Showing papers by "University of Kiel published in 2016"
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TL;DR: The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies.
5,321 citations
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TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
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University of British Columbia1, National Autonomous University of Mexico2, Arizona State University3, National University of Cordoba4, University of Oxford5, University of Vermont6, Helmholtz Centre for Environmental Research - UFZ7, Charles Sturt University8, Lüneburg University9, Oregon State University10, Georgia Institute of Technology11, University of Kiel12, Ikerbasque13, University of Victoria14
TL;DR: It is proposed that focusing only on instrumental or intrinsic values may fail to resonate with views on personal and collective well-being, or “what is right,” with regard to nature and the environment, and it is time to engage seriously with a third class of values, one with diverse roots and current expressions: relational values.
Abstract: A cornerstone of environmental policy is the debate over protecting nature for humans’ sake (instrumental values) or for nature’s (intrinsic values) (1). We propose that focusing only on instrumental or intrinsic values may fail to resonate with views on personal and collective well-being, or “what is right,” with regard to nature and the environment. Without complementary attention to other ways that value is expressed and realized by people, such a focus may inadvertently promote worldviews at odds with fair and desirable futures. It is time to engage seriously with a third class of values, one with diverse roots and current expressions: relational values. By doing so, we reframe the discussion about environmental protection, and open the door to new, potentially more productive policy approaches.
977 citations
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University of East Anglia1, Norfolk and Norwich University Hospital2, Leiden University Medical Center3, University of Barcelona4, Claude Bernard University Lyon 15, University of Kiel6, Tallaght Hospital7, University of Oxford8, University of Paris9, University of Pennsylvania10, Linköping University11, Charles University in Prague12, Lund University13, Ankara University14
TL;DR: The 2009 European League Against Rheumatism recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated and 15 recommendations were developed, covering general aspects, such as attaining remission.
Abstract: In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.
893 citations
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Stellenbosch University1, University of Western Australia2, University of Kiel3, University of Geneva4, Free University of Berlin5, University of Nova Gorica6, Slovenian Academy of Sciences and Arts7, Macedonian Academy of Sciences and Arts8, Academy of Sciences of the Czech Republic9, University of Vienna10, University of Bayreuth11, Complutense University of Madrid12, Masaryk University13, Sapienza University of Rome14, University of Zielona Góra15, University of Münster16, University of Göttingen17, Russian Academy of Sciences18, Slovak Academy of Sciences19, Wageningen University and Research Centre20, Radboud University Nijmegen21, National Academy of Sciences of Ukraine22, University of Lisbon23, University of Vechta24, University of California, Davis25, University of Patras26
TL;DR: This paper features the first comprehensive and critical account of European syntaxa and synthesizes more than 100 yr of classification effort by European phytosociologists.
Abstract: Aims: Vegetation classification consistent with the
Braun-Blanquet approach is widely used in Europe for applied
vegetation science, conservation planning and land management.
During the long history of syntaxonomy, many concepts and names
of vegetation units have been proposed, but there has been no
single classification system integrating these units. Here we
(1) present a comprehensive, hierarchical, syntaxonomic system
of alliances, orders and classes of Braun-Blanquet syntaxonomy
for vascular plant, bryophyte and lichen, and algal communities
of Europe; (2) briefly characterize in ecological and
geographic terms accepted syntaxonomic concepts; (3) link
available synonyms to these accepted concepts; and (4) provide
a list of diagnostic species for all classes. LocationEuropean
mainland, Greenland, Arctic archipelagos (including Iceland,
Svalbard, Novaya Zemlya), Canary Islands, Madeira, Azores,
Caucasus, Cyprus. Methods: We evaluated approximately 10000
bibliographic sources to create a comprehensive list of
previously proposed syntaxonomic units. These units were
evaluated by experts for their floristic and ecological
distinctness, clarity of geographic distribution and compliance
with the nomenclature code. Accepted units were compiled into
three systems of classes, orders and alliances
(EuroVegChecklist, EVC) for communities dominated by vascular
plants (EVC1), bryophytes and lichens (EVC2) and algae (EVC3).
