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Showing papers by "University of Bonn published in 2017"


Journal ArticleDOI
Bin Zhou1, James Bentham1, Mariachiara Di Cesare2, Honor Bixby1  +787 moreInstitutions (231)
TL;DR: The number of adults with raised blood pressure increased from 594 million in 1975 to 1·13 billion in 2015, with the increase largely in low-income and middle-income countries, and the contributions of changes in prevalence versus population growth and ageing to the increase.

1,573 citations


Journal ArticleDOI
TL;DR: Investigating the impacts of temperature on yields of the four crops by compiling extensive published results from four analytical methods consistently showed negative temperature impacts on crop yield at the global scale, generally underpinned by similar impacts at country and site scales.
Abstract: Wheat, rice, maize, and soybean provide two-thirds of human caloric intake. Assessing the impact of global temperature increase on production of these crops is therefore critical to maintaining global food supply, but different studies have yielded different results. Here, we investigated the impacts of temperature on yields of the four crops by compiling extensive published results from four analytical methods: global grid-based and local point-based models, statistical regressions, and field-warming experiments. Results from the different methods consistently showed negative temperature impacts on crop yield at the global scale, generally underpinned by similar impacts at country and site scales. Without CO2 fertilization, effective adaptation, and genetic improvement, each degree-Celsius increase in global mean temperature would, on average, reduce global yields of wheat by 6.0%, rice by 3.2%, maize by 7.4%, and soybean by 3.1%. Results are highly heterogeneous across crops and geographical areas, with some positive impact estimates. Multimethod analyses improved the confidence in assessments of future climate impacts on global major crops and suggest crop- and region-specific adaptation strategies to ensure food security for an increasing world population.

1,442 citations


Proceedings Article
06 Aug 2017
TL;DR: The analysis suggests that the notions of effective capacity which are dataset independent are unlikely to explain the generalization performance of deep networks when trained with gradient based methods because training data itself plays an important role in determining the degree of memorization.
Abstract: We examine the role of memorization in deep learning, drawing connections to capacity, generalization, and adversarial robustness. While deep networks are capable of memorizing noise data, our results suggest that they tend to prioritize learning simple patterns first. In our experiments, we expose qualitative differences in gradient-based optimization of deep neural networks (DNNs) on noise vs. real data. We also demonstrate that for appropriately tuned explicit regularization (e.g., dropout) we can degrade DNN training performance on noise datasets without compromising generalization on real data. Our analysis suggests that the notions of effective capacity which are dataset independent are unlikely to explain the generalization performance of deep networks when trained with gradient based methods because training data itself plays an important role in determining the degree of memorization.

1,080 citations


Journal ArticleDOI
TL;DR: The importance of better reference values is demonstrated, and the need for London-dispersion corrections in density functional theory (DFT) treatments of thermochemical problems is re-emphasised, to inspire a change in the user community's perception of common DFT methods.
Abstract: We present the GMTKN55 benchmark database for general main group thermochemistry, kinetics and noncovalent interactions. Compared to its popular predecessor GMTKN30 [Goerigk and Grimme J. Chem. Theory Comput., 2011, 7, 291], it allows assessment across a larger variety of chemical problems—with 13 new benchmark sets being presented for the first time—and it also provides reference values of significantly higher quality for most sets. GMTKN55 comprises 1505 relative energies based on 2462 single-point calculations and it is accessible to the user community via a dedicated website. Herein, we demonstrate the importance of better reference values, and we re-emphasise the need for London-dispersion corrections in density functional theory (DFT) treatments of thermochemical problems, including Minnesota methods. We assessed 217 variations of dispersion-corrected and -uncorrected density functional approximations, and carried out a detailed analysis of 83 of them to identify robust and reliable approaches. Double-hybrid functionals are the most reliable approaches for thermochemistry and noncovalent interactions, and they should be used whenever technically feasible. These are, in particular, DSD-BLYP-D3(BJ), DSD-PBEP86-D3(BJ), and B2GPPLYP-D3(BJ). The best hybrids are ωB97X-V, M052X-D3(0), and ωB97X-D3, but we also recommend PW6B95-D3(BJ) as the best conventional global hybrid. At the meta-generalised-gradient (meta-GGA) level, the SCAN-D3(BJ) method can be recommended. Other meta-GGAs are outperformed by the GGA functionals revPBE-D3(BJ), B97-D3(BJ), and OLYP-D3(BJ). We note that many popular methods, such as B3LYP, are not part of our recommendations. In fact, with our results we hope to inspire a change in the user community's perception of common DFT methods. We also encourage method developers to use GMTKN55 for cross-validation studies of new methodologies.

