Showing papers by "University of Marburg published in 2020"
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TL;DR: The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route and work that may provide a basis for development of anticoronaviral drugs.
Abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
2,342 citations
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TL;DR: A phase 1/2, single-blind, randomized controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control was conducted.
1,899 citations
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TL;DR: Survival analysis revealed that male, elder age, leukocytosis, high LDH level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19.
Abstract: Background In December 2019, the coronavirus disease 2019 (COVID-19) outbreak occurred in Wuhan. Data on the clinical characteristics and outcomes of patients with severe COVID-19 are limited. Objective We sought to evaluate the severity on admission, complications, treatment, and outcomes of patients with COVID-19. Methods Patients with COVID-19 admitted to Tongji Hospital from January 26, 2020, to February 5, 2020, were retrospectively enrolled and followed-up until March 3, 2020. Potential risk factors for severe COVID-19 were analyzed by a multivariable binary logistic model. Cox proportional hazard regression model was used for survival analysis in severe patients. Results We identified 269 (49.1%) of 548 patients as severe cases on admission. Older age, underlying hypertension, high cytokine levels (IL-2R, IL-6, IL-10, and TNF-α), and high lactate dehydrogenase level were significantly associated with severe COVID-19 on admission. The prevalence of asthma in patients with COVID-19 was 0.9%, markedly lower than that in the adult population of Wuhan. The estimated mortality was 1.1% in nonsevere patients and 32.5% in severe cases during the average 32 days of follow-up period. Survival analysis revealed that male sex, older age, leukocytosis, high lactate dehydrogenase level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19. Conclusions Patients with older age, hypertension, and high lactate dehydrogenase level need careful observation and early intervention to prevent the potential development of severe COVID-19. Severe male patients with heart injury, hyperglycemia, and high-dose corticosteroid use may have a high risk of death.
1,690 citations
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TL;DR: A group of 126 German nationals was evacuated from Wuhan to Frankfurt after screening for symptoms of Covid-19 and was to undergo a 14-day quarantine a day later.
Abstract: Coronavirus in Travelers Returning from China A group of 126 German nationals was evacuated from Wuhan to Frankfurt after screening for symptoms of Covid-19 and was to undergo a 14-day quarantine a...
541 citations
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23 Jul 2020
TL;DR: It is shown that S can be cleaved by the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at theS2′ site, and this approach has considerable therapeutic potential for treatment of COVID-19.
Abstract: The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study, we show that S can be cleaved by the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2' site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 expression. Furthermore, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851 in human airway cells. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Combining various TMPRSS2 inhibitors with furin inhibitor MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. Therefore, this approach has considerable therapeutic potential for treatment of COVID-19.
539 citations
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Swiss Federal Institute for Forest, Snow and Landscape Research1, University of Marburg2, Spanish National Research Council3, Institut national de la recherche agronomique4, Center for International Forestry Research5, Aristotle University of Thessaloniki6, National Research Council7, Vytautas Magnus University8, University of Oulu9, Uppsala University10, King Juan Carlos University11, Université Paris-Saclay12, Science for Life Laboratory13
TL;DR: This dataset of individual tree-core characteristics including ring-width series and whole-core wood density was collected for seven ecologically and economically important European tree species, covering most of the geographical and climatic range occupied by the selected species.
Abstract: The dataset presented here was collected by the GenTree project (EU-Horizon 2020), which aims to improve the use of forest genetic resources across Europe by better understanding how trees adapt to their local environment. This dataset of individual tree-core characteristics including ring-width series and whole-core wood density was collected for seven ecologically and economically important European tree species: silver birch (Betula pendula), European beech (Fagus sylvatica), Norway spruce (Picea abies), European black poplar (Populus nigra), maritime pine (Pinus pinaster), Scots pine (Pinus sylvestris), and sessile oak (Quercus petraea). Tree-ring width measurements were obtained from 3600 trees in 142 populations and whole-core wood density was measured for 3098 trees in 125 populations. This dataset covers most of the geographical and climatic range occupied by the selected species. The potential use of it will be highly valuable for assessing ecological and evolutionary responses to environmental conditions as well as for model development and parameterization, to predict adaptability under climate change scenarios.
467 citations
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Katrina L. Grasby1, Neda Jahanshad2, Jodie N. Painter1, Lucía Colodro-Conde3 +356 more•Institutions (115)
TL;DR: Results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness and find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function.
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
436 citations
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TL;DR: It was found that higher restrictions due to lockdown measures, a greater reduction of social contacts and greater perceived changes in life were associated with higher mental health impairments, and a subjectively assumed but not an officially announced stay-at-home order was associated with poorer mental health.