Results: EVC1 includes 109 classes, 300 orders and 1108
alliances; EVC2 includes 27 classes, 53 orders and 137
alliances, and EVC3 includes 13 classes, 24 orders and 53
alliances. In total 13448 taxa were assigned as indicator
species to classes of EVC1, 2087 to classes of EVC2 and 368 to
classes of EVC3. Accepted syntaxonomic concepts are summarized
in a series of appendices, and detailed information on each is
accessible through the software tool EuroVegBrowser.
Conclusions: This paper features the first comprehensive and
critical account of European syntaxa and synthesizes more than
100 yr of classification effort by European phytosociologists.
It aims to document and stabilize the concepts and nomenclature
of syntaxa for practical uses, such as calibration of habitat
classification used by the European Union, standardization of
terminology for environmental assessment, management and
conservation of nature areas, landscape planning and education.
The presented classification systems provide a baseline for
future development and revision of European syntaxonomy.
817 citations
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Wellcome Trust Sanger Institute1, Katholieke Universiteit Leuven2, Montreal Heart Institute3, Canterbury Christ Church University4, Wellcome Trust Centre for Human Genetics5, University of Chicago6, University of Kiel7, Peninsula College of Medicine and Dentistry8, Royal Adelaide Hospital9, University of Adelaide10, Casa Sollievo della Sofferenza11, Ludwig Maximilian University of Munich12, Johns Hopkins University13, Yale University14, Broad Institute15, Cedars-Sinai Medical Center16, University of Pittsburgh17, University of Auckland18, University of Otago19, Christchurch Hospital20, Children's Hospital of Philadelphia21, Örebro University22, Oslo University Hospital23, University of Edinburgh24, Lithuanian University of Health Sciences25, University of Western Australia26, University of Cambridge27, University of Liège28, Leiden University Medical Center29, University Medical Center Groningen30, Royal Hospital for Sick Children31, Newcastle University32, University of Toronto33, QIMR Berghofer Medical Research Institute34, Royal Brisbane and Women's Hospital35
TL;DR: The largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.
563 citations
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Institut Gustave Roussy1, University of Paris2, French Institute of Health and Medical Research3, Pasteur Institute4, University of Caen Lower Normandy5, Université Paris-Saclay6, University of Burgundy7, Pierre-and-Marie-Curie University8, Paris Descartes University9, Centre national de la recherche scientifique10, PSL Research University11, Cornell University12, Monash University13, University of Kiel14, Aix-Marseille University15
TL;DR: Enterococcus hirae and B. intestinihominis represent valuable "oncomicrobiotics" ameliorating the efficacy of the most common alkylating immunomodulatory compound CTX, and selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy.
560 citations
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University of Kiel1, Wellcome Trust2, University of Oxford3, University of Ulsan4, Harvard University5, Broad Institute6, University of Toronto7, University of Oslo8, University of California, San Diego9, University of Tartu10, University of Groningen11, Karolinska Institutet12, Ikerbasque13, Örebro University14, University of Copenhagen15, University of Bonn16, Mayo Clinic17, King's College London18, Veterans Health Administration19, University of Michigan20, Cedars-Sinai Medical Center21, University of Cambridge22, Queensland University of Technology23, University of Queensland24
TL;DR: The COMorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity), and the strong comor bid between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease.
Abstract: We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
558 citations
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TL;DR: How IL-6 pathways are involved in the physiology and pathophyiology of the liver and how these different pathways can be selectively inhibited and therapeutically exploited for the treatment of liver pathologies is described.
558 citations
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Imperial College London1, Cardiff University2, University of Auckland3, University of Kiel4, Goethe University Frankfurt5, Federal University of São Paulo6, McGill University7, University of Bristol8, Birkbeck, University of London9, University of North Carolina at Chapel Hill10, University College London11, Beckley Foundation12
TL;DR: Three complementary neuroimaging techniques, implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects, contributing important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics.