1,079 citations


Journal ArticleDOI
TL;DR: The thoroughly updated antiSMASH version 4 is presented, which adds several novel features, including prediction of gene cluster boundaries using the ClusterFinder method or the newly integrated CASSIS algorithm, improved substrate specificity prediction for non-ribosomal peptide synthetase adenylation domains based on the new SANDPUMA algorithm, and several usability features have been updated and improved.
Abstract: Many antibiotics, chemotherapeutics, crop protection agents and food preservatives originate from molecules produced by bacteria, fungi or plants. In recent years, genome mining methodologies have been widely adopted to identify and characterize the biosynthetic gene clusters encoding the production of such compounds. Since 2011, the â € antibiotics and secondary metabolite analysis shell - antiSMASH' has assisted researchers in efficiently performing this, both as a web server and a standalone tool. Here, we present the thoroughly updated antiSMASH version 4, which adds several novel features, including prediction of gene cluster boundaries using the ClusterFinder method or the newly integrated CASSIS algorithm, improved substrate specificity prediction for non-ribosomal peptide synthetase adenylation domains based on the new SANDPUMA algorithm, improved predictions for terpene and ribosomally synthesized and post-translationally modified peptides cluster products, reporting of sequence similarity to proteins encoded in experimentally characterized gene clusters on a per-protein basis and a domain-level alignment tool for comparative analysis of trans-AT polyketide synthase assembly line architectures. Additionally, several usability features have been updated and improved. Together, these improvements make antiSMASH up-to-date with the latest developments in natural product research and will further facilitate computational genome mining for the discovery of novel bioactive molecules.

1,043 citations


Journal ArticleDOI
TL;DR: The accuracy of the method, called Geometry, Frequency, Noncovalent, eXtended TB (GFN-xTB), is extensively benchmarked for various systems in comparison with existing semiempirical approaches, and the method is applied to a few representative structural problems in chemistry.
Abstract: We propose a novel, special purpose semiempirical tight binding (TB) method for the calculation of structures, vibrational frequencies, and noncovalent interactions of large molecular systems with 1000 or more atoms. The functional form of the method is related to the self-consistent density functional TB scheme and mostly avoids element-pair-specific parameters. The parametrization covers all spd-block elements and the lanthanides up to Z = 86 using reference data at the hybrid density functional theory level. Key features of the Hamiltonian are the use of partially polarized Gaussian-type orbitals, a double-ζ orbital basis for hydrogen, atomic-shell charges, diagonal third-order charge fluctuations, coordination number-dependent energy levels, a noncovalent halogen-bond potential, and the well-established D3 dispersion correction. The accuracy of the method, called Geometry, Frequency, Noncovalent, eXtended TB (GFN-xTB), is extensively benchmarked for various systems in comparison with existing semiempi...

896 citations


Journal ArticleDOI
TL;DR: In this article, a centralized analysis pipeline was applied to a SCZ cohort of 21,094 cases and 20,227 controls, and a global enrichment of copy number variants (CNVs) was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies.
Abstract: Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

774 citations


Journal ArticleDOI
TL;DR: The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas, based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline.
Abstract: The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.

773 citations


Journal ArticleDOI
28 Dec 2017-Cell
TL;DR: It is demonstrated that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis and the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX 4, thereby preventing fatal epileptic seizures.

759 citations


Journal ArticleDOI
Rebecca Sims1, Sven J. van der Lee2, Adam C. Naj3, Céline Bellenguez4  +484 moreInstitutions (120)
TL;DR: Three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease are observed, providing additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's Disease.
Abstract: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

