Showing papers by "University of Marburg published in 2019"
TL;DR: The authors show that the ATPase function of the chromatin remodeler SMARCAD1 facilitates the binding of KAP1 to ERVs and is required for their repression in embryonic stem cells.
Abstract: Endogenous retroviruses (ERVs) can confer benefits to their host but present a threat to genome integrity if not regulated correctly. Here we identify the SWI/SNF-like remodeler SMARCAD1 as a key factor in the control of ERVs in embryonic stem cells. SMARCAD1 is enriched at ERV subfamilies class I and II, particularly at active intracisternal A-type particles (IAPs), where it preserves repressive histone methylation marks. Depletion of SMARCAD1 results in de-repression of IAPs and adjacent genes. Recruitment of SMARCAD1 to ERVs is dependent on KAP1, a central component of the silencing machinery. SMARCAD1 and KAP1 occupancy at ERVs is co-dependent and requires the ATPase function of SMARCAD1. Our findings uncover a role for the enzymatic activity of SMARCAD1 in cooperating with KAP1 to silence ERVs. This reveals ATP-dependent chromatin remodeling as an integral step in retrotransposon regulation in stem cells and advances our understanding of the mechanisms driving heterochromatin establishment.
1,686 citations
Heidelberg University1, University of Marburg2, Queen Mary University of London3, University of Leeds4, Rutgers University5, University of New South Wales6, University of Münster7, Aarhus University8, Columbia University9, University of Chieti-Pescara10, University of Oslo11, Karolinska Institutet12, Université catholique de Louvain13, University of Sydney14, Paris Descartes University15, University of Western Australia16, Royal Perth Hospital17, University of Dundee18, Maastricht University19, Katholieke Universiteit Leuven20, National Yang-Ming University21, Taipei Veterans General Hospital22
TL;DR: In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in this proposal, this subgroup is called “chronic primary pain,” and in 6 other subgroups, pain is secondary to an underlying disease.
Abstract: Chronic pain is a major source of suffering. It interferes with daily functioning and often is accompanied by distress. Yet, in the International Classification of Diseases, chronic pain diagnoses are not represented systematically. The lack of appropriate codes renders accurate epidemiological investigations difficult and impedes health policy decisions regarding chronic pain such as adequate financing of access to multimodal pain management. In cooperation with the WHO, an IASP Working Group has developed a classification system that is applicable in a wide range of contexts, including pain medicine, primary care, and low-resource environments. Chronic pain is defined as pain that persists or recurs for more than 3 months. In chronic pain syndromes, pain can be the sole or a leading complaint and requires special treatment and care. In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in our proposal, we call this subgroup "chronic primary pain." In 6 other subgroups, pain is secondary to an underlying disease: chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. These conditions are summarized as "chronic secondary pain" where pain may at least initially be conceived as a symptom. Implementation of these codes in the upcoming 11th edition of International Classification of Diseases will lead to improved classification and diagnostic coding, thereby advancing the recognition of chronic pain as a health condition in its own right.
1,311 citations
University of Manchester1, University of Barcelona2, University of Texas Health Science Center at San Antonio3, National Institutes of Health4, McGill University Health Centre5, Brigham and Women's Hospital6, Temple University7, Flinders University8, Royal Devon and Exeter Hospital9, University of Michigan10, University of the Republic11, NewYork–Presbyterian Hospital12, Central University of Venezuela13, University of Ferrara14, Paris Descartes University15, University of British Columbia16, University of Birmingham17, University of Marburg18
TL;DR: Blood eosinophils are recommended as a biomarker to support clinical decisions regarding the use of inhaled corticosteroids in chronic obstructive pulmonary disease patients, based on recent evidence from clinical trials.