Abstract: Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.
526 citations
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TL;DR: Genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci identify other important points of host–microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components.
Abstract: Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr-/- mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10-8) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.
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TL;DR: The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and riteximab is associated with less toxic effects.
Abstract: Summary Background Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab. Methods Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33–81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1:1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m 2 per day) and cyclophosphamide (250 mg/m 2 per day) for the first 3 days or to intravenous bendamustine (90 mg/m 2 per day) for the first 2 days of each cycle. Rituximab 375 mg/m 2 was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m 2 during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2-year progression-free survival with bendamustine and rituximab was not 67·5% or less with a corresponding non-inferiority margin of 1·388 for the hazard ratio (HR) based on the 90·4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522. Findings 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37·1 months (IQR 31·0–45·5) median progression-free survival was 41·7 months (95% CI 34·9–45·3) with bendamustine and rituximab and 55·2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1·643, 90·4% CI 1·308–2·064). As the upper limit of the 90·4% CI was greater than 1·388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 [84%] of 279 vs 164 [59%] of 278, and 109 [39%] vs 69 [25%], respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years. Interpretation The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects. Funding Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research.
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University of Bern1, Technische Universität München2, University of Jena3, Smithsonian Conservation Biology Institute4, University of Natural Resources and Life Sciences, Vienna5, University of Tübingen6, University of Cologne7, Leibniz Association8, University of Freiburg9, Lund University10, Technische Universität Darmstadt11, University of Göttingen12, Helmholtz Centre for Environmental Research - UFZ13, University of Kiel14, University of Potsdam15, University of Münster16, University of Ulm17, University of Würzburg18, Max Planck Society19, Xavier University20, Free University of Berlin21, University of Salzburg22, Smithsonian Tropical Research Institute23, Karlsruhe Institute of Technology24, University of Giessen25
TL;DR: It is demonstrated that primary producers, herbivorous insects and microbial decomposers seem to be particularly important drivers of ecosystem functioning, as shown by the strong and frequent positive associations of their richness or abundance with multiple ecosystem services.
Abstract: Many experiments have shown that loss of biodiversity reduces the capacity of ecosystems to provide the multiple services on which humans depend. However, experiments necessarily simplify the complexity of natural ecosystems and will normally control for other important drivers of ecosystem functioning, such as the environment or land use. In addition, existing studies typically focus on the diversity of single trophic groups, neglecting the fact that biodiversity loss occurs across many taxa and that the functional effects of any trophic group may depend on the abundance and diversity of others. Here we report analysis of the relationships between the species richness and abundance of nine trophic groups, including 4,600 above- and below-ground taxa, and 14 ecosystem services and functions and with their simultaneous provision (or multifunctionality) in 150 grasslands. We show that high species richness in multiple trophic groups (multitrophic richness) had stronger positive effects on ecosystem services than richness in any individual trophic group; this includes plant species richness, the most widely used measure of biodiversity. On average, three trophic groups influenced each ecosystem service, with each trophic group influencing at least one service. Multitrophic richness was particularly beneficial for 'regulating' and 'cultural' services, and for multifunctionality, whereas a change in the total abundance of species or biomass in multiple trophic groups (the multitrophic abundance) positively affected supporting services. Multitrophic richness and abundance drove ecosystem functioning as strongly as abiotic conditions and land-use intensity, extending previous experimental results to real-world ecosystems. Primary producers, herbivorous insects and microbial decomposers seem to be particularly important drivers of ecosystem functioning, as shown by the strong and frequent positive associations of their richness or abundance with multiple ecosystem services. Our results show that multitrophic richness and abundance support ecosystem functioning, and demonstrate that a focus on single groups has led to researchers to greatly underestimate the functional importance of biodiversity.
