Showing papers by "University of Lausanne published in 2018"
University of Minnesota1, University of Colorado Boulder2, VU University Amsterdam3, Harvard University4, University of Southern California5, University of Queensland6, University of Tartu7, Erasmus University Rotterdam8, Hospital for Special Surgery9, University of Copenhagen10, Statens Serum Institut11, Broad Institute12, University of Essex13, University of Edinburgh14, University of Cambridge15, University Hospital of Lausanne16, Geisinger Health System17, Wenzhou Medical College18, Stanford University19, University of North Carolina at Chapel Hill20, University of Wisconsin-Madison21, Hofstra University22, The Feinstein Institute for Medical Research23, University of Dundee24, University of Toronto25, Princeton University26, National Bureau of Economic Research27, New York University Shanghai28, Queen's University29, Karolinska Institutet30, Uppsala University31, University of Lausanne32, New York University33, Stockholm School of Economics34
TL;DR: A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance ineducational attainment and 7–10% ofthe variance in cognitive performance, which substantially increases the utility ofpolygenic scores as tools in research.
Abstract: Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
1,658 citations
Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan1, Brendan Bulik-Sullivan2 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
1,357 citations
TL;DR: In insights into the role of alcohol consumption in the genetic architecture of hypertension, a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions is conducted.
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1,218 citations
TL;DR: To avoid a global collapse in the ability to control fungal infections and to avoid critical failures in medicine and food security, the authors must improve the stewardship of extant chemicals, promote new antifungal discovery, and leverage emerging technologies for alternative solutions.
Abstract: The recent rate of emergence of pathogenic fungi that are resistant to the limited number of commonly used antifungal agents is unprecedented. The azoles, for example, are used not only for human and animal health care and crop protection but also in antifouling coatings and timber preservation. The ubiquity and multiple uses of azoles have hastened the independent evolution of resistance in many environments. One consequence is an increasing risk in human health care from naturally occurring opportunistic fungal pathogens that have acquired resistance to this broad class of chemicals. To avoid a global collapse in our ability to control fungal infections and to avoid critical failures in medicine and food security, we must improve our stewardship of extant chemicals, promote new antifungal discovery, and leverage emerging technologies for alternative solutions.
807 citations
Catholic University of the Sacred Heart1, Memorial Sloan Kettering Cancer Center2, International Agency for Research on Cancer3, University Health Network4, University of Lausanne5, Centre Hospitalier Universitaire de Grenoble6, Utrecht University7, Charité8, University of Texas MD Anderson Cancer Center9, Technische Universität München10, Belfast Health and Social Care Trust11, University of Zurich12, University of Nottingham13, Beatson West of Scotland Cancer Centre14, Tohoku University15, University of Verona16, Institut Gustave Roussy17, University of Bologna18, Radboud University Nijmegen19
TL;DR: This work believes this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.
688 citations
TL;DR: The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.
Abstract: Evidence from mouse chronic viral infection models suggests that CD8+ T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1–) from non-small-cell lung cancer patients. PD-1T T cells showed a markedly different transcriptional and metabolic profile from PD-1N and PD-1– lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1T cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention. Tumor-infiltrating CD8+ T cells with high expression of PD-1 in non-small-cell lung cancer are distinct from exhausted T cells in chronic virus infection, have high tumor reactivity and associate with response to PD-1-targeted immunotherapy.