Abstract: Precision medicine is a patient-specific approach that integrates all relevant clinical, genetic and biological information in order to optimise the therapeutic benefit relative to the possibility of side-effects for each individual. Recent clinical trials have shown that higher blood eosinophil counts are associated with a greater efficacy of inhaled corticosteroids (ICSs) in chronic obstructive pulmonary disease (COPD) patients. Blood eosinophil counts are a biomarker with potential to be used in clinical practice, to help target ICS treatment with more precision in COPD patients with a history of exacerbations despite appropriate bronchodilator treatment. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 pharmacological treatment algorithms, based on the ABCD assessment, can be applied relatively easily to treatment-naive individuals at initial presentation. However, their use is more problematic during follow-up in patients who are already on maintenance treatment. There is a need for a different system to guide COPD pharmacological management during follow-up. Recent large randomised controlled trials have provided important new information concerning the therapeutic effects of ICSs and long-acting bronchodilators on exacerbations. The new evidence regarding blood eosinophils and inhaled treatments, and the need to distinguish between initial and follow-up pharmacological management, led to changes in the GOLD pharmacological treatment recommendations. This article explains the evidence and rationale for the GOLD 2019 pharmacological treatment recommendations.
1,122 citations
TL;DR: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community providing the theory and key practical aspects offlow cytometry enabling immunologists to avoid the common errors that often undermine immunological data.
Abstract: These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
698 citations
University of Pennsylvania1, University of Texas MD Anderson Cancer Center2, University of Marburg3, Memorial Sloan Kettering Cancer Center4, University of Bologna5, Carlos III Health Institute6, University of Maryland, Baltimore7, University of Chicago8, University of Minnesota9, University of Alabama at Birmingham10, Medical University of South Carolina11, University of California, San Francisco12, Thomas Jefferson University13, National Taiwan University14, Yale University15, Centre Hospitalier Universitaire de Toulouse16, University of Fukui17, Seoul National University18, University of Ulsan19, Wake Forest University20, Harvard University21, Astellas Pharma22, Johns Hopkins University23
TL;DR: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML.
Abstract: Background Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemothera...
687 citations
TL;DR: The results suggest that major drivers of arthropod decline act at larger spatial scales, and are associated with agriculture at the landscape level, which implies that policies need to address the landscape scale to mitigate the negative effects of land-use practices.
Abstract: Recent reports of local extinctions of arthropod species1, and of massive declines in arthropod biomass2, point to land-use intensification as a major driver of decreasing biodiversity. However, to our knowledge, there are no multisite time series of arthropod occurrences across gradients of land-use intensity with which to confirm causal relationships. Moreover, it remains unclear which land-use types and arthropod groups are affected, and whether the observed declines in biomass and diversity are linked to one another. Here we analyse data from more than 1 million individual arthropods (about 2,700 species), from standardized inventories taken between 2008 and 2017 at 150 grassland and 140 forest sites in 3 regions of Germany. Overall gamma diversity in grasslands and forests decreased over time, indicating loss of species across sites and regions. In annually sampled grasslands, biomass, abundance and number of species declined by 67%, 78% and 34%, respectively. The decline was consistent across trophic levels and mainly affected rare species; its magnitude was independent of local land-use intensity. However, sites embedded in landscapes with a higher cover of agricultural land showed a stronger temporal decline. In 30 forest sites with annual inventories, biomass and species number—but not abundance—decreased by 41% and 36%, respectively. This was supported by analyses of all forest sites sampled in three-year intervals. The decline affected rare and abundant species, and trends differed across trophic levels. Our results show that there are widespread declines in arthropod biomass, abundance and the number of species across trophic levels. Arthropod declines in forests demonstrate that loss is not restricted to open habitats. Our results suggest that major drivers of arthropod decline act at larger spatial scales, and are (at least for grasslands) associated with agriculture at the landscape level. This implies that policies need to address the landscape scale to mitigate the negative effects of land-use practices. Analyses of a dataset of arthropod biomass, abundance and diversity in grassland and forest habitats in Germany for the period 2008–2017 reveal that drivers of arthropod declines act at the landscape level.
625 citations
TL;DR: This article analyzes the interaction of nanoparticle surface and ligands with different chemical groups, the types of bonding, the final dispersibility of ligand-coated nanoparticles in complex media, their reactivity, and their performance in biomedicine, photodetectors, photovoltaic devices, light-emitting devices, sensors, memory devices, thermoelectric applications, and catalysis.