730 citations


Journal ArticleDOI
Lianne Schmaal1, Derrek P. Hibar2, Philipp G. Sämann3, Geoffrey B. Hall4, Bernhard T. Baune5, Neda Jahanshad2, Joshua W. Cheung2, T.G.M. van Erp6, Daniel Bos7, M. A. Ikram7, Meike W. Vernooij7, Wiro J. Niessen7, Wiro J. Niessen8, Henning Tiemeier9, Henning Tiemeier7, A. Hofman7, Katharina Wittfeld10, Hans-Jörgen Grabe11, Hans-Jörgen Grabe10, Deborah Janowitz11, Robin Bülow11, M Selonke11, Henry Völzke11, Dominik Grotegerd12, Udo Dannlowski13, Udo Dannlowski12, Volker Arolt12, Nils Opel12, Walter Heindel12, Harald Kugel12, D. Hoehn3, Michael Czisch3, Baptiste Couvy-Duchesne14, Baptiste Couvy-Duchesne15, Miguel E. Rentería14, Lachlan T. Strike15, Margaret J. Wright15, Natalie T. Mills15, Natalie T. Mills14, G.I. de Zubicaray16, Katie L. McMahon15, Sarah E. Medland14, Nicholas G. Martin14, Nathan A. Gillespie17, Roberto Goya-Maldonado18, Oliver Gruber19, Bernd Krämer19, Sean N. Hatton20, Jim Lagopoulos20, Ian B. Hickie20, Thomas Frodl21, Thomas Frodl22, Angela Carballedo22, Eva-Maria Frey23, L. S. van Velzen1, B.W.J.H. Penninx1, M-J van Tol24, N.J. van der Wee25, Christopher G. Davey26, Ben J. Harrison26, Benson Mwangi27, Bo Cao27, Jair C. Soares27, Ilya M. Veer28, Henrik Walter28, D. Schoepf29, Bartosz Zurowski30, Carsten Konrad13, Elisabeth Schramm31, Claus Normann31, Knut Schnell19, Matthew D. Sacchet32, Ian H. Gotlib32, Glenda MacQueen33, Beata R. Godlewska34, Thomas Nickson35, Andrew M. McIntosh36, Andrew M. McIntosh35, Martina Papmeyer35, Martina Papmeyer37, Heather C. Whalley35, Jeremy Hall38, Jeremy Hall35, J.E. Sussmann35, Meng Li39, Martin Walter40, Martin Walter39, Lyubomir I. Aftanas, Ivan Brack, Nikolay A. Bokhan41, Nikolay A. Bokhan42, Nikolay A. Bokhan43, Paul M. Thompson2, Dick J. Veltman1 
TL;DR: In this article, the authors present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD.
Abstract: The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Journal ArticleDOI
TL;DR: An international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016, the present guidelines related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy.
Abstract: Turner syndrome affects 25-50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.

Journal ArticleDOI
TL;DR: A strong and coherent body of evidence allows identification of actionable preventive, diagnostic and therapeutic strategies to effectively promote periodontal health and general wellbeing, and better manage the socio-economic consequences.
Abstract: Background The global burden of periodontal diseases remains high. Population growth trends, changes in risk factors and improved tooth retention will increase the socio-economic burden of periodontitis that is responsible for 3,5 million years lived with disability, 54 billion USD/year in lost productivity and a major portion of the 442 billion USD/year cost for oral diseases. Methods In the context of the Milan World Exhibition 2015 “Feeding the Planet, Energy for Life”, a green paper was developed and offered for global consultation by the European Federation of Periodontology. The final draft was endorsed by professional organizations around the world and is presented to stakeholders as a call for global action. Results Specific actions for the public, policymakers, educators, and professional organizations have been identified in the areas of prevention, detection and care. These actions align public interest and knowledge, need for self-care, professional intervention and policies to the best scientific evidence to proactively promote periodontal health and effectively manage the global burden of periodontal diseases, in accordance with WHO/UN priorities and strategies for tackling common non-communicable diseases (NCDs) via the Common Risk Factor Approach. Conclusions A strong and coherent body of evidence allows identification of actionable preventive, diagnostic and therapeutic strategies to effectively promote periodontal health and general wellbeing, and better manage the socio-economic consequences. Action requires consideration of the specific national scenarios. This article is protected by copyright. All rights reserved.

Journal ArticleDOI
Robert A. Scott1, Laura J. Scott2, Reedik Mägi3, Letizia Marullo4  +213 moreInstitutions (66)
01 Nov 2017-Diabetes
TL;DR: This article conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel.
Abstract: To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects) We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology

Journal ArticleDOI
20 Dec 2017-Nature
TL;DR: Findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer’s disease.
Abstract: The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.

Journal ArticleDOI
TL;DR: In this article, the authors report world averages of measurements of b-hadron, c-, c-, and tau-lepton properties obtained by the Heavy Flavor Averaging Group (HFAG) using results available through the end of 2011.
Abstract: This article reports world averages of measurements of b-hadron, c-hadron, and tau-lepton properties obtained by the Heavy Flavor Averaging Group (HFAG) using results available through the end of 2011. In some cases results available in the early part of 2012 are included. For the averaging, common input parameters used in the various analyses are adjusted (rescaled) to common values, and known correlations are taken into account. The averages include branching fractions, lifetimes, neutral meson mixing parameters, CP violation parameters, parameters of semileptonic decays and CKM matrix elements.


Journal ArticleDOI
TL;DR: The role ofmicroglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed.
Abstract: Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an "activated state"). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer's disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed.

