Showing papers by "University of Tübingen published in 2015"
TL;DR: DIAMOND is introduced, an open-source algorithm based on double indexing that is 20,000 times faster than BLASTX on short reads and has a similar degree of sensitivity.
Abstract: The alignment of sequencing reads against a protein reference database is a major computational bottleneck in metagenomics and data-intensive evolutionary projects. Although recent tools offer improved performance over the gold standard BLASTX, they exhibit only a modest speedup or low sensitivity. We introduce DIAMOND, an open-source algorithm based on double indexing that is 20,000 times faster than BLASTX on short reads and has a similar degree of sensitivity.
7,164 citations
University Hospital Bonn1, University of California, Riverside2, Harvard University3, Case Western Reserve University4, University of Illinois at Chicago5, European Institute6, Stanford University7, VA Palo Alto Healthcare System8, Spanish National Research Council9, Cleveland Clinic Lerner Research Institute10, Hong Kong University of Science and Technology11, University of California, Los Angeles12, University of Southern Denmark13, University of Cambridge14, University of Manchester15, Ikerbasque16, University of the Basque Country17, RIKEN Brain Science Institute18, University of Eastern Finland19, University of Massachusetts Medical School20, University of Bonn21, Center of Advanced European Studies and Research22, University of Southern California23, University of South Florida24, Duke University25, Southampton General Hospital26, Moorgreen Hospital27, University of Southampton28, Louisiana State University29, Imperial College London30, Centre national de la recherche scientifique31, Karolinska Institutet32, Max Planck Society33, University of Tübingen34, University of Groningen35, University of Colorado Denver36, Douglas Mental Health University Institute37
TL;DR: Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.
Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.
3,947 citations
TL;DR: Investigating the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab found no recurrent neoantigen peptide sequences predicted responder patient populations, suggesting detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
Abstract: Monoclonal antibodies directed against cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
2,065 citations
The Catholic University of America1, Royal Prince Alfred Hospital2, University of Toronto3, Centre for Addiction and Mental Health4, Università Campus Bio-Medico5, University of Eastern Finland6, Monash University7, Medical University of South Carolina8, Paris 12 Val de Marne University9, University of Regensburg10, University of Brescia11, University of Göttingen12, Beth Israel Deaconess Medical Center13, University of Siena14, University College London15, Copenhagen University Hospital16, Fukushima Medical University17, University of Tübingen18
TL;DR: These guidelines provide an up-date of previous IFCN report on “Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application” and include some recent extensions and developments.
1,850 citations
TL;DR: AntiSMASH as mentioned in this paper is a web server and stand-alone tool for the automatic genomic identification and analysis of biosynthetic gene clusters, available at http://antismash.org.
Abstract: Microbial secondary metabolism constitutes a rich source of antibiotics, chemotherapeutics, insecticides and other high-value chemicals. Genome mining of gene clusters that encode the biosynthetic pathways for these metabolites has become a key methodology for novel compound discovery. In 2011, we introduced antiSMASH, a web server and stand-alone tool for the automatic genomic identification and analysis of biosynthetic gene clusters, available at http://antismash.secondarymetabolites.org. Here, we present version 3.0 of antiSMASH, which has undergone major improvements. A full integration of the recently published ClusterFinder algorithm now allows using this probabilistic algorithm to detect putative gene clusters of unknown types. Also, a new dereplication variant of the ClusterBlast module now identifies similarities of identified clusters to any of 1172 clusters with known end products. At the enzyme level, active sites of key biosynthetic enzymes are now pinpointed through a curated pattern-matching procedure and Enzyme Commission numbers are assigned to functionally classify all enzyme-coding genes. Additionally, chemical structure prediction has been improved by incorporating polyketide reduction states. Finally, in order for users to be able to organize and analyze multiple antiSMASH outputs in a private setting, a new XML output module allows offline editing of antiSMASH annotations within the Geneious software.
1,691 citations
TL;DR: In this article, major new initiatives in hydropower development are now under way, and at least 3,700 major dams, each with a capacity of more than 1MW, are either planned or under construction, primarily in countries with emerging economies.