Abstract: The design of nanoparticles is critical for their efficient use in many applications ranging from biomedicine to sensing and energy. While shape and size are responsible for the properties of the inorganic nanoparticle core, the choice of ligands is of utmost importance for the colloidal stability and function of the nanoparticles. Moreover, the selection of ligands employed in nanoparticle synthesis can determine their final size and shape. Ligands added after nanoparticle synthesis infer both new properties as well as provide enhanced colloidal stability. In this article, we provide a comprehensive review on the role of the ligands with respect to the nanoparticle morphology, stability, and function. We analyze the interaction of nanoparticle surface and ligands with different chemical groups, the types of bonding, the final dispersibility of ligand-coated nanoparticles in complex media, their reactivity, and their performance in biomedicine, photodetectors, photovoltaic devices, light-emitting devices, sensors, memory devices, thermoelectric applications, and catalysis.
616 citations
McGill University1, University of Oxford2, Innsbruck Medical University3, Mayo Clinic4, University of Marburg5, University of Paris6, Vita-Salute San Raffaele University7, University of Cagliari8, University of Bologna9, University of Montpellier10, University of Genoa11, University of Göttingen12, Harvard University13, First Faculty of Medicine, Charles University in Prague14, Seoul National University Hospital15, Charité16, French Institute of Health and Medical Research17, University of Sydney18, Brigham and Women's Hospital19, Université du Québec à Montréal20
TL;DR: In a prospective multicentre study involving 1280 patients with idiopathic RBD, Postuma et al. test the predictive power of 21 prodromal markers of neurodegeneration, providing a template for planning neuroprotective trials.
Abstract: Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.
544 citations
University of Sydney1, Maastricht University2, Katholieke Universiteit Leuven3, University of Marburg4, Queen Mary University of London5, Rutgers University6, University of New South Wales7, University of Münster8, University of Chieti-Pescara9, University of Paris10, Karolinska Institutet11, Aarhus University12, Heidelberg University13
TL;DR: The goal here is to create a classification that is useful in both primary care and specialized pain management settings for the development of individualized management plans, and to assist both clinicians and researchers by providing a more accurate description of each diagnostic category.
Abstract: This article describes a proposal for the new diagnosis of chronic primary pain (CPP) in ICD-11. Chronic primary pain is chosen when pain has persisted for more than 3 months and is associated with significant emotional distress and/or functional disability, and the pain is not better accounted for by another condition. As with all pain, the article assumes a biopsychosocial framework for understanding CPP, which means all subtypes of the diagnosis are considered to be multifactorial in nature, with biological, psychological, and social factors contributing to each. Unlike the perspectives found in DSM-5 and ICD-10, the diagnosis of CPP is considered to be appropriate independently of identified biological or psychological contributors, unless another diagnosis would better account for the presenting symptoms. Such other diagnoses are called "chronic secondary pain" where pain may at least initially be conceived as a symptom secondary to an underlying disease. The goal here is to create a classification that is useful in both primary care and specialized pain management settings for the development of individualized management plans, and to assist both clinicians and researchers by providing a more accurate description of each diagnostic category.
541 citations
University of Duisburg-Essen1, University of Miami2, University of California, San Francisco3, Duke University4, Northwestern University5, International University of Health and Welfare6, Boehringer Ingelheim7, University of Mannheim8, University of Melbourne9, University of Lisbon10, University of Marburg11, University of Erlangen-Nuremberg12, Hallym University13, Katholieke Universiteit Leuven14, Military Medical Academy15, University of California, Los Angeles16, Ruhr University Bochum17, Sapienza University of Rome18
TL;DR: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke, but there were more clinically relevant nonmajor bleeding events in the dabig atran group.
Abstract: BACKGROUND: Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. METHODS: We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. RESULTS: A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. CONCLUSIONS: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).
496 citations
Günter Blöschl1, Marc F. P. Bierkens2, António Chambel3, Christophe Cudennec4 +209 more•Institutions (124)
TL;DR: In this article, a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts is described. But despite the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work.
Abstract: This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through online media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focused on the process-based understanding of hydrological variability and causality at all space and time scales. Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come.