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Harvard University1, Broad Institute2, University of Oslo3, Oslo University Hospital4, University of Helsinki5, University of Tartu6, Boston Children's Hospital7, Illumina8, Charité9, Brigham and Women's Hospital10, deCODE genetics11, Medical Research Council12, VU University Amsterdam13, Leiden University14, Helsinki University Central Hospital15, University of Tübingen16, Ludwig Maximilian University of Munich17, Karolinska Institutet18, QIMR Berghofer Medical Research Institute19, University of Ulm20, University of Oulu21, King's College London22, Erasmus University Medical Center23, University of Tampere24, University of Duisburg-Essen25, Washington University in St. Louis26, University Medical Center Groningen27, Wellcome Trust Sanger Institute28, University of Oxford29, John Radcliffe Hospital30, Max Planck Society31, University of Kiel32, Technische Universität München33, National Institutes of Health34, Norwegian Institute of Public Health35, University of Copenhagen36, Mental Health Services37, Lundbeck38, University of Turku39, Turku University Hospital40, University of Hamburg41, St George's, University of London42, University of Iceland43, Queensland University of Technology44
TL;DR: For example, the authors identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to date is the first to be identified on chromosome X.
Abstract: Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.
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Wouter van Rheenen1, Aleksey Shatunov2, Annelot M. Dekker1, Russell L. McLaughlin3 +184 more•Institutions (54)
TL;DR: Evidence of ALS being a complex genetic trait with a polygenic architecture is established and the SNP-based heritability is estimated at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%).
Abstract: To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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TL;DR: It is confirmed that imposed task states can alter the correlation structure of BOLD activity, and it is found that observations of "dynamic" BOLD correlations during the resting state are largely explained by sampling variability.
Abstract: Measurement of correlations between brain regions (functional connectivity) using blood oxygen level dependent (BOLD) fMRI has proven to be a powerful tool for studying the functional organization of the brain. Recently, dynamic functional connectivity has emerged as a major topic in the resting-state BOLD fMRI literature. Here, using simulations and multiple sets of empirical observations, we confirm that imposed task states can alter the correlation structure of BOLD activity. However, we find that observations of "dynamic" BOLD correlations during the resting state are largely explained by sampling variability. Beyond sampling variability, the largest part of observed "dynamics" during rest is attributable to head motion. An additional component of dynamic variability during rest is attributable to fluctuating sleep state. Thus, aside from the preceding explanatory factors, a single correlation structure-as opposed to a sequence of distinct correlation structures-may adequately describe the resting state as measured by BOLD fMRI. These results suggest that resting-state BOLD correlations do not primarily reflect moment-to-moment changes in cognitive content. Rather, resting-state BOLD correlations may predominantly reflect processes concerned with the maintenance of the long-term stability of the brain's functional organization.
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TL;DR: A meta-analysis of genome-wide association studies for estimated glomerular filtration rate suggests that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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Ghent University1, Leibniz Institute of Marine Sciences2, University of Paris3, Stazione Zoologica Anton Dohrn4, University of Udine5, Institut national de la recherche agronomique6, University of Münster7, University of Düsseldorf8, University of Gothenburg9, Joint Genome Institute10, Åbo Akademi University11, Nord University12, Delaware Biotechnology Institute13, University of the Algarve14, King Abdullah University of Science and Technology15, University of Kiel16, University of Pretoria17
TL;DR: The genome of Zostera marina, the first, to the authors' knowledge, marine angiosperm to be fully sequenced, reveals unique insights into the genomic losses and gains involved in achieving the structural and physiological adaptations required for its marine lifestyle.