Abstract: Human population growth, economic development, climate change, and the need to close the electricity access gap have stimulated the search for new sources of renewable energy. In response to this need, major new initiatives in hydropower development are now under way. At least 3,700 major dams, each with a capacity of more than 1 MW, are either planned or under construction, primarily in countries with emerging economies. These dams are predicted to increase the present global hydroelectricity capacity by 73 % to about 1,700 GW. Even such a dramatic expansion in hydropower capacity will be insufficient to compensate for the increasing electricity demand. Furthermore, it will only partially close the electricity gap, may not substantially reduce greenhouse gas emission (carbon dioxide and methane), and may not erase interdependencies and social conflicts. At the same time, it is certain to reduce the number of our planet’s remaining free-flowing large rivers by about 21 %. Clearly, there is an urgent need to evaluate and to mitigate the social, economic, and ecological ramifications of the current boom in global dam construction.
1,462 citations
University of Florida1, University of Bonn2, Institut national de la recherche agronomique3, Blaise Pascal University4, Stanford University5, Prince of Songkla University6, Agricultural Research Service7, University of Arizona8, International Maize and Wheat Improvement Center9, Kansas State University10, International Water Management Institute11, Washington State University12, Michigan State University13, CGIAR14, University of Leeds15, Counterintelligence Field Activity16, Spanish National Research Council17, University of Tübingen18, University of Guelph19, University of Maryland, College Park20, Texas A&M University21, Aarhus University22, Potsdam Institute for Climate Impact Research23, Indian Agricultural Research Institute24, Goddard Institute for Space Studies25, Rothamsted Research26, University of Hohenheim27, Wageningen University and Research Centre28, Chinese Academy of Sciences29, Commonwealth Scientific and Industrial Research Organisation30, China Agricultural University31, Nanjing Agricultural University32
TL;DR: The authors systematically tested 30 different wheat crop models of the Agricultural Model Intercomparison and Improvement Project against field experiments in which growing season mean temperatures ranged from 15 degrees C to 32 degrees C, including experiments with artificial heating.
Abstract: Crop models are essential tools for assessing the threat of climate change to local and global food production(1). Present models used to predict wheat grain yield are highly uncertain when simulating how crops respond to temperature(2). Here we systematically tested 30 different wheat crop models of the Agricultural Model Intercomparison and Improvement Project against field experiments in which growing season mean temperatures ranged from 15 degrees C to 32 degrees C, including experiments with artificial heating. Many models simulated yields well, but were less accurate at higher temperatures. The model ensemble median was consistently more accurate in simulating the crop temperature response than any single model, regardless of the input information used. Extrapolating the model ensemble temperature response indicates that warming is already slowing yield gains at a majority of wheat-growing locations. Global wheat production is estimated to fall by 6% for each degrees C of further temperature increase and become more variable over space and time.
1,461 citations
University of California, Los Angeles1, Vanderbilt University2, University of Zurich3, University of Duisburg-Essen4, University of Paris-Sud5, Harvard University6, Sheba Medical Center7, New York University8, University of Colorado Denver9, University of Arizona10, Netherlands Cancer Institute11, Durham University12, Seattle Cancer Care Alliance13, University of Tübingen14, University of Pennsylvania15, Temple University16, University of North Carolina at Chapel Hill17, University of Pittsburgh18, Memorial Sloan Kettering Cancer Center19, Merck & Co.20, University of California, San Francisco21
TL;DR: In this article, the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma were compared.
Abstract: Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0–1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF V600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45–0·73; p Interpretation These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
1,333 citations
University of Adelaide1, Harvard University2, Broad Institute3, Howard Hughes Medical Institute4, University of Mainz5, Max Planck Society6, University of Tübingen7, Hungarian Academy of Sciences8, Stockholm University9, Facultad de Filosofía y Letras10, The Heritage Foundation11, University of Basel12, Autonomous University of Barcelona13, University of Valladolid14, Hartwick College15
TL;DR: In this paper, the authors generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost 400,000 polymorphisms.