Columbia University1, Aarhus University2, CHU Ambroise Paré3, Queen Mary University of London4, University of Kiel5, University of Leeds6, Rutgers University7, University of New South Wales8, Sapienza University of Rome9, University Health Network10, University of Toronto11, University of Münster12, University of Chieti-Pescara13, University of Oslo14, Karolinska Institutet15, University of Marburg16, Université catholique de Louvain17, University of Sydney18, University of Liverpool19, University of Paris20, Johns Hopkins University21, Imperial College London22, California Pacific Medical Center23, Royal Perth Hospital24, Icahn School of Medicine at Mount Sinai25, University of Dundee26, Katholieke Universiteit Leuven27, Maastricht University28, National Yang-Ming University29, Heidelberg University30
TL;DR: The most common conditions of peripheral neuropathic pain are trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neural gia, and painful radiculopathy.
Abstract: The upcoming 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO) offers a unique opportunity to improve the representation of painful disorders. For this purpose, the International Association for the Study of Pain (IASP) has convened an interdisciplinary task force of pain specialists. Here, we present the case for a reclassification of nervous system lesions or diseases associated with persistent or recurrent pain for ≥3 months. The new classification lists the most common conditions of peripheral neuropathic pain: trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, poststroke pain, and pain associated with multiple sclerosis. Diseases not explicitly mentioned in the classification are captured in residual categories of ICD-11. Conditions of chronic neuropathic pain are either insufficiently defined or missing in the current version of the ICD, despite their prevalence and clinical importance. We provide the short definitions of diagnostic entities for which we submitted more detailed content models to the WHO. Definitions and content models were established in collaboration with the Classification Committee of the IASP's Neuropathic Pain Special Interest Group (NeuPSIG). Up to 10% of the general population experience neuropathic pain. The majority of these patients do not receive satisfactory relief with existing treatments. A precise classification of chronic neuropathic pain in ICD-11 is necessary to document this public health need and the therapeutic challenges related to chronic neuropathic pain.
University of Würzburg1, Lund University2, Swedish University of Agricultural Sciences3, Commonwealth Scientific and Industrial Research Organisation4, University of Reading5, Wageningen University and Research Centre6, University of Padua7, University of Rennes8, University of Salamanca9, Agrocampus Ouest10, Sant'Anna School of Advanced Studies11, Spanish National Research Council12, Aix-Marseille University13, University of Kiel14, University of Freiburg15, University of Jyväskylä16, University of Koblenz and Landau17, University of Marburg18, Technische Universität München19, University of Natural Resources and Life Sciences, Vienna20, National University of Río Negro21, Instituto Nacional de Biodiversidad22, University of Giessen23, University of Belgrade24, Institut national de la recherche agronomique25, University of Extremadura26, University of Bordeaux27, University of Bern28, CABI29, University of Göttingen30, Pir Mehr Ali Shah Arid Agriculture University31
TL;DR: In landscapes with high edge density, 70% of pollinator and 44% of natural enemy species reached highest abundances and pollination and pest control improved 1.7- and 1.4-fold respectively, suggesting that enhancing edge density in European agroecosystems can promote functional biodiversity and yield-enhancing ecosystem services.
Abstract: Managing agricultural landscapes to support biodiversity and ecosystem services is a key aim of a sustainable agriculture. However, how the spatial arrangement of crop fields and other habitats in landscapes impacts arthropods and their functions is poorly known. Synthesising data from 49 studies (1515 landscapes) across Europe, we examined effects of landscape composition (% habitats) and configuration (edge density) on arthropods in fields and their margins, pest control, pollination and yields. Configuration effects interacted with the proportions of crop and non-crop habitats, and species’ dietary, dispersal and overwintering traits led to contrasting responses to landscape variables. Overall, however, in landscapes with high edge density, 70% of pollinator and 44% of natural enemy species reached highest abundances and pollination and pest control improved 1.7- and 1.4-fold respectively. Arable-dominated landscapes with high edge densities achieved high yields. This suggests that enhancing edge density in European agroecosystems can promote functional biodiversity and yield-enhancing ecosystem services.
TL;DR: The representation of chronic postsurgical and posttraumatic pain in ICD-11 is expected to make the diagnosis of chronic posttraumatic or postsurgical pain statistically visible and, it is hoped, stimulate research into these pain syndromes.