Abstract: The COVID-19 pandemic is suggested to have a negative impact on mental health. To prevent the spread of Sars-CoV-2, governments worldwide have implemented different forms of public health measures ranging from physical distancing recommendations to stay-at-home orders, which have disrupted individuals' everyday life tremendously. However, evidence on the associations of the COVID-19 pandemic and public health measures with mental health are limited so far. In this study, we investigated the role of sociodemographic and COVID-19 related factors for immediate mental health consequences in a nationwide community sample of adults from Germany (N = 4335). Specifically, we examined the effects of different forms and levels of restriction resulting from public health measures (e.g. quarantine, stay-at-home order) on anxiety and depression symptomatology, health anxiety, loneliness, the occurrence of fearful spells, psychosocial distress and life-satisfaction. We found that higher restrictions due to lockdown measures, a greater reduction of social contacts and greater perceived changes in life were associated with higher mental health impairments. Importantly, a subjectively assumed but not an officially announced stay-at-home order was associated with poorer mental health. Our findings underscore the importance of adequate risk communication and targeted mental health recommendations especially for vulnerable groups during these challenging times.
349 citations
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TL;DR: It is demonstrated that SARS-CoV-2-neutralizing antibodies are readily generated from a diverse pool of precursors, fostering hope for rapid induction of a protective immune response upon vaccination.
329 citations
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Johns Hopkins University1, Erasmus University Medical Center2, University of Pittsburgh3, Harvard University4, University of Marburg5, University of Verona6, Yale University7, University of Amsterdam8, Columbia University9, Columbia University Medical Center10, Icahn School of Medicine at Mount Sinai11, New York University12, University of Michigan13, Leiden University14
TL;DR: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise.
Abstract: Background and aim: The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals). Methods: A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed. Results: Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions. Conclusions: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.
311 citations
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University of Marburg1, Goethe University Frankfurt2, University Medical Center Freiburg3, University of Münster4, Dresden University of Technology5, University of Hamburg6, Technische Universität München7, Augsburg College8, RWTH Aachen University9, Innsbruck Medical University10, University of Tübingen11, Ludwig Maximilian University of Munich12, University of Mainz13
TL;DR: Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib, and maintenance therapy reduces the risk of relapse and death after H CT for FLT3-ITD-positive AML.
Abstract: PURPOSEDespite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kin...
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Humboldt University of Berlin1, McMaster University2, National Institutes of Health3, Ghent University Hospital4, University of Amsterdam5, University of Marburg6, Nova Southeastern University7, Transylvania University8, Charité9, Woolcock Institute of Medical Research10, Laval University11, Humanitas University12, University of Cartagena13, University of South Florida14, University of Porto15, Federal University of Bahia16, University of Naples Federico II17, Université Paris-Saclay18, Saint Louis University19, Istanbul University20, Erasmus University Rotterdam21, University of Helsinki22, Odense University Hospital23, University of Crete24, Chiba University25, Wrocław Medical University26, Ukrainian Medical Stomatological Academy27, Hacettepe University28, Medical University of Łódź29, Vilnius University30, National Research Council31, University of Tennessee32, Oslo University Hospital33, University of Beira Interior34, Karolinska Institutet35, University of Cologne36, University of Barcelona37, Russian National Research Medical University38, Monash University39, Ajou University40, Charles University in Prague41, University of Genoa42, Pasteur Institute43, University of Southampton44, University of Edinburgh45, Medical University of Warsaw46, University College London47, Imperial College London48, University of Coimbra49, University of Turku50, University of Bari51, Celal Bayar University52
TL;DR: Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines forThe disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.
Abstract: The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.
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TL;DR: It is shown that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile and suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid liganded, which should be taken into account for future descriptions of ligand action at this important therapeutic target.
Abstract: Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein–biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin–mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target.
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Humanitas University1, University of Cartagena2, University of Genoa3, Hebron University4, University of Veterinary Medicine Vienna5, University of Helsinki6, Autonomous University of Barcelona7, University of Paris8, University of Montpellier9, Erasmus University Rotterdam10, Universidad Autónoma de Nuevo León11, Mayo Clinic12, Kırıkkale University13, University of São Paulo14, University of South Florida15, San Juan de Dios Educational Foundation16, University of Marburg17, Nippon Medical School18, Federal University of Paraná19, University of Missouri–Kansas City20, Royal Children's Hospital21, Tan Tock Seng Hospital22, I.M. Sechenov First Moscow State Medical University23, Medical University of Vienna24, Johns Hopkins University School of Medicine25, Charité26
TL;DR: A thorough and updated critical appraisal of the most frequently used diagnostic tests, both in vivo and in vitro, and discusses skin tests, challenges, and serological and cellular in vitro tests, and provides an overview of indications, advantages and disadvantages of each in conditions such as respiratory, food, venom, drug, and occupational allergy.