Abstract: We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost 400,000 polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of Western and Far Eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ∼8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ∼24,000-year-old Siberian. By ∼6,000-5,000 years ago, farmers throughout much of Europe had more hunter-gatherer ancestry than their predecessors, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but also from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ∼4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ∼75% of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ∼3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for a steppe origin of at least some of the Indo-European languages of Europe.
1,332 citations
Mater Health Services1, University of Sydney2, National and Kapodistrian University of Athens3, The Royal Marsden NHS Foundation Trust4, University of Tübingen5, University of Kiel6, Aix-Marseille University7, Paris Diderot University8, Sir Charles Gairdner Hospital9, Netherlands Cancer Institute10, Karolinska University Hospital11, Heidelberg University12, German Cancer Research Center13, Northwood University14, Institut Gustave Roussy15, University of Paris-Sud16, University of California, Los Angeles17, Novartis18, Merck & Co.19, Harvard University20
TL;DR: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma.
1,099 citations
Harvard University1, Broad Institute2, Howard Hughes Medical Institute3, University College Dublin4, Emory University5, Trinity College, Dublin6, University of Copenhagen7, University of Adelaide8, Russian Academy of Sciences9, Complutense University of Madrid10, Rovira i Virgili University11, University of Valladolid12, University of Tübingen13, Max Planck Society14, Danube Private University15, University of Basel16, Hartwick College17, Pompeu Fabra University18
TL;DR: A genome-wide scan for selection using ancient DNA is reported, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 bc, including 163 with newly reported data.
Abstract: Ancient DNA makes it possible to observe natural selection directly by analysing samples from populations before, during and after adaptation events. Here we report a genome-wide scan for selection using ancient DNA, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 bc, including 163 with newly reported data. The new samples include, to our knowledge, the first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones, and who we show were members of the population that was the source of Europe's first farmers. We also report a transect of the steppe region in Samara between 5600 and 300 bc, which allows us to identify admixture into the steppe from at least two external sources. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height.
Proceedings Article•
07 Dec 2015TL;DR: A new model of natural textures based on the feature spaces of convolutional neural networks optimised for object recognition is introduced, showing that across layers the texture representations increasingly capture the statistical properties of natural images while making object information more and more explicit.
Abstract: Here we introduce a new model of natural textures based on the feature spaces of convolutional neural networks optimised for object recognition. Samples from the model are of high perceptual quality demonstrating the generative power of neural networks trained in a purely discriminative fashion. Within the model, textures are represented by the correlations between feature maps in several layers of the network. We show that across layers the texture representations increasingly capture the statistical properties of natural images while making object information more and more explicit. The model provides a new tool to generate stimuli for neuroscience and might offer insights into the deep representations learned by convolutional neural networks.
University of Lisbon1, University of Mississippi2, Institut d'Astrophysique de Paris3, Perimeter Institute for Theoretical Physics4, Sapienza University of Rome5, University of Cambridge6, California Institute of Technology7, Cornell University8, Max Planck Society9, Montana State University10, Princeton University11, University of Oxford12, McMaster University13, University of Aveiro14, University of Tübingen15, Naresuan University16, Rochester Institute of Technology17, University of Oldenburg18, Georgia Institute of Technology19, University of Wisconsin–Milwaukee20, University of Illinois at Urbana–Champaign21, University of Florida22, The Chinese University of Hong Kong23, Northwestern University24, Case Western Reserve University25, Sao Paulo State University26, Cardiff University27, Imperial College London28, Grand Valley State University29, Kyoto University30
TL;DR: In this article, a catalog of modified theories of gravity for which strong-field predictions have been computed and contrasted to Einstein's theory is presented, and the current understanding of the structure and dynamics of compact objects in these theories is summarized.
Abstract: One century after its formulation, Einstein's general relativity (GR) has made remarkable predictions and turned out to be compatible with all experimental tests. Most of these tests probe the theory in the weak-field regime, and there are theoretical and experimental reasons to believe that GR should be modified when gravitational fields are strong and spacetime curvature is large. The best astrophysical laboratories to probe strong-field gravity are black holes and neutron stars, whether isolated or in binary systems. We review the motivations to consider extensions of GR. We present a (necessarily incomplete) catalog of modified theories of gravity for which strong-field predictions have been computed and contrasted to Einstein's theory, and we summarize our current understanding of the structure and dynamics of compact objects in these theories. We discuss current bounds on modified gravity from binary pulsar and cosmological observations, and we highlight the potential of future gravitational wave measurements to inform us on the behavior of gravity in the strong-field regime.