Abstract: Seagrasses colonized the sea on at least three independent occasions to form the basis of one of the most productive and widespread coastal ecosystems on the planet. Here we report the genome of Zostera marina (L.), the first, to our knowledge, marine angiosperm to be fully sequenced. This reveals unique insights into the genomic losses and gains involved in achieving the structural and physiological adaptations required for its marine lifestyle, arguably the most severe habitat shift ever accomplished by flowering plants. Key angiosperm innovations that were lost include the entire repertoire of stomatal genes, genes involved in the synthesis of terpenoids and ethylene signalling, and genes for ultraviolet protection and phytochromes for far-red sensing. Seagrasses have also regained functions enabling them to adjust to full salinity. Their cell walls contain all of the polysaccharides typical of land plants, but also contain polyanionic, low-methylated pectins and sulfated galactans, a feature shared with the cell walls of all macroalgae and that is important for ion homoeostasis, nutrient uptake and O2/CO2 exchange through leaf epidermal cells. The Z. marina genome resource will markedly advance a wide range of functional ecological studies from adaptation of marine ecosystems under climate warming, to unravelling the mechanisms of osmoregulation under high salinities that may further inform our understanding of the evolution of salt tolerance in crop plants.
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TL;DR: In this paper, several passive filter topologies used to interface voltage-source converters with the utility grid are reviewed and evaluated in terms of damping capability, stored energy in the passive components, and power loss in the damping circuit.
Abstract: In order to reduce size and cost, high-order passive filters are generally preferred in power converters to cancel out high-frequency harmonics caused by pulsewidth modulation. However, the filter resonance peaks may require the use of passive dampers to stabilize the interactions between the load and source impedances. Furthermore, the stabilizing effect is more difficult to be guaranteed for cost-optimized filters, which are characterized by low-inductance and high-capacitance passive components. In this paper, several passive filter topologies used to interface voltage-source converters with the utility grid are reviewed and evaluated in terms of damping capability, stored energy in the passive components, and power loss in the damping circuit. In addition, the influences of different switching frequencies of power converters on the passive filter design are discussed in the range 1–15 kHz. Illustrative design examples of the passive filters and experimental data are also provided.
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Wayne State University1, Stony Brook University2, University of Connecticut3, Harvard University4, Max Planck Society5, University of Kiel6, University College Cork7, Swarthmore College8, University of Vermont9, Indiana University10, York University11, University of Rennes12, Tel Aviv University13, Vanderbilt University14
TL;DR: Holobionts and hologenomes are incontrovertible, multipartite entities that result from ecological, evolutionary, and genetic processes at various levels that constitute a wider vocabulary and framework for host biology in light of the microbiome.
Abstract: Given the complexity of host-microbiota symbioses, scientists and phi- losophers are asking questions at new biological levels of hierarchical organization— what is a holobiont and hologenome? When should this vocabulary be applied? Are these concepts a null hypothesis for host-microbe systems or limited to a certain spectrum of symbiotic interactions such as host-microbial coevolution? Critical dis- course is necessary in this nascent area, but productive discourse requires that skep- tics and proponents use the same lexicon. For instance, critiquing the hologenome concept is not synonymous with critiquing coevolution, and arguing that an entity is not a primary unit of selection dismisses the fact that the hologenome concept has always embraced multilevel selection. Holobionts and hologenomes are incontro- vertible, multipartite entities that result from ecological, evolutionary, and genetic processes at various levels. They are not restricted to one special process but consti- tute a wider vocabulary and framework for host biology in light of the microbiome.
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TL;DR: In this paper, the authors describe the consequences of defective LC3-associated phagocytosis in vivo and show that mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage.
Abstract: Defects in clearance of dying cells have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Mice lacking molecules associated with dying cell clearance develop SLE-like disease, and phagocytes from patients with SLE often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we and others described a form of noncanonical autophagy known as LC3-associated phagocytosis (LAP), in which phagosomes containing engulfed particles, including dying cells, recruit elements of the autophagy pathway to facilitate maturation of phagosomes and digestion of their contents. Genome-wide association studies have identified polymorphisms in the Atg5 (ref. 8) and possibly Atg7 (ref. 9) genes, involved in both canonical autophagy and LAP, as markers of a predisposition for SLE. Here we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. When dying cells are injected into LAP-deficient mice, they are engulfed but not efficiently degraded and trigger acute elevation of pro-inflammatory cytokines but not anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient, mice accelerated the development of SLE-like disease, including increased serum levels of autoantibodies. By contrast, mice deficient in genes required for canonical autophagy but not LAP do not display defective dying cell clearance, inflammatory cytokine production, or SLE-like disease, and, like wild-type mice, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE.