Abstract: Chronic pain after tissue trauma is frequent and may have a lasting impact on the functioning and quality of life of the affected person. Despite this, chronic postsurgical and posttraumatic pain is underrecognised and, consequently, undertreated. It is not represented in the current Interna
University of Bern1, King's College London2, École Polytechnique Fédérale de Lausanne3, Francis Crick Institute4, Peking University5, Leiden University6, University of Copenhagen7, Centre national de la recherche scientifique8, Claude Bernard University Lyon 19, French Institute of Health and Medical Research10, University of Marburg11, University of Tsukuba12, ETH Zurich13, University of Lugano14, Beth Israel Deaconess Medical Center15, University of Lausanne16, University of Montpellier17
TL;DR: Current understanding of how genetic, environmental and immune-related factors contribute to a prominent orexin signalling deficiency in patients with NT1 are focused on, along with uncertainties concerning the ‘narcoleptic borderland’, including narcolepsy type 2 (NT2).
Abstract: Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep-wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02. Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep-wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the 'narcoleptic borderland', including narcolepsy type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed.
University of Würzburg1, University of Bayreuth2, University of Marburg3, University of Göttingen4, University of Ulm5, University of Bern6, University of Copenhagen7, Karlsruhe Institute of Technology8, Tanzania Commission for Science and Technology9, Technische Universität München10, College of African Wildlife Management11, University of Jena12, University of Oldenburg13, University of KwaZulu-Natal14, University of Dar es Salaam15, Tanzania Wildlife Research Institute16, Goethe University Frankfurt17, Kazan Federal University18, Smithsonian Tropical Research Institute19
TL;DR: The study reveals that climate can modulate the effects of land use on biodiversity and ecosystem functioning, and points to a lowered resistance of ecosystems in climatically challenging environments to ongoing land-use changes in tropical mountainous regions.
Abstract: Agriculture and the exploitation of natural resources have transformed tropical mountain ecosystems across the world, and the consequences of these transformations for biodiversity and ecosystem functioning are largely unknown1-3. Conclusions that are derived from studies in non-mountainous areas are not suitable for predicting the effects of land-use changes on tropical mountains because the climatic environment rapidly changes with elevation, which may mitigate or amplify the effects of land use4,5. It is of key importance to understand how the interplay of climate and land use constrains biodiversity and ecosystem functions to determine the consequences of global change for mountain ecosystems. Here we show that the interacting effects of climate and land use reshape elevational trends in biodiversity and ecosystem functions on Africa's largest mountain, Mount Kilimanjaro (Tanzania). We find that increasing land-use intensity causes larger losses of plant and animal species richness in the arid lowlands than in humid submontane and montane zones. Increases in land-use intensity are associated with significant changes in the composition of plant, animal and microorganism communities; stronger modifications of plant and animal communities occur in arid and humid ecosystems, respectively. Temperature, precipitation and land use jointly modulate soil properties, nutrient turnover, greenhouse gas emissions, plant biomass and productivity, as well as animal interactions. Our data suggest that the response of ecosystem functions to land-use intensity depends strongly on climate; more-severe changes in ecosystem functioning occur in the arid lowlands and the cold montane zone. Interactions between climate and land use explained-on average-54% of the variation in species richness, species composition and ecosystem functions, whereas only 30% of variation was related to single drivers. Our study reveals that climate can modulate the effects of land use on biodiversity and ecosystem functioning, and points to a lowered resistance of ecosystems in climatically challenging environments to ongoing land-use changes in tropical mountainous regions.
TL;DR: ZetaView provided a more accurate and repeatable depiction of EV concentration, whereas NanoSight NS300 supplied size measurements of higher resolution that failed to report a peak EV diameter below 60 nm compared to TEM and SP-IRIS.
Abstract: The expanding field of extracellular vesicle (EV) research needs reproducible and accurate methods to characterize single EVs. Nanoparticle Tracking Analysis (NTA) is commonly used to determine EV ...