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Lithuanian University of Health Sciences1, University of Bern2, University of Sassari3, Catholic University of Leuven4, Aarhus University5, University of Copenhagen6, University of Marburg7, Universidade Federal do Rio Grande do Sul8, University of Melbourne9, King's College London10, El Bosque University11, Indiana University – Purdue University Indianapolis12, Witten/Herdecke University13, University of Greifswald14, University of Michigan15, Tufts University16
TL;DR: A 2-day workshop of ORCA and the IADR Cariology Research Group was organized to discuss and reach consensus on definitions of the most commonly used terms in cariology, selecting terms related to definition, diagnosis, risk assessment, and monitoring of dental caries.
Abstract: A 2-day workshop of ORCA and the IADR Cariology Research Group was organized to discuss and reach consensus on definitions of the most commonly used terms in cariology. The aims were to identify and to select the most commonly used terms of dental caries and dental caries management and to define them based on current concepts. Terms related to definition, diagnosis, risk assessment, and monitoring of dental caries were included. The Delphi process was used to establish terms to be considered using the nominal group method favored by consensus. Of 222 terms originally suggested by six cariologists from different countries, a total of 59 terms were reviewed after removing duplicates and unnecessary words. Sixteen experts in cariology took part in the process of reaching consensus about the definitions of the selected caries terms. Decisions were made following thorough "round table" discussions of each term and confirmed by secret electronic voting. Full agreement (100%) was reached on 17 terms, while the definitions of 6 terms were below the agreed 80% threshold of consensus. The suggested terminology is recommended for use in research, in public health, as well as in clinical practice.
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University of Melbourne1, Brigham and Women's Hospital2, Beth Israel Deaconess Medical Center3, University of Southern California4, University Medical Center Groningen5, Novosibirsk State University6, University of Münster7, Trinity College, Dublin8, Mental Health Services9, Florida State University10, University of California, San Francisco11, University of Queensland12, University of Minnesota13, Otto-von-Guericke University Magdeburg14, Stanford University15, University of Cape Town16, University of Edinburgh17, University of Sydney18, University of Marburg19, University of Maryland, Baltimore20, Humboldt University of Berlin21, University of Calgary22, QIMR Berghofer Medical Research Institute23, Alberta Children's Hospital24, Autonomous University of Barcelona25, Harvard University26, Max Planck Society27, Heidelberg University28, National University of Singapore29, Nanyang Technological University30, Leiden University Medical Center31, Leiden University32, Polytechnic University of Valencia33, University of Tübingen34
TL;DR: In this paper, the authors examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium.
Abstract: Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.
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Wellcome Trust Sanger Institute1, European Bioinformatics Institute2, University of Queensland3, University of Edinburgh4, Technische Universität München5, Max Planck Society6, King's College London7, University of Basel8, University of Marburg9, University Hospital Bonn10, Greifswald University Hospital11, Kaiser Permanente12, Stanford University13, University College London14, QIMR Berghofer Medical Research Institute15, VU University Amsterdam16, Lundbeck17, Aarhus University Hospital18, University of Liverpool19, Harvard University20, University of Lausanne21, Johns Hopkins University School of Medicine22, Broad Institute23, Heidelberg University24, Erasmus University Medical Center25, Dalhousie University26, Karolinska Institutet27, Columbia University28, Virginia Commonwealth University29, Semel Institute for Neuroscience and Human Behavior30
TL;DR: In this paper, the authors report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD.
Abstract: Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.
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TL;DR: In two mouse models of intestinal cancer, mutant p53 has an oncogenic effect in the distal gut but a tumour-suppressive effect inThe proximal gut, and these opposing properties are determined by the gut microbiome.