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University of Jena1, Technische Universität München2, State University of Campinas3, University of Freiburg4, University of Bern5, Lund University6, University of Natural Resources and Life Sciences, Vienna7, University of Ulm8, Leibniz Association9, Helmholtz Centre for Environmental Research - UFZ10, Leipzig University11, University of Cologne12, Technische Universität Darmstadt13, University of Würzburg14, University of Kiel15, University of Giessen16, University of Göttingen17, Max Planck Society18, University of Potsdam19, Fujian Agriculture and Forestry University20, Martin Luther University of Halle-Wittenberg21, University of Salzburg22, Free University of Berlin23
TL;DR: It is shown that even moderate increases in local land-use intensity (LUI) cause biotic homogenization across microbial, plant and animal groups, both above- and belowground, and that this is largely independent of changes in α-diversity.
Abstract: Land-use intensification is a major driver of biodiversity loss. Alongside reductions in local species diversity, biotic homogenization at larger spatial scales is of great concern for conservation. Biotic homogenization means a decrease in β-diversity (the compositional dissimilarity between sites). Most studies have investigated losses in local (α)-diversity and neglected biodiversity loss at larger spatial scales. Studies addressing β-diversity have focused on single or a few organism groups (for example, ref. 4), and it is thus unknown whether land-use intensification homogenizes communities at different trophic levels, above- and belowground. Here we show that even moderate increases in local land-use intensity (LUI) cause biotic homogenization across microbial, plant and animal groups, both above- and belowground, and that this is largely independent of changes in α-diversity. We analysed a unique grassland biodiversity dataset, with abundances of more than 4,000 species belonging to 12 trophic groups. LUI, and, in particular, high mowing intensity, had consistent effects on β-diversity across groups, causing a homogenization of soil microbial, fungal pathogen, plant and arthropod communities. These effects were nonlinear and the strongest declines in β-diversity occurred in the transition from extensively managed to intermediate intensity grassland. LUI tended to reduce local α-diversity in aboveground groups, whereas the α-diversity increased in belowground groups. Correlations between the β-diversity of different groups, particularly between plants and their consumers, became weaker at high LUI. This suggests a loss of specialist species and is further evidence for biotic homogenization. The consistently negative effects of LUI on landscape-scale biodiversity underscore the high value of extensively managed grasslands for conserving multitrophic biodiversity and ecosystem service provision. Indeed, biotic homogenization rather than local diversity loss could prove to be the most substantial consequence of land-use intensification.
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University of Washington1, University of Cambridge2, University of Leicester3, University of Lübeck4, University of Copenhagen5, University of Wisconsin–Milwaukee6, University of Michigan7, Montreal Heart Institute8, University of Oxford9, Broad Institute10, Samsung Medical Center11, University of Amsterdam12, Queen Mary University of London13, University of Göttingen14, University of Dundee15, University of Verona16, Vanderbilt University17, University of Kiel18, University of Bonn19, University of Basel20, Norwegian University of Science and Technology21, Umeå University22, University of Duisburg-Essen23, Technische Universität München24, University of Tartu25, Lund University26, University of Ottawa27, King Abdulaziz University28, Merck & Co.29, Ohio State University30, National Institutes of Health31, Johns Hopkins University32, Harvard University33, University of Insubria34, University of Glasgow35, Leiden University36, Queen's University Belfast37, Pierre-and-Marie-Curie University38, Wellcome Trust Sanger Institute39, University of Leeds40, Duke University41, University of Pennsylvania42
TL;DR: It was found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
Abstract: BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we ...
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TL;DR: In this paper, the authors proposed a distributed electric distribution system based on a unidirectional information flow from sources to control centers, which limits the use of renewable energy resources and offers poor EV infrastructure.