Washington University in St. Louis1, Technical University of Madrid2, Beijing Institute of Genomics3, Georgia State University4, United States Army Medical Research Institute of Infectious Diseases5, Commonwealth Scientific and Industrial Research Organisation6, Columbia University7, University of Texas Medical Branch8, Friedrich Loeffler Institute9, National Institutes of Health10, Instituto Biológico11, Albert Einstein College of Medicine12, Erasmus University Rotterdam13, University of Queensland14, University of Marburg15, Humboldt University of Berlin16, Robert Koch Institute17, International Atomic Energy Agency18, University of Pittsburgh19, University of Warwick20, World Health Organization21, Empresa Brasileira de Pesquisa Agropecuária22, Boston University23, Public Health England24, Kyoto University25, Murdoch University26, Huazhong Agricultural University27, University of São Paulo28, Laval University29, Okayama University30, United States Geological Survey31, United States Department of Agriculture32, Northwestern University33, Icahn School of Medicine at Mount Sinai34, Institut de recherche pour le développement35, Ohio State University36, Katholieke Universiteit Leuven37, South Dakota State University38, Novosibirsk State University39, University of Veterinary Medicine Vienna40, University of Medicine and Health Sciences41, University of Bergen42, Texas A&M University43, Queen's University Belfast44, Centers for Disease Control and Prevention45, University of Sydney46, University of Oxford47, Defence Science and Technology Laboratory48, Queensland University of Technology49, Colorado State University50, Hokkaido University51, Pasteur Institute52, National University of Singapore53, North Carolina State University54, Universidade Federal de Viçosa55, Fudan University56, Chinese Center for Disease Control and Prevention57
TL;DR: The updated taxonomy of the order Mononegavirales is presented as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
Abstract: In February 2019, following the annual taxon ratification vote, the order Mononegavirales was amended by the addition of four new subfamilies and 12 new genera and the creation of 28 novel species. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
TL;DR: An update of the most recent findings in the tumour microenvironment in PDA is provided and their translational and clinical implications for basic scientists and clinicians alike are discussed.
Abstract: Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.
TL;DR: It is shown that a SCFA, pentanoate, suppresses autoimmune inflammation in mouse models of colitis and multiple sclerosis via epigenetic modulation of immune cell metabolic and functional pathways.
Abstract: Short-chain fatty acids (SCFAs) have immunomodulatory effects, but the underlying mechanisms are not well understood. Here we show that pentanoate, a physiologically abundant SCFA, is a potent regulator of immunometabolism. Pentanoate induces IL-10 production in lymphocytes by reprogramming their metabolic activity towards elevated glucose oxidation. Mechanistically, this reprogramming is mediated by supplying additional pentanoate-originated acetyl-CoA for histone acetyltransferases, and by pentanoate-triggered enhancement of mTOR activity. In experimental mouse models of colitis and multiple sclerosis, pentanoate-induced regulatory B cells mediate protection from autoimmune pathology. Additionally, pentanoate shows a potent histone deacetylase-inhibitory activity in CD4+ T cells, thereby reducing their IL-17A production. In germ-free mice mono-colonized with segmented filamentous bacteria (SFB), pentanoate inhibits the generation of small-intestinal Th17 cells and ameliorates SFB-promoted inflammation in the central nervous system. Taken together, by enhancing IL-10 production and suppressing Th17 cells, the SCFA pentanoate might be of therapeutic relevance for inflammatory and autoimmune diseases.
TL;DR: Single-cell tracking of up to 10,000 bacteria reveals the structure and dynamics of 3D biofilms—providing evidence to suggest that both local ordering and global biofilm architecture emerge from mechanical interactions.
Abstract: Surface-attached bacterial biofilms are self-replicating active liquid crystals and the dominant form of bacterial life on earth (1-4). In conventional liquid crystals and solid-state materials, the interaction potentials between the molecules that comprise the system determine the material properties. However, for growth-active biofilms it is unclear whether potential-based descriptions can account for the experimentally observed morphologies, and which potentials would be relevant. Here, we overcame previous limitations of single-cell imaging techniques (5,6) to reconstruct and track all individual cells inside growing three-dimensional (3D) biofilms with up to 10,000 individuals. Based on these data, we identify, constrain, and provide a microscopic basis for an effective cell-cell interaction potential, which captures and predicts the growth dynamics, emergent architecture, and local liquid crystalline order of Vibrio cholerae biofilms. Furthermore, we show how external fluid flows control the microscopic structure and 3D morphology of biofilms. Our analysis implies that local cellular order and global biofilm architecture in these active bacterial communities can arise from mechanical cell-cell interactions, which cells can modulate by regulating the production of particular matrix components. These results establish an experimentally validated foundation for improved continuum theories of active matter and thereby contribute to solving the important problem of controlling biofilm growth.