669 citations
University of North Carolina at Chapel Hill1, University of Pennsylvania2, University of Colorado Denver3, Tel Aviv University4, Baylor University Medical Center5, Durham University6, University of California, San Diego7, Mayo Clinic8, Northwestern University9, Nestlé10, Tufts University11, Boston Children's Hospital12, Icahn School of Medicine at Mount Sinai13, University of Texas Southwestern Medical Center14, Cincinnati Children's Hospital Medical Center15, Baylor College of Medicine16, Nationwide Children's Hospital17, University of Paris18, University of Health Sciences Antigua19, University of Illinois at Urbana–Champaign20, Shimane University21, University Hospitals Coventry and Warwickshire NHS Trust22, Harvard University23, Juntendo University24, University of Ljubljana25, National and Kapodistrian University of Athens26, University of Utah27, University of Adelaide28, University of South Florida29, University of Lausanne30, University College London31, Kaiser Permanente32, University of Newcastle33, Vanderbilt University34, Vrije Universiteit Brussel35, Federal University of Paraná36, Children's Memorial Hospital37, University of Amsterdam38
TL;DR: An updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement, and the evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EOE than as a diagnostic criterion.
621 citations
Drexel University1, Fujian Agriculture and Forestry University2, University of Utah3, Max Planck Society4, University College London5, University of Lausanne6, Lawrence Berkeley National Laboratory7, University of California, San Francisco8, University of California, San Diego9, Georgia Institute of Technology10
TL;DR: GOATOOLS, a Python-based library, makes it more efficient to stay current with the latest ontologies and annotations, perform gene ontology enrichment analyses to determine over- and under-represented terms, and organize results for greater clarity and easier interpretation using a novel GOATOOLs GO grouping method.
Abstract: The biological interpretation of gene lists with interesting shared properties, such as up- or down-regulation in a particular experiment, is typically accomplished using gene ontology enrichment analysis tools. Given a list of genes, a gene ontology (GO) enrichment analysis may return hundreds of statistically significant GO results in a "flat" list, which can be challenging to summarize. It can also be difficult to keep pace with rapidly expanding biological knowledge, which often results in daily changes to any of the over 47,000 gene ontologies that describe biological knowledge. GOATOOLS, a Python-based library, makes it more efficient to stay current with the latest ontologies and annotations, perform gene ontology enrichment analyses to determine over- and under-represented terms, and organize results for greater clarity and easier interpretation using a novel GOATOOLS GO grouping method. We performed functional analyses on both stochastic simulation data and real data from a published RNA-seq study to compare the enrichment results from GOATOOLS to two other popular tools: DAVID and GOstats. GOATOOLS is freely available through GitHub: https://github.com/tanghaibao/goatools .
603 citations
TL;DR: Targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation are introduced.
Abstract: Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.
599 citations
TL;DR: Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system.
Abstract: Lactate in the brain has long been associated with ischaemia; however, more recent evidence shows that it can be found there under physiological conditions. In the brain, lactate is formed predominantly in astrocytes from glucose or glycogen in response to neuronal activity signals. Thus, neurons and astrocytes show tight metabolic coupling. Lactate is transferred from astrocytes to neurons to match the neuronal energetic needs, and to provide signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. In addition, lactate affects several homeostatic functions. Overall, lactate ensures adequate energy supply, modulates neuronal excitability levels and regulates adaptive functions in order to set the 'homeostatic tone' of the nervous system.
595 citations
German Center for Neurodegenerative Diseases1, Salk Institute for Biological Studies2, Paracelsus Private Medical University of Salzburg3, University of Pennsylvania4, University of Auckland5, King's College London6, University of Gothenburg7, Charité8, University of Zurich9, National Institutes of Health10, Princeton University11, Columbia University12, French Institute of Health and Medical Research13, University of Lausanne14, Fundación Instituto Leloir15, University of Wisconsin-Madison16, University of Amsterdam17, Karolinska Institutet18
TL;DR: It is argued that there is currently no reason to abandon the idea that adult-generated neurons make important functional contributions to neural plasticity and cognition across the human lifespan.