Tulane University1, Colorado State University2, University of Tübingen3, Applied Science Private University4, Université de Montréal5, United Arab Emirates University6, Rush University Medical Center7, Baylor College of Medicine8, Mount Sinai St. Luke's and Mount Sinai Roosevelt9, Nara Medical University10, National Technical University of Athens11, University of Illinois at Urbana–Champaign12, Creighton University13, Shanmugha Arts, Science, Technology & Research Academy14, University of Rome Tor Vergata15, Purdue University16, Wayne State University17, University of Glasgow18, New York Medical College19, Mayo Clinic20
TL;DR: The advances made toward understanding the basis of cancer immune evasion are discussed, the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection are summarized and some natural agents and phytochemicals merit further study.
Posted Content•
TL;DR: This work introduces an artificial system based on a Deep Neural Network that creates artistic images of high perceptual quality and offers a path forward to an algorithmic understanding of how humans create and perceive artistic imagery.
Abstract: In fine art, especially painting, humans have mastered the skill to create unique visual experiences through composing a complex interplay between the content and style of an image. Thus far the algorithmic basis of this process is unknown and there exists no artificial system with similar capabilities. However, in other key areas of visual perception such as object and face recognition near-human performance was recently demonstrated by a class of biologically inspired vision models called Deep Neural Networks. Here we introduce an artificial system based on a Deep Neural Network that creates artistic images of high perceptual quality. The system uses neural representations to separate and recombine content and style of arbitrary images, providing a neural algorithm for the creation of artistic images. Moreover, in light of the striking similarities between performance-optimised artificial neural networks and biological vision, our work offers a path forward to an algorithmic understanding of how humans create and perceive artistic imagery.
TL;DR: Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented and act as proposals to assist in assessing similarity in the context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty.
Posted Content•
TL;DR: This work shows that failure to converge typically is not due to a suboptimal estimation algorithm, but is a consequence of attempting to fit a model that is too complex to be properly supported by the data, irrespective of whether estimation is based on maximum likelihood or on Bayesian hierarchical modeling with uninformative or weakly informative priors.
Abstract: The analysis of experimental data with mixed-effects models requires decisions about the specification of the appropriate random-effects structure. Recently, Barr, Levy, Scheepers, and Tily, 2013 recommended fitting `maximal' models with all possible random effect components included. Estimation of maximal models, however, may not converge. We show that failure to converge typically is not due to a suboptimal estimation algorithm, but is a consequence of attempting to fit a model that is too complex to be properly supported by the data, irrespective of whether estimation is based on maximum likelihood or on Bayesian hierarchical modeling with uninformative or weakly informative priors. Importantly, even under convergence, overparameterization may lead to uninterpretable models. We provide diagnostic tools for detecting overparameterization and guiding model simplification.
Radboud University Nijmegen1, European Organisation for Research and Treatment of Cancer2, Université catholique de Louvain3, Katholieke Universiteit Leuven4, Charité5, Utrecht University6, PSL Research University7, François Rabelais University8, Institut Gustave Roussy9, University of Tübingen10, University of Amsterdam11, University of Zurich12, Rambam Health Care Campus13
TL;DR: In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival, disease-free survival and distant disease- free survival were improved, and breast-cancer mortality was reduced.
Abstract: BACKGROUND The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P = 0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P = 0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P = 0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P = 0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.)
University of Barcelona1, Hacettepe University2, Cajal Institute3, European Medicines Agency4, University of Antwerp5, Brighton and Sussex Medical School6, GlaxoSmithKline7, Radboud University Nijmegen8, European Centre for Disease Prevention and Control9, Center for Disease Dynamics, Economics & Policy10, European Food Safety Authority11, University of Seville12, Southmead Hospital13, University College Dublin14, Aix-Marseille University15, Carlos III Health Institute16, University of Tübingen17, University of Warwick18
TL;DR: The views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies are summarized, providing expert recommendations to tackle the global threat of antimacterial resistance.