TL;DR: This review examines the basis of the commonly used quantum chemical methods for calculating molecules and for analyzing their electronic structure and the bonding situation in selected representative molecules of main-group atoms is discussed.
Abstract: The focus of this review is the presentation of the most important aspects of chemical bonding in molecules of the main group atoms according to the current state of knowledge. Special attention is...
Memorial Sloan Kettering Cancer Center1, University of Michigan2, Mayo Clinic3, Harvard University4, Northwestern University5, The Royal Marsden NHS Foundation Trust6, University of Zurich7, University of Marburg8, European Association of Nuclear Medicine9, Radboud University Nijmegen10, Georgetown University11, Odense University Hospital12
TL;DR: The 2015 American Thyroid Association (ATA) management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer was met with disagreement by t... as discussed by the authors, which was published in 2015.
Abstract: Background: Publication of the 2015 American Thyroid Association (ATA) management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer was met with disagreement by t...
TL;DR: It is shown that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases, and that children living in German non- Farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk.
Abstract: Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today1. The asthma-protective effect of farms appears to be associated with rich home dust microbiota2,3, which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts4 that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children2 and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention. Exposure to a farm-like house dust microbiome is associated with protection against asthma development in children living in urban environments.
TL;DR: It is demonstrated that all HRV-measures were lower in MD than in healthy controls and thus strengthens evidence for lower HRV as a potential cardiovascular risk factor in these patients.
Abstract: BackgroundMajor depression (MD) is a risk factor for cardiovascular disease. Reduced heart rate variability (HRV) has been observed in MD. Given the predictive value of HRV for cardiovascular health, reduced HRV might be one physiological factor that mediates this association.MethodsThe purpose of this study was to provide up-to-date random-effects meta-analyses of studies which compare resting-state measures of HRV between unmedicated adults with MD and controls. Database search considered English and German literature to July 2018.ResultsA total of 21 studies including 2250 patients and 1982 controls were extracted. Significant differences between patients and controls were found for (i) frequency domains such as HF-HRV [Hedges' g = −0.318; 95% CI (−0.388 to −0.247)], LF-HRV (Hedges' g = −0.195; 95% CI (−0.332 to −0.059)], LF/HF-HRV (Hedges' g = 0.195; 95% CI (0.086–0.303)] and VLF-HRV (Hedges' g = −0.096; 95% CI (−0.179 to −0.013)), and for (ii) time-domains such as IBI (Hedges' g = −0.163; 95% CI (−0.304 to −0.022)], RMSSD (Hedges' g = −0.462; 95% CI (−0.612 to −0.312)] and SDNN (Hedges' g = −0.266; 95% CI (−0.431 to −0.100)].ConclusionsOur findings demonstrate that all HRV-measures were lower in MD than in healthy controls and thus strengthens evidence for lower HRV as a potential cardiovascular risk factor in these patients.
TL;DR: In this paper, the secondary messenger c-diAMP has been shown to adapt to osmotic forces in the life of bacteria-assembled in biofilms, and the authors assess mechanisms that permit the perception of Osmotic stress by bacterial cells and provide an overview of the systems that allow them to genetically and physiologically cope with this ubiquitous environmental cue.
Abstract: The cytoplasm of bacterial cells is a highly crowded cellular compartment that possesses considerable osmotic potential. As a result, and owing to the semipermeable nature of the cytoplasmic membrane and the semielastic properties of the cell wall, osmotically driven water influx will generate turgor, a hydrostatic pressure considered critical for growth and viability. Both increases and decreases in the external osmolarity inevitably trigger water fluxes across the cytoplasmic membrane, thus impinging on the degree of cellular hydration, molecular crowding, magnitude of turgor, and cellular integrity. Here, we assess mechanisms that permit the perception of osmotic stress by bacterial cells and provide an overview of the systems that allow them to genetically and physiologically cope with this ubiquitous environmental cue. We highlight recent developments implicating the secondary messenger c-di-AMP in cellular adjustment to osmotic stress and the role of osmotic forces in the life of bacteria-assembled in biofilms.