Journal ArticleDOI
TL;DR: In patients with drug‐resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the second most common lesion in both groups.
Abstract: BackgroundDetailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. MethodsWe report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). ResultsThe onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of...

Journal ArticleDOI
TL;DR: The review focuses on the recent discovery of tyrosinase inhibitors that are directly involved in the inhibition of tyosinase catalytic activity and functionality from all sources, including laboratory synthetic methods, natural products, virtual screening and structure-based molecular docking studies.
Abstract: Melanogenesis is a process to synthesize melanin, which is a primary responsible for the pigmentation of human skin, eye and hair. Although numerous enzymatic catalyzed and chemical reactions are involved in melanogenesis process, the enzymes such as tyrosinase and tyrosinase-related protein-1 (TRP-1) and TRP-2 played a major role in melanin synthesis. Specifically, tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin synthesis, and the downregulation of tyrosinase is the most prominent approach for the development of melanogenesis inhibitors. Therefore, numerous inhibitors that target tyrosinase have been developed in recent years. The review focuses on the recent discovery of tyrosinase inhibitors that are directly involved in the inhibition of tyrosinase catalytic activity and functionality from all sources, including laboratory synthetic methods, natural products, virtual screening and structure-based molecular docking studies.

Journal ArticleDOI
TL;DR: Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours.
Abstract: Summary Background The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups. Methods In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip. Findings We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma. Interpretation DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma. Funding German Cancer Aid, Else Kroner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.

Proceedings ArticleDOI
01 Oct 2017
TL;DR: This work learns a mapping from the source to the target domain by jointly solving an assignment problem that labels those target instances that potentially belong to the categories of interest present in the source dataset.
Abstract: When the training and the test data belong to different domains, the accuracy of an object classifier is significantly reduced. Therefore, several algorithms have been proposed in the last years to diminish the so called domain shift between datasets. However, all available evaluation protocols for domain adaptation describe a closed set recognition task, where both domains, namely source and target, contain exactly the same object classes. In this work, we also explore the field of domain adaptation in open sets, which is a more realistic scenario where only a few categories of interest are shared between source and target data. Therefore, we propose a method that fits in both closed and open set scenarios. The approach learns a mapping from the source to the target domain by jointly solving an assignment problem that labels those target instances that potentially belong to the categories of interest present in the source dataset. A thorough evaluation shows that our approach outperforms the state-of-the-art.


Journal ArticleDOI
Morad Aaboud, Georges Aad1, Brad Abbott2, Jalal Abdallah3  +2845 moreInstitutions (197)
TL;DR: This paper presents a short overview of the changes to the trigger and data acquisition systems during the first long shutdown of the LHC and shows the performance of the trigger system and its components based on the 2015 proton–proton collision data.
Abstract: During 2015 the ATLAS experiment recorded 3.8 fb(-1) of proton-proton collision data at a centre-of-mass energy of 13 TeV. The ATLAS trigger system is a crucial component of the experiment, respons ...

Journal ArticleDOI
TL;DR: In this paper, the authors examined key interactions of double-neutron star (DNS) systems and evaluated their accretion history during the high-mass X-ray binary stage, the common envelope phase, and the subsequent Case BB mass transfer.
Abstract: Double neutron star (DNS) systems represent extreme physical objects and the endpoint of an exotic journey of stellar evolution and binary interactions. Large numbers of DNS systems and their mergers are anticipated to be discovered using the Square Kilometre Array searching for radio pulsars, and the high-frequency gravitational wave detectors (LIGO/VIRGO), respectively. Here we discuss all key properties of DNS systems, as well as selection effects, and combine the latest observational data with new theoretical progress on various physical processes with the aim of advancing our knowledge on their formation. We examine key interactions of their progenitor systems and evaluate their accretion history during the high-mass X-ray binary stage, the common envelope phase, and the subsequent Case BB mass transfer, and argue that the first-formed NSs have accreted at most $\sim 0.02\,{M}_{\odot }$. We investigate DNS masses, spins, and velocities, and in particular correlations between spin period, orbital period, and eccentricity. Numerous Monte Carlo simulations of the second supernova (SN) events are performed to extrapolate pre-SN stellar properties and probe the explosions. All known close-orbit DNS systems are consistent with ultra-stripped exploding stars. Although their resulting NS kicks are often small, we demonstrate a large spread in kick magnitudes that may, in general, depend on the past interaction history of the exploding star and thus correlate with the NS mass. We analyze and discuss NS kick directions based on our SN simulations. Finally, we discuss the terminal evolution of close-orbit DNS systems until they merge and possibly produce a short γ-ray burst.