Aarhus University1, University of Erlangen-Nuremberg2, University of Bergen3, University of Rostock4, University of Picardie Jules Verne5, Austrian Academy of Sciences6, University of Natural Resources and Life Sciences, Vienna7, University of Turin8, University of Edinburgh9, University of Lausanne10, Swiss Federal Institute for Forest, Snow and Landscape Research11, University of Warsaw12, Polish Academy of Sciences13, University of Vienna14, University of Innsbruck15, Spanish National Research Council16, International Agency for Research on Cancer17, Norwegian University of Life Sciences18, Martin Luther University of Halle-Wittenberg19, University of Aberdeen20, Slovak Academy of Sciences21, Helmholtz Centre for Environmental Research - UFZ22, United States Environmental Protection Agency23, University College of Southeast Norway24, University of Geneva25, École Polytechnique Fédérale de Lausanne26
TL;DR: Analysis of changes in plant species richness on mountain summits over the past 145 years suggests that increased climatic warming has led to an acceleration in species richness increase, strikingly synchronized with accelerated global warming.
Abstract: Globally accelerating trends in societal development and human environmental impacts since the mid-twentieth century
1–7
are known as the Great Acceleration and have been discussed as a key indicator of the onset of the Anthropocene epoch
6
. While reports on ecological responses (for example, changes in species range or local extinctions) to the Great Acceleration are multiplying
8, 9
, it is unknown whether such biotic responses are undergoing a similar acceleration over time. This knowledge gap stems from the limited availability of time series data on biodiversity changes across large temporal and geographical extents. Here we use a dataset of repeated plant surveys from 302 mountain summits across Europe, spanning 145 years of observation, to assess the temporal trajectory of mountain biodiversity changes as a globally coherent imprint of the Anthropocene. We find a continent-wide acceleration in the rate of increase in plant species richness, with five times as much species enrichment between 2007 and 2016 as fifty years ago, between 1957 and 1966. This acceleration is strikingly synchronized with accelerated global warming and is not linked to alternative global change drivers. The accelerating increases in species richness on mountain summits across this broad spatial extent demonstrate that acceleration in climate-induced biotic change is occurring even in remote places on Earth, with potentially far-ranging consequences not only for biodiversity, but also for ecosystem functioning and services.
Georgia Institute of Technology1, Leipzig University2, Johns Hopkins University3, University of Cambridge4, University of Tartu5, Ontario Institute for Cancer Research6, University of Washington7, VU University Amsterdam8, University of Chicago9, Greifswald University Hospital10, University of Bristol11, Erasmus University Rotterdam12, University of Exeter13, University of Lausanne14, University of Geneva15, Swiss Institute of Bioinformatics16, University of Helsinki17, Weizmann Institute of Science18, Agency for Science, Technology and Research19, University of Queensland20, Leiden University Medical Center21, University of Liège22, University of Oxford23, University of Tampere24, Stanford University25, Turku University Hospital26, Maastricht University Medical Centre27, Karolinska Institutet28, Radboud University Nijmegen29, Utrecht University30, European Bioinformatics Institute31
TL;DR: It is observed that cis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting the ability to use cis- eZTLs to pinpoint causal genes within susceptibility loci.
Abstract: While many disease-associated variants have been identified through genome-wide association studies, their downstream molecular consequences remain unclear. To identify these effects, we performed cis- and trans-expression quantitative trait locus (eQTL) analysis in blood from 31,684 individuals through the eQTLGen Consortium. We observed that cis-eQTLs can be detected for 88% of the studied genes, but that they have a different genetic architecture compared to disease-associated variants, limiting our ability to use cis-eQTLs to pinpoint causal genes within susceptibility loci. In contrast, trans-eQTLs (detected for 37% of 10,317 studied trait-associated variants) were more informative. Multiple unlinked variants, associated to the same complex trait, often converged on trans-genes that are known to play central roles in disease etiology. We observed the same when ascertaining the effect of polygenic scores calculated for 1,263 genome-wide association study (GWAS) traits. Expression levels of 13% of the studied genes correlated with polygenic scores, and many resulting genes are known to drive these traits.
Richard A. Klein1, Michelangelo Vianello2, Fred Hasselman3, Byron G. Adams4 +187 more•Institutions (118)
TL;DR: This paper conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings, and found that very little heterogeneity was attributable to the order in which the tasks were performed or whether the task were administered in lab versus online.