Abstract: The increasing proliferation of renewable energy resources and new sizeable loads like electric vehicle (EV) charging stations has posed many technical and operational challenges to distribution grids [1]. Encouraged by attractive tax incentives and promotion policies, local grid end consumers are becoming not only consumers of electricity but, in many cases, also producers. The actual electric distribution system limits the use of renewable energy resources, offers poor EV infrastructure, and is based on a unidirectional information flow from sources to control centers.
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Tongji University1, University of Paris2, University of Kiel3, University of Hamburg4, Academia Sinica5, Chulalongkorn University6, National Cheng Kung University7, National Sun Yat-sen University8, University of the Philippines9, Hanoi University of Mining and Geology10, Universiti Malaysia Terengganu11, Indonesian Institute of Sciences12, Chinese Academy of Sciences13
TL;DR: In this paper, the authors synthesize existing clay mineralogical and geochemical data from similar to 1500 samples from the seafloor and surrounding rivers, deepwater mooring observation results, and high resolution glacial-cyclic clay mineralogy records from six high-quality sediment cores.
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TL;DR: Using whole-genome sequencing, this work proposes an evolutionary scenario where the Satellite chromosome arose by a rare recombination event about 500,000 years ago and resolved the enigma of how such complex phenotypic differences can have a simple genetic basis.
Abstract: Leif Andersson and colleagues report the genome sequence of the ruff, a bird species with three male morphs with different reproductive strategies. Satellite and faeder morphs differ from the common independent morph by a 4.5-Mb inversion that occurred approximately 3.8 million years ago, and multiple genetic changes within this inverted region are associated with the satellite and faeder morphs. The ruff is a Palearctic wader with a spectacular lekking behavior where highly ornamented males compete for females1,2,3,4. This bird has one of the most remarkable mating systems in the animal kingdom, comprising three different male morphs (independents, satellites and faeders) that differ in behavior, plumage color and body size. Remarkably, the satellite and faeder morphs are controlled by dominant alleles5,6. Here we have used whole-genome sequencing and resolved the enigma of how such complex phenotypic differences can have a simple genetic basis. The Satellite and Faeder alleles are both associated with a 4.5-Mb inversion that occurred about 3.8 million years ago. We propose an evolutionary scenario where the Satellite chromosome arose by a rare recombination event about 500,000 years ago. The ruff mating system is the result of an evolutionary process in which multiple genetic changes contributing to phenotypic differences between morphs have accumulated within the inverted region.
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TL;DR: With regard to the outstanding clinical activity of the anti-PD-1 antibodies, therapy restart is the principal therapeutic option after recovery of grade 2 AEOSI, or diminution of higher grade skin or endocrine events to mild severity.
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Université libre de Bruxelles1, Memorial Sloan Kettering Cancer Center2, Mayo Clinic3, University of Milan4, National Institutes of Health5, GlaxoSmithKline6, University of Toronto7, Peking Union Medical College8, University of Kiel9, Breast International Group10, The Breast Cancer Research Foundation11, Ludwig Maximilian University of Munich12, Russian Academy13, Sungkyunkwan University14, National Taiwan University15, Curie Institute16, Johns Hopkins University17, The Royal Marsden NHS Foundation Trust18, University of Sydney19, University of Bern20, Harvard University21
TL;DR: Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity, and one year of adjuvant T remains standard of care.
Abstract: BackgroundLapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain.MethodsIn the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T.ResultsBetween June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-spec...
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TL;DR: A modified, recombinant dimerized version of sgp130 (sgp130Fc) has successfully been used to block inflammatory processes in mice and may also be used in the clarification of IL-6 trans-signaling in neurological diseases.
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TL;DR: The present results provide the first evidence that LSD selectively expands global connectivity in the brain, compromising the brain's modular and "rich-club" organization and, simultaneously, the perceptual boundaries between the self and the environment.