Abstract: Somatic mutations in p53, which inactivate the tumour-suppressor function of p53 and often confer oncogenic gain-of-function properties, are very common in cancer1,2. Here we studied the effects of hotspot gain-of-function mutations in Trp53 (the gene that encodes p53 in mice) in mouse models of WNT-driven intestinal cancer caused by Csnk1a1 deletion3,4 or ApcMin mutation5. Cancer in these models is known to be facilitated by loss of p533,6. We found that mutant versions of p53 had contrasting effects in different segments of the gut: in the distal gut, mutant p53 had the expected oncogenic effect; however, in the proximal gut and in tumour organoids it had a pronounced tumour-suppressive effect. In the tumour-suppressive mode, mutant p53 eliminated dysplasia and tumorigenesis in Csnk1a1-deficient and ApcMin/+ mice, and promoted normal growth and differentiation of tumour organoids derived from these mice. In these settings, mutant p53 was more effective than wild-type p53 at inhibiting tumour formation. Mechanistically, the tumour-suppressive effects of mutant p53 were driven by disruption of the WNT pathway, through preventing the binding of TCF4 to chromatin. Notably, this tumour-suppressive effect was completely abolished by the gut microbiome. Moreover, a single metabolite derived from the gut microbiota—gallic acid—could reproduce the entire effect of the microbiome. Supplementing gut-sterilized p53-mutant mice and p53-mutant organoids with gallic acid reinstated the TCF4–chromatin interaction and the hyperactivation of WNT, thus conferring a malignant phenotype to the organoids and throughout the gut. Our study demonstrates the substantial plasticity of a cancer mutation and highlights the role of the microenvironment in determining its functional outcome. In two mouse models of intestinal cancer, mutant p53 has an oncogenic effect in the distal gut but a tumour-suppressive effect in the proximal gut, and these opposing properties are determined by the gut microbiome.
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Cornell University1, Kanazawa University2, University of Zurich3, University of Cambridge4, University of Toulouse5, University of Arizona6, University of Marburg7, University of Leeds8, Polytechnic University of Valencia9, University of Göttingen10, University of Düsseldorf11, University of Bristol12, Boyce Thompson Institute for Plant Research13, University of California, Davis14, Wageningen University and Research Centre15, University of Bonn16, Hiroshima University17, University of Freiburg18, Smithsonian Institution19, Laval University20, University of Münster21, University of Alberta22, Rikkyo University23
TL;DR: High-quality genomes of Anthoceros hornworts are provided and candidate genes involved in cyanobacterial symbiosis are identified and found that LCIB, a Chlamydomonas CCM gene, is present in hornwort but absent in other plant lineages, implying a possible conserved role in CCM function.
Abstract: Hornworts comprise a bryophyte lineage that diverged from other extant land plants >400 million years ago and bears unique biological features, including a distinct sporophyte architecture, cyanobacterial symbiosis and a pyrenoid-based carbon-concentrating mechanism (CCM). Here, we provide three high-quality genomes of Anthoceros hornworts. Phylogenomic analyses place hornworts as a sister clade to liverworts plus mosses with high support. The Anthoceros genomes lack repeat-dense centromeres as well as whole-genome duplication, and contain a limited transcription factor repertoire. Several genes involved in angiosperm meristem and stomatal function are conserved in Anthoceros and upregulated during sporophyte development, suggesting possible homologies at the genetic level. We identified candidate genes involved in cyanobacterial symbiosis and found that LCIB, a Chlamydomonas CCM gene, is present in hornworts but absent in other plant lineages, implying a possible conserved role in CCM function. We anticipate that these hornwort genomes will serve as essential references for future hornwort research and comparative studies across land plants.
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TL;DR: This review summarizes the molecular mechanisms underlying the ISC protein-mediated maturation of mitochondrial Fe/S proteins and the importance for human disease.
Abstract: Mitochondria are essential in most eukaryotes and are involved in numerous biological functions including ATP production, cofactor biosyntheses, apoptosis, lipid synthesis, and steroid metabolism. Work over the past two decades has uncovered the biogenesis of cellular iron-sulfur (Fe/S) proteins as the essential and minimal function of mitochondria. This process is catalyzed by the bacteria-derived iron-sulfur cluster assembly (ISC) machinery and has been dissected into three major steps: de novo synthesis of a [2Fe-2S] cluster on a scaffold protein; Hsp70 chaperone-mediated trafficking of the cluster and insertion into [2Fe-2S] target apoproteins; and catalytic conversion of the [2Fe-2S] into a [4Fe-4S] cluster and subsequent insertion into recipient apoproteins. ISC components of the first two steps are also required for biogenesis of numerous essential cytosolic and nuclear Fe/S proteins, explaining the essentiality of mitochondria. This review summarizes the molecular mechanisms underlying the ISC protein-mediated maturation of mitochondrial Fe/S proteins and the importance for human disease.
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TL;DR: A single dose of ChAdOx1 MERS was safe at doses up to 5 × 1010 viral particles with no vaccine-related serious adverse events reported by 12 months, and one serious adverse event reported was deemed to be not related to Ch adenovirus-vectored vaccine.
