaplastic astrocytoma and glioblastoma from the NOA-04 trial and from a prospective translational cohort study of the German Glioma Network. Patients with anaplastic astrocytomas carried IDH1 mutations in 60%, and patients with glioblastomas in 7.2%. IDH1 was the most prominent single prognostic factor (RR 2.7; 95% CI 1.6–4.5) followed by age, diagnosis and MGMT. The sequence from more favorable to poorer outcome was (1) anaplastic astrocytoma with IDH1 mutation, (2) glioblastoma with IDH1 mutation, (3) anaplastic astrocytoma without IDH1 mutation and (4) glioblastoma without IDH1 mutation (p < 0.0001). In this combined set of anaplastic astrocytomas and glioblastomas both, IDH1 mutation and IDH1 expression status were of greater prognostic relevance than histological diagnosis according to the current WHO classification system. Our data indicate that much of the prognostic significance of patient age is due to the predominant occurrence of IDH1 mutations in younger patients. Immunohistochemistry using a mutation-specific antibody recognizing the R132H mutation yielded similar results. We propose to complement the current WHO classification and grading of high-grade astrocytic gliomas by the IDH1 mutation status and to use this combined histological and molecular classification in future clinical trials.
TL;DR: A reversible germ-free colonization system in mice that is independent of diet or antibiotic manipulation is reported, and specific IgA induction occurred as a stepwise response to current bacterial exposure, such that the antibody repertoire matched the existing commensal content.
Abstract: The lower intestine of adult mammals is densely colonized with nonpathogenic (commensal) microbes. Gut bacteria induce protective immune responses, which ensure host-microbial mutualism. The continuous presence of commensal intestinal bacteria has made it difficult to study mucosal immune dynamics. Here, we report a reversible germ-free colonization system in mice that is independent of diet or antibiotic manipulation. A slow (more than 14 days) onset of a long-lived (half-life over 16 weeks), highly specific anticommensal immunoglobulin A (IgA) response in germ-free mice was observed. Ongoing commensal exposure in colonized mice rapidly abrogated this response. Sequential doses lacked a classical prime-boost effect seen in systemic vaccination, but specific IgA induction occurred as a stepwise response to current bacterial exposure, such that the antibody repertoire matched the existing commensal content.