Abstract: We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely high-powered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.
TL;DR: The present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide, and is believed to be the first ever large-scale coordinated study of WM microstructural differences in schizophrenia.
Abstract: The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.
TL;DR: In this review, selected aspects of P. aeruginosa antimicrobial resistance and infection management will be addressed and clinical approaches to patients with bacteremia, ventilator-associated pneumonia, urinary tract infections and skin soft tissue infections are discussed.
Abstract: Infections with Pseudomonas aeruginosa have become a real concern in hospital-acquired infections, especially in critically ill and immunocompromised patients. The major problem leading to high mortality lies in the appearance of drug-resistant strains. Therefore, a vast number of approaches to develop novel anti-infectives is currently pursued. Diverse strategies range from killing (new antibiotics) to disarming (antivirulence) the pathogen. In this review, selected aspects of P. aeruginosa antimicrobial resistance and infection management will be addressed. Many studies have been performed to evaluate the risk factors for resistance and the potential consequences on mortality and attributable mortality. The review also looks at the mechanisms associated with resistance - P. aeruginosa is a pathogen presenting a large genome, and it can develop a large number of factors associated with antibiotic resistance involving almost all classes of antibiotics. Clinical approaches to patients with bacteremia, ventilator-associated pneumonia, urinary tract infections and skin soft tissue infections are discussed. Antibiotic combinations are reviewed as well as an analysis of pharmacokinetic and pharmacodynamic parameters to optimize P. aeruginosa treatment. Limitations of current therapies, the potential for alternative drugs and new therapeutic options are also discussed.
TL;DR: It is found that calcium influx through GSDMD pores serves as a signal for cells to initiate membrane repair by recruiting the endosomal sorting complexes required for transport (ESCRT) machinery to damaged membrane areas, such as the plasma membrane.
Abstract: Pyroptosis is a lytic form of cell death that is induced by inflammatory caspases upon activation of the canonical or noncanonical inflammasome pathways. These caspases cleave gasdermin D (GSDMD) to generate an N-terminal GSDMD fragment, which executes pyroptosis by forming membrane pores. We found that calcium influx through GSDMD pores serves as a signal for cells to initiate membrane repair by recruiting the endosomal sorting complexes required for transport (ESCRT) machinery to damaged membrane areas, such as the plasma membrane. Inhibition of the ESCRT-III machinery strongly enhances pyroptosis and interleukin-1β release in both human and murine cells after canonical or noncanonical inflammasome activation. These results not only attribute an anti-inflammatory role to membrane repair by the ESCRT-III system but also provide insight into general cellular survival mechanisms during pyroptosis.
University of Geneva1, University of Helsinki2, Katholieke Universiteit Leuven3, University of Washington4, University of Wisconsin-Madison5, Heidelberg University6, German Cancer Research Center7, University of Nottingham8, VU University Amsterdam9, University of California, Irvine10, University of California, San Francisco11, French Institute of Health and Medical Research12, Harvard University13, Maine Medical Center14, University of Turin15, National Institutes of Health16, University of Texas Southwestern Medical Center17, University of Lausanne18, University of Missouri19, École Polytechnique Fédérale de Lausanne20, Uppsala University21, University of Arkansas for Medical Sciences22, University of Bern23, University of Virginia24, Imperial College London25, University of California, San Diego26, University College London27, Flanders Institute for Biotechnology28, University of Oxford29, University of California, Los Angeles30, University of Texas MD Anderson Cancer Center31, University of Toronto32, University of Illinois at Chicago33, University of Amsterdam34, George Washington University35, University of Liège36, University of Eastern Finland37, Ludwig Institute for Cancer Research38, Indiana University39, University of Edinburgh40, Maastricht University41, Loyola University Medical Center42, National Scientific and Technical Research Council43, University of Bari44, University of Fribourg45, Ohio State University46, University of Melbourne47, University of Antwerp48, University of Münster49
TL;DR: In vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis are described and critical aspects that are relevant for their execution and proper interpretation are highlighted.