01 Jan 2019
TL;DR: The main characteristics of this systematic method of qualitative data analysis are presented and a simple example of the process is given so that readers can assess whether this method might be useful for their own research.
Abstract: Thematic analysis, often called Qualitative Content Analysis (QCA) in Europe, is one of the most commonly used methods for analyzing qualitative data. This paper presents the basics of this systematic method of qualitative data analysis, highlights its key characteristics, and describes a typical workflow. The aim is to present the main characteristics and to give a simple example of the process so that readers can assess whether this method might be useful for their own research. Special attention is paid to the formation of categories, since all scholars agree that categories are at the heart of the method.
TL;DR: It is confirmed that spatial cross-validation is essential in preventing overoptimistic model performance and that in addition to spatial validation, a spatial variable selection must be considered in spatial predictions of ecological data to produce reliable predictions.
University of Marburg1, University of Bayreuth2, University of Greifswald3, Lund University4, Lanzhou University5, University of Göttingen6, Montana State University7, University of Cambridge8, Leibniz University of Hanover9, Senckenberg Museum10, University of Innsbruck11, China University of Geosciences (Wuhan)12, Chinese Academy of Sciences13, American Museum of Natural History14, Royal Botanic Garden Edinburgh15, University of Rostock16, University of Kiel17, Karlsruhe Institute of Technology18, Dresden University of Technology19
TL;DR: Traditional migratory rangeland management was sustainable over millennia, and possibly still offers the best strategy to conserve and possibly increase C stocks in the Kobresia turf.
Transylvania University1, Charité2, Swiss Institute of Allergy and Asthma Research3, Wrocław Medical University4, National Institutes of Health5, Istanbul Medeniyet University6, Saga Group7, Hacettepe University8, University of Cologne9, Complutense University of Madrid10, National and Kapodistrian University of Athens11, University of Manchester12, University of Southampton13, Hospital Clínico San Carlos14, University of Messina15, University of Marburg16, St Mary's Hospital17, University Hospital Southampton NHS Foundation Trust18, University of Edinburgh19, Medical University of Graz20, University of Amsterdam21, Erasmus University Rotterdam22, University of Los Andes23
TL;DR: The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence‐based recommendations for the use of house dust mites (HDM) AIT as add‐on treatment for HDM‐driven allergic asthma.
Abstract: Allergen immunotherapy (AIT) has been in use for the treatment of allergic disease for more than 100 years. Asthma treatment relies mainly on corticosteroids and other controllers recommended to achieve and maintain asthma control, prevent exacerbations, and improve quality of life. AIT is underused in asthma, both in children and in adults. Notably, patients with allergic asthma not adequately controlled on pharmacotherapy (including biologics) represent an unmet health need. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline providing evidence-based recommendations for the use of house dust mites (HDM) AIT as add-on treatment for HDM-driven allergic asthma. This guideline was developed by a multi-disciplinary working group using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. HDM AIT was separately evaluated by route of administration and children and adults: subcutaneous (SCIT) and sublingual AIT (SLIT), drops, and tablets. Recommendations were formulated for each. The important prerequisites for successful treatment with HDM AIT are (a) selection of patients most likely to respond to AIT and (b) use of allergen extracts and desensitization protocols of proven efficacy. To date, only AIT with HDM SLIT-tablet has demonstrated a robust effect in adults for critical end points (exacerbations, asthma control, and safety). Thus, it is recommended as an add-on to regular asthma therapy for adults with controlled or partially controlled HDM-driven allergic asthma (conditional recommendation, moderate-quality evidence). HDM SCIT is recommended for adults and children, and SLIT drops are recommended for children with controlled HDM-driven allergic asthma as the add-on to regular asthma therapy to decrease symptoms and medication needs (conditional recommendation, low-quality evidence).