Abstract: In the last decade we have witnessed a dramatic increase in the proportion and absolute number of bacterial pathogens resistant to multiple antibacterial agents. Multidrug-resistant bacteria are currently considered as an emergent global disease and a major public health problem. The B-Debate meeting brought together renowned experts representing the main stakeholders (i.e. policy makers, public health authorities, regulatory agencies, pharmaceutical companies and the scientific community at large) to review the global threat of antibiotic resistance and come up with a coordinated set of strategies to fight antimicrobial resistance in a multifaceted approach. We summarize the views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies, providing expert recommendations to tackle the global threat of antimicrobial resistance.
University Hospital Heidelberg1, German Cancer Research Center2, Heidelberg University3, Ludwig Maximilian University of Munich4, University of Würzburg5, University of Bonn6, University of Bergen7, Medical University of Vienna8, Max Planck Society9, University of Tübingen10, University of Calgary11
TL;DR: It is shown that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances, which develops functional multicellular network structures.
Abstract: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
TL;DR: This work proposes the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard, to facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters.
Abstract: A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
TL;DR: It is indicated that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders.
Abstract: Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
TL;DR: The Jiangmen Underground Neutrino Observatory (JUNO) as mentioned in this paper is a 20 kton multi-purpose underground liquid scintillator detector with the determination of the neutrino mass hierarchy as a primary physics goal.
Abstract: The Jiangmen Underground Neutrino Observatory (JUNO), a 20 kton multi-purpose underground liquid scintillator detector, was proposed with the determination of the neutrino mass hierarchy as a primary physics goal. It is also capable of observing neutrinos from terrestrial and extra-terrestrial sources, including supernova burst neutrinos, diffuse supernova neutrino background, geoneutrinos, atmospheric neutrinos, solar neutrinos, as well as exotic searches such as nucleon decays, dark matter, sterile neutrinos, etc. We present the physics motivations and the anticipated performance of the JUNO detector for various proposed measurements. By detecting reactor antineutrinos from two power plants at 53-km distance, JUNO will determine the neutrino mass hierarchy at a 3-4 sigma significance with six years of running. The measurement of antineutrino spectrum will also lead to the precise determination of three out of the six oscillation parameters to an accuracy of better than 1\%. Neutrino burst from a typical core-collapse supernova at 10 kpc would lead to ~5000 inverse-beta-decay events and ~2000 all-flavor neutrino-proton elastic scattering events in JUNO. Detection of DSNB would provide valuable information on the cosmic star-formation rate and the average core-collapsed neutrino energy spectrum. Geo-neutrinos can be detected in JUNO with a rate of ~400 events per year, significantly improving the statistics of existing geoneutrino samples. The JUNO detector is sensitive to several exotic searches, e.g. proton decay via the $p\to K^++\bar
u$ decay channel. The JUNO detector will provide a unique facility to address many outstanding crucial questions in particle and astrophysics. It holds the great potential for further advancing our quest to understanding the fundamental properties of neutrinos, one of the building blocks of our Universe.
TL;DR: Current understanding of neutrophils in host-pathogen interactions and disease involvement is summarized, illustrating the versatility and plasticity of the neutrophil, moving between host defence, immune modulation, and tissue damage.
Abstract: Neutrophils, the most abundant human immune cells, are rapidly recruited to sites of infection, where they fulfill their life-saving antimicrobial functions. While traditionally regarded as short-lived phagocytes, recent findings on long-term survival, neutrophil extracellular trap (NET) formation, heterogeneity and plasticity, suppressive functions, and tissue injury have expanded our understanding of their diverse role in infection and inflammation. This review summarises our current understanding of neutrophils in host-pathogen interactions and disease involvement, illustrating the versatility and plasticity of the neutrophil, moving between host defence, immune modulation, and tissue damage.