Abstract: The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
TL;DR: A diet rich in the fermentable fiber inulin and the associated metabolites—short‐chain fatty acids—improve the response of mice to influenza infection by dampening deleterious immunopathology caused by neutrophils while enhancing anti‐viral CD8+ T cell responses through a boost in T cell metabolism.
TL;DR: In this article, a review of available evidence on the potential role of Ca in the stabilisation of organic carbon (SOC) pools is presented, highlighting the importance of pH as a potential predictor of SOC stabilisation mechanisms mediated by Al- or Fe- to Ca, and their respective effects on SOC dynamics.
Abstract: Soils play an essential role in the global cycling of carbon and understanding the stabilisation mechanisms behind the preservation of soil organic carbon (SOC) pools is of globally recognised significance. Until recently, research into SOC stabilisation has predominantly focused on acidic soil environments and the interactions between SOC and aluminium (Al) or iron (Fe). The interactions between SOC and calcium (Ca) have typically received less attention, with fewer studies conducted in alkaline soils. Although it has widely been established that exchangeable Ca (CaExch) positively correlates with SOC concentration and its resistance to oxidation, the exact mechanisms behind this relationship remain largely unidentified. This synthesis paper critically assesses available evidence on the potential role of Ca in the stabilisation of SOC and identifies research topics that warrant further investigation. Contrary to the common view of the chemistry of base cations in soils, chemical modelling indicates that Ca2+ can readily exchange its hydration shell and create inner sphere complexes with organic functional groups. This review therefore argues that both inner- and outer-sphere bridging by Ca2+ can play an active role in the stabilisation of SOC. Calcium carbonate (CaCO3) can influence occluded SOC stability through its role in the stabilisation of aggregates; however, it could also play an unaccounted role in the direct sorption and inclusion of SOC. Finally, this review highlights the importance of pH as a potential predictor of SOC stabilisation mechanisms mediated by Al- or Fe- to Ca, and their respective effects on SOC dynamics.
Oslo University Hospital1, University College London2, University of Texas MD Anderson Cancer Center3, University of Valencia4, University of Technology, Sydney5, Vrije Universiteit Brussel6, University of Edinburgh7, University of Vic8, Princess Margaret Cancer Centre9, Haukeland University Hospital10, King's College London11, University Hospital Heidelberg12, Copenhagen University Hospital13, University of Lausanne14, University of Göttingen15
TL;DR: This Commission proposes the use of standardised care pathways and multidisciplinary teams to promote integration of oncology and palliative care, and calls for changes at the system level to coordinate the activities of professionals, and for the development and implementation of new and improved education programmes, with the overall goal of improving patient care.
Abstract: Full integration of oncology and palliative care relies on the specific knowledge and skills of two modes of care: the tumour-directed approach, the main focus of which is on treating the disease; and the host-directed approach, which focuses on the patient with the disease. This Commission addresses how to combine these two paradigms to achieve the best outcome of patient care. Randomised clinical trials on integration of oncology and palliative care point to health gains: improved survival and symptom control, less anxiety and depression, reduced use of futile chemotherapy at the end of life, improved family satisfaction and quality of life, and improved use of health-care resources. Early delivery of patient-directed care by specialist palliative care teams alongside tumour-directed treatment promotes patient-centred care. Systematic assessment and use of patient-reported outcomes and active patient involvement in the decisions about cancer care result in better symptom control, improved physical and mental health, and better use of health-care resources. The absence of international agreements on the content and standards of the organisation, education, and research of palliative care in oncology are major barriers to successful integration. Other barriers include the common misconception that palliative care is end-of-life care only, stigmatisation of death and dying, and insufficient infrastructure and funding. The absence of established priorities might also hinder integration more widely. This Commission proposes the use of standardised care pathways and multidisciplinary teams to promote integration of oncology and palliative care, and calls for changes at the system level to coordinate the activities of professionals, and for the development and implementation of new and improved education programmes, with the overall goal of improving patient care. Integration raises new research questions, all of which contribute to improved clinical care. When and how should palliative care be delivered? What is the optimal model for integrated care? What is the biological and clinical effect of living with advanced cancer for years after diagnosis? Successful integration must challenge the dualistic perspective of either the tumour or the host, and instead focus on a merged approach that places the patient's perspective at the centre. To succeed, integration must be anchored by management and policy makers at all levels of health care, followed by adequate resource allocation, a willingness to prioritise goals and needs, and sustained enthusiasm to help generate support for better integration. This integrated model must be reflected in international and national cancer plans, and be followed by developments of new care models, education and research programmes, all of which should be adapted to the specific cultural contexts within which they are situated. Patient-centred care should be an integrated part of oncology care independent of patient prognosis and treatment intention. To achieve this goal it must be based on changes in professional cultures and priorities in health care.