Journal ArticleDOI
TL;DR: Extended statistical measures show that errors for dispersion coefficients with the proposed D4 method are significantly lower than with D3 and other, computationally more involved schemes, and accurate isotropic charge and hybridization dependent, atom-in-molecule static polarizabilities are obtained with an unprecedented efficiency.
Abstract: A new model, termed D4, for the efficient computation of molecular dipole-dipole dispersion coefficients is presented. As in the related, well established D3 scheme, these are obtained as a sum of atom-in-molecule dispersion coefficients over atom pairs. Both models make use of dynamic polarizabilities obtained from first-principles time-dependent density functional theory calculations for atoms in different chemical environments employing fractional atomic coordination numbers for interpolation. Different from the D3 model, the coefficients are obtained on-the-fly by numerical Casimir-Polder integration of the dynamic, atomic polarizabilities α(iω). Most importantly, electronic density information is now incorporated via atomic partial charges computed at a semi-empirical quantum mechanical tight-binding level, which is used to scale the polarizabilities. Extended statistical measures show that errors for dispersion coefficients with the proposed D4 method are significantly lower than with D3 and other, computationally more involved schemes. Alongside, accurate isotropic charge and hybridization dependent, atom-in-molecule static polarizabilities are obtained with an unprecedented efficiency. Damping function parameters are provided for three standard density functionals, i.e., TPSS, PBE0, and B3LYP, allowing evaluation of the new DFT-D4 model for common non-covalent interaction energy benchmark sets.

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M. G. Aartsen1, Markus Ackermann, Jenni Adams2, Juanan Aguilar3  +355 moreInstitutions (48)
TL;DR: The design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and the methodology for drilling and deployment are described, including the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis.
Abstract: The IceCube Neutrino Observatory is a cubic-kilometer-scale high-energy neutrino detector built into the ice at the South Pole. Construction of IceCube, the largest neutrino detector built to date, was completed in 2011 and enabled the discovery of high-energy astrophysical neutrinos. We describe here the design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and our methodology for drilling and deployment. We also describe the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis. Due to a rigorous pre-deployment protocol, 98.4% of the DOMs in the deep ice are operating and collecting data. IceCube routinely achieves a detector uptime of 99% by emphasizing software stability and monitoring. Detector operations have been stable since construction was completed, and the detector is expected to operate at least until the end of the next decade.

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TL;DR: A rapid search in PubMed shows that using "flow cytometry immunology" as a search term yields more than 68 000 articles, the first of which is not about lymphocytes as mentioned in this paper.
Abstract: The marriage between immunology and cytometry is one of the most stable and productive in the recent history of science. A rapid search in PubMed shows that, as of July 2017, using “flow cytometry immunology” as a search term yields more than 68 000 articles, the first of which, interestingly, is not about lymphocytes. It might be stated that, after a short engagement, the exchange of the wedding rings between immunology and cytometry officially occurred when the idea to link fluorochromes to monoclonal antibodies came about. After this, recognizing different types of cells became relatively easy and feasible not only by using a simple fluorescence microscope, but also by a complex and sometimes esoteric instrument, the flow cytometer that is able to count hundreds of cells in a single second, and can provide repetitive results in a tireless manner. Given this, the possibility to analyse immune phenotypes in a variety of clinical conditions has changed the use of the flow cytometer, which was incidentally invented in the late 1960s to measure cellular DNA by using intercalating dyes, such as ethidium bromide. The epidemics of HIV/AIDS in the 1980s then gave a dramatic impulse to the technology of counting specific cells, since it became clear that the quantification of the number of peripheral blood CD4+ T cells was crucial to follow the course of the infection, and eventually for monitoring the therapy. As a consequence, the development of flow cytometers that had to be easy-to-use in all clinical laboratories helped to widely disseminate this technology. Nowadays, it is rare to find an immunological paper or read a conference abstract in which the authors did not use flow cytometry as the main tool to dissect the immune system and identify its fine and complex functions. Of note, recent developments have created the sophisticated technology of mass cytometry, which is able to simultaneously identify dozens of molecules at the single cell level and allows us to better understand the complexity and beauty of the immune system.

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TL;DR: In a soil-incubation experiment in a climate-controlled chamber with three levels of microplastic added to loess soil collected from the Loess Plateau in China,microplastic addition stimulated enzymatic activity, activated pools of organic C, N, and P, and was beneficial for the accumulation of dissolved organic C and N.

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TL;DR: These findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-β-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.
Abstract: Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-β-signaling-dependent conversion of NK cells (CD49a-CD49b+Eomes+) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a+CD49b+Eomes+) populations and ILC1 (CD49a+CD49b-Eomesint) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-β-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.