Mayo Clinic1, University of Kansas2, Ohio State University3, Harvard University4, Ludwig Maximilian University of Munich5, University of California, Los Angeles6, University of Erlangen-Nuremberg7, University of Ulm8, Aristotle University of Thessaloniki9, University of Helsinki10, University of Southampton11, University of Sheffield12, University of Tübingen13, Roswell Park Cancer Institute14
TL;DR: Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCa2.
Abstract: Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P .001) and had higher-grade tumors (P .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives. J Clin Oncol 33:304-311. © 2014 by American Society of Clinical Oncology
Kyriaki Michailidou1, Jonathan Beesley2, Sara Lindström3, Sander Canisius +280 more•Institutions (76)
TL;DR: 15 new loci associated with breast cancer at P < 5 × 10−8 are identified, and one association appears to be driven by an amino acid substitution encoded in EXO1, which is found in women of European ancestry.
Abstract: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
TL;DR: A mechanism by which mTOR controls the SASP is reported by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1.
Abstract: Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.
University of Bern1, University of Tübingen2, University of Freiburg3, Technische Universität Darmstadt4, University of Ulm5, University of Münster6, Xavier University7, Smithsonian Institution8, Free University of Berlin9, Max Planck Society10, University of Würzburg11, Smithsonian Tropical Research Institute12, Technische Universität München13, University of Jena14, University of Göttingen15, Karlsruhe Institute of Technology16, University of Potsdam17
TL;DR: Biodiversity loss explained indirect effects in a region of intermediate productivity and was most damaging when land‐use objectives favoured supporting and cultural services, and functional composition shifts, towards fast‐growing plant species, strongly increased provisioning services in more inherently unproductive grasslands.
Abstract: Global change, especially land-use intensification, affects human well-being by impacting the delivery of multiple ecosystem services (multifunctionality). However, whether biodiversity loss is a major component of global change effects on multifunctionality in real-world ecosystems, as in experimental ones, remains unclear. Therefore, we assessed biodiversity, functional composition and 14 ecosystem services on 150 agricultural grasslands differing in land-use intensity. We also introduce five multifunctionality measures in which ecosystem services were weighted according to realistic land-use objectives. We found that indirect land-use effects, i.e. those mediated by biodiversity loss and by changes to functional composition, were as strong as direct effects on average. Their strength varied with land-use objectives and regional context. Biodiversity loss explained indirect effects in a region of intermediate productivity and was most damaging when land-use objectives favoured supporting and cultural services. In contrast, functional composition shifts, towards fast-growing plant species, strongly increased provisioning services in more inherently unproductive grasslands.
TL;DR: To successfully fight this enigmatic illness, understanding of the underlying biological and psychosocial mechanisms has to be enhanced, strategies for prevention and early intervention improved, and treatments targeted through improved understanding of specific disease mechanisms targeted.
TL;DR: The study demonstrated the feasibility of the auditoryBCI with healthy users and stresses the importance of training with auditory multiclass BCIs, especially for potential end-users of BCI with disease.
Abstract: Brain-computer interfaces (BCIs) can serve as muscle independent communication aids. Persons, who are unable to control their eye muscles (e.g., in the completely locked-in state) or have severe visual impairments for other reasons, need BCI systems that do not rely on the visual modality. For this reason, BCIs that employ auditory stimuli were suggested. In this study, a multiclass BCI spelling system was implemented that uses animal voices with directional cues to code rows and columns of a letter matrix. To reveal possible training effects with the system, 11 healthy participants performed spelling tasks on 2 consecutive days. In a second step, the system was tested by a participant with amyotrophic lateral sclerosis (ALS) in two sessions. In the first session, healthy participants spelled with an average accuracy of 76% (3.29 bits/min) that increased to 90% (4.23 bits/min) on the second day. Spelling accuracy by the participant with ALS was 20% in the first and 47% in the second session. The results indicate a strong training effect for both the healthy participants and the participant with ALS. While healthy participants reached high accuracies in the first session and second session, accuracies for the participant with ALS were not sufficient for satisfactory communication in both sessions. More training sessions might be needed to improve spelling accuracies. The study demonstrated the feasibility of the auditory BCI with healthy users and stresses the importance of training with auditory multiclass BCIs, especially for potential end-users of BCI with disease.