University of Lorraine1, Michigan State University2, Duke University3, University of California, Berkeley4, University of Bordeaux5, Leibniz Association6, Max Planck Society7, University of Lausanne8, Oak Ridge National Laboratory9, University of Tennessee10, Cornell University11, Eötvös Loránd University12, University of Turin13, Fujian Agriculture and Forestry University14, University of Groningen15, Helmholtz Centre for Environmental Research - UFZ16
TL;DR: A particular focus is placed on the understanding of BFI within complex microbial communities and in regard of the metaorganism concept, as well as recent discoveries that clarify the (molecular) mechanisms involved in bacterial-fungal relationships.
Abstract: Fungi and bacteria are found living together in a wide variety of environments. Their interactions are significant drivers of many ecosystem functions and are important for the health of plants and animals. A large number of fungal and bacterial families engage in complex interactions that lead to critical behavioural shifts of the microorganisms ranging from mutualism to antagonism. The importance of bacterial-fungal interactions (BFI) in environmental science, medicine and biotechnology has led to the emergence of a dynamic and multidisciplinary research field that combines highly diverse approaches including molecular biology, genomics, geochemistry, chemical and microbial ecology, biophysics and ecological modelling. In this review, we discuss recent advances that underscore the roles of BFI across relevant habitats and ecosystems. A particular focus is placed on the understanding of BFI within complex microbial communities and in regard of the metaorganism concept. We also discuss recent discoveries that clarify the (molecular) mechanisms involved in bacterial-fungal relationships, and the contribution of new technologies to decipher generic principles of BFI in terms of physical associations and molecular dialogues. Finally, we discuss future directions for research in order to stimulate synergy within the BFI research area and to resolve outstanding questions.
TL;DR: The unexpected discovery that gasdermin D (GSDMD) connects these cell death modalities and provides host defense against extracellular pathogens, whereas macrophage death by pyroptosis enables defense against intracellular pathogens.
Abstract: Neutrophil extrusion of neutrophil extracellular traps (NETs) and concomitant cell death (NETosis) provides host defense against extracellular pathogens, whereas macrophage death by pyroptosis enables defense against intracellular pathogens. We report the unexpected discovery that gasdermin D (GSDMD) connects these cell death modalities. We show that neutrophil exposure to cytosolic lipopolysaccharide or cytosolic Gram-negative bacteria ( Salmonella Δ sifA and Citrobacter rodentium ) activates noncanonical (caspase-4/11) inflammasome signaling and triggers GSDMD-dependent neutrophil death. GSDMD-dependent death induces neutrophils to extrude antimicrobial NETs. Caspase-11 and GSDMD are required for neutrophil plasma membrane rupture during the final stage of NET extrusion. Unexpectedly, caspase-11 and GSDMD are also required for early features of NETosis, including nuclear delobulation and DNA expansion; this is mediated by the coordinate actions of caspase-11 and GSDMD in mediating nuclear membrane permeabilization and histone degradation. In vivo application of deoxyribonuclease I to dissolve NETs during murine Salmonella Δ sifA challenge increases bacterial burden in wild-type but not in Casp11 −/− and Gsdmd −/− mice. Our studies reveal that neutrophils use an inflammasome- and GSDMD-dependent mechanism to activate NETosis as a defense response against cytosolic bacteria.
TL;DR: The results of this prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplexEncephalitis, and it was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simple X virus reactivation.
Abstract: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication.
We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis.
Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001).
The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy.
Mutua Madrilena Foundation, Fondation de l'Universite de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundacio CELLEX.
University of Salford1, University of Queensland2, University of Western Australia3, Queensland University of Technology4, University of Lausanne5, Wildfowl & Wetlands Trust6, Canadian Parks and Wilderness Society7, University of Évora8, University of Freiburg9, University of Melbourne10, University of Plymouth11, Mississippi State University12, Australian Institute of Marine Science13, Griffith University14, Zurich University of Applied Sciences/ZHAW15, University of British Columbia16, Duke University17, Finnish Environment Institute18, University of Adelaide19, King Fahd University of Petroleum and Minerals20, IFREMER21, University of California, Davis22, Technical University of Madrid23, National Institute of Water and Atmospheric Research24, Memorial University of Newfoundland25, Royal Society for the Protection of Birds26, University of Kansas27, University of California, Merced28, University of the Sunshine Coast29, Nelson Mandela Metropolitan University30, Swedish University of Agricultural Sciences31, University of Grenoble32, Oregon State University33, University of Toronto34, Gulf of Maine Research Institute35, University of Georgia36, Newcastle University37, Parks Canada38, Humboldt University of Berlin39
TL;DR: Of high importance is the identification of a widely applicable set of transferability metrics, with appropriate tools to quantify the sources and impacts of prediction uncertainty under novel conditions.
Abstract: Predictive models are central to many scientific disciplines and vital for informing management in a rapidly changing world However, limited understanding of the accuracy and precision of models transferred to novel conditions (their ‘transferability’) undermines confidence in their predictions Here, 50 experts identified priority knowledge gaps which, if filled, will most improve model transfers These are summarized into six technical and six fundamental challenges, which underlie the combined need to intensify research on the determinants of ecological predictability, including species traits and data quality, and develop best practices for transferring models Of high importance is the identification of a widely applicable set of transferability metrics, with appropriate tools to quantify the sources and impacts of prediction uncertainty under novel conditions
First Faculty of Medicine, Charles University in Prague1, Medical University of Vienna2, Linköping University3, Institut Gustave Roussy4, University of Cologne5, University of Milan6, University of Lausanne7, Belfast Health and Social Care Trust8, University College Hospital9, Leiden University10, Athens State University11, Medical University of Graz12
TL;DR: The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncologists (ESTRO), and the European Pathology (EPSP) jointly developed clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide.
Abstract: Background Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer. Objective The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide. Methods The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives. Results The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.
University of Amsterdam1, University of Bergen2, Pedagogical and Technological University of Colombia3, Goethe University Frankfurt4, Leipzig University5, University of Göttingen6, University of Zurich7, University of Michigan8, University of Copenhagen9, Imperial College London10, University of Lausanne11
TL;DR: In this article, the authors integrate multiple datasets to assess the relationships between species richness in mountains, geology and climate at global and regional scales, and find that centres of species richness correlate with areas of high temperatures, annual rainfall and topographic relief, supporting previous studies.
Abstract: Mountains are key features of the Earth’s surface and host a substantial proportion of the world’s species. However, the links between the evolution and distribution of biodiversity and the formation of mountains remain poorly understood. Here, we integrate multiple datasets to assess the relationships between species richness in mountains, geology and climate at global and regional scales. Specifically, we analyse how erosion, relief, soil and climate relate to the geographical distribution of terrestrial tetrapods, which include amphibians, birds and mammals. We find that centres of species richness correlate with areas of high temperatures, annual rainfall and topographic relief, supporting previous studies. We unveil additional links between mountain-building processes and biodiversity: species richness correlates with erosion rates and heterogeneity of soil types, with a varying response across continents. These additional links are prominent but under-explored, and probably relate to the interplay between surface uplift, climate change and atmospheric circulation through time. They are also influenced by the location and orientation of mountain ranges in relation to air circulation patterns, and how species diversification, dispersal and refugia respond to climate change. A better understanding of biosphere–lithosphere interactions is needed to understand the patterns and evolution of mountain biodiversity across space and time.
TL;DR: The epidemiology of invasive candidiasis has evolved in recent years, warranting a review of the changes and the implications for current and future diagnosis and treatment, and the call for vigilance in detection and advances in treatment.
Abstract: The epidemiology of invasive candidiasis has evolved in recent years, warranting a review of the changes and the implications for current and future diagnosis and treatment. The overall burden of invasive candidiasis remains high, particularly in the expanding populations of patients at risk of opportunistic infection, such as the elderly or immunosuppressed. Progressive shifts from Candida albicans to non-albicans Candida spp. have been observed globally. The recent emergence of novel, multiresistant species, such as Candida auris, amplifies the call for vigilance in detection and advances in treatment. Among the current treatment options, fluconazole is still widely used throughout the world. Increased resistance to fluconazole, both acquired and naturally emerging, has been observed. Resistance to echinocandins is presently low but this may change with increased use. Improvement of diagnostic techniques and strategies, development of international surveillance networks and implementation of antifungal stewardship programmes represent major challenges for a better epidemiological control of invasive candidiasis.
TL;DR: It is found that there has been extensive interchange of evolutionary lineages among different regions and biomes, over the course of tens of millions of years, and Amazonia stands out as the primary source of diversity, which can be mainly explained by the total amount of time Amazonian lineages have occupied the region.
Abstract: The American tropics (the Neotropics) are the most species-rich realm on Earth, and for centuries, scientists have attempted to understand the origins and evolution of their biodiversity. It is now clear that different regions and taxonomic groups have responded differently to geological and climatic changes. However, we still lack a basic understanding of how Neotropical biodiversity was assembled over evolutionary timescales. Here we infer the timing and origin of the living biota in all major Neotropical regions by performing a cross-taxonomic biogeographic analysis based on 4,450 species from six major clades across the tree of life (angiosperms, birds, ferns, frogs, mammals, and squamates), and integrate >1.3 million species occurrences with large-scale phylogenies. We report an unprecedented level of biotic interchange among all Neotropical regions, totaling 4,525 dispersal events. About half of these events involved transitions between major environmental types, with a predominant directionality from forested to open biomes. For all taxonomic groups surveyed here, Amazonia is the primary source of Neotropical diversity, providing >2,800 lineages to other regions. Most of these dispersal events were to Mesoamerica (∼1,500 lineages), followed by dispersals into open regions of northern South America and the Cerrado and Chaco biomes. Biotic interchange has taken place for >60 million years and generally increased toward the present. The total amount of time lineages spend in a region appears to be the strongest predictor of migration events. These results demonstrate the complex origin of tropical ecosystems and the key role of biotic interchange for the assembly of regional biotas.
TL;DR: It is concluded that negative selection acts pervasively on the genetic variants associated with human complex traits using genome-wide SNP data estimated using BayesS.
Abstract: We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero effects), and the relationship between SNP effect size and minor allele frequency for complex traits in conventionally unrelated individuals using genome-wide SNP data. We apply the method to 28 complex traits in the UK Biobank data (N = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (P < 0.05/28) signatures of natural selection in the genetic architecture of 23 traits, including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. The significant estimates of the relationship between effect size and minor allele frequency in complex traits are consistent with a model of negative (or purifying) selection, as confirmed by forward simulation. We conclude that negative selection acts pervasively on the genetic variants associated with human complex traits.