Abstract: Summary Background Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans. Methods This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18–50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 × 109 viral particles, the intermediate-dose group received 2·5 × 1010 viral particles, and the high-dose group received 5 × 1010 viral particles. The primary objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by interferon-γ-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov , NCT03399578 . Findings Between March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were available for follow-up at 6 months, but five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 × 1010 viral particles with no vaccine-related serious adverse events reported by 12 months. One serious adverse event reported was deemed to be not related to ChAdOx1 MERS. 92 (74% [95% CI 66–81]) of 124 solicited adverse events were mild, 31 (25% [18–33]) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5·83 [95% CI 2·11–17·42], p Interpretation ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials. Funding UK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research.
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University of California, Davis1, University of Eastern Finland2, National Institute for Health and Welfare3, Boston Children's Hospital4, University of Zurich5, Swiss Institute of Allergy and Asthma Research6, University of Lorraine7, Centre national de la recherche scientifique8, University Hospital Regensburg9, University of Marburg10, University of Helsinki11, University of Aberdeen12, Ludwig Maximilian University of Munich13
TL;DR: The gut microbiome may contribute to asthma protection through metabolites, supporting the concept of a gut-lung axis in humans.
Abstract: Growing up on a farm is associated with an asthma-protective effect, but the mechanisms underlying this effect are largely unknown. In the Protection against Allergy: Study in Rural Environments (PASTURE) birth cohort, we modeled maturation using 16S rRNA sequence data of the human gut microbiome in infants from 2 to 12 months of age. The estimated microbiome age (EMA) in 12-month-old infants was associated with previous farm exposure (β = 0.27 (0.12–0.43), P = 0.001, n = 618) and reduced risk of asthma at school age (odds ratio (OR) = 0.72 (0.56–0.93), P = 0.011). EMA mediated the protective farm effect by 19%. In a nested case–control sample (n = 138), we found inverse associations of asthma with the measured level of fecal butyrate (OR = 0.28 (0.09–0.91), P = 0.034), bacterial taxa that predict butyrate production (OR = 0.38 (0.17–0.84), P = 0.017) and the relative abundance of the gene encoding butyryl–coenzyme A (CoA):acetate–CoA-transferase, a major enzyme in butyrate metabolism (OR = 0.43 (0.19–0.97), P = 0.042). The gut microbiome may contribute to asthma protection through metabolites, supporting the concept of a gut–lung axis in humans. Growing up in the rich microbial environment of a farm strongly influences the maturation of the gut microbiome in the first year of life, which helps protect against the development of asthma in children.
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Hospital Sant Joan de Déu Barcelona1, Swiss Institute of Allergy and Asthma Research2, University of Southampton3, St Mary's Hospital4, University Hospital Southampton NHS Foundation Trust5, Medical University of Graz6, Carlos III Health Institute7, CEU San Pablo University8, Istanbul Medeniyet University9, University of Pisa10, I.M. Sechenov First Moscow State Medical University11, Charité12, National Institutes of Health13, Odense University Hospital14, Istanbul University15, University of Padua16, University of Messina17, University of Marburg18, Imperial College London19
TL;DR: This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy to improve the patient's adherence to the treatment.
Abstract: Allergen immunotherapy is a cornerstone in the treatment of allergic children. The clinical efficiency relies on a well-defined immunologic mechanism promoting regulatory T cells and downplaying the immune response induced by allergens. Clinical indications have been well documented for respiratory allergy in the presence of rhinitis and/or allergic asthma, to pollens and dust mites. Patients who have had an anaphylactic reaction to hymenoptera venom are also good candidates for allergen immunotherapy. Administration of allergen is currently mostly either by subcutaneous injections or by sublingual administration. Both methods have been extensively studied and have pros and cons. Specifically in children, the choice of the method of administration according to the patient's profile is important. Although allergen immunotherapy is widely used, there is a need for improvement. More particularly, biomarkers for prediction of the success of the treatments are needed. The strength and efficiency of the immune response may also be boosted by the use of better adjuvants. Finally, novel formulations might be more efficient and might improve the patient's adherence to the treatment. This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy.
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TL;DR: A number of technological advances have recently opened the door to forward genetics as well as extremely efficient and precise genome editing in P. patens, and areas where this moss has had the most impact on plant biology are described.
Abstract: Since the discovery two decades ago that transgenes are efficiently integrated into the genome by homologous recombination in the moss Physcomitrella patens, it has been a premier model system to study evolutionary development (evo-devo) questions, stem cell reprogramming, as well as explore the biology of non-vascular plants. P. patens was the first non-seed plant to have its genome sequenced and with this level of genomic information together with increasing molecular genetic tools, a large number of reverse genetic studies have propelled the use of this model system. However, a number of technological advances have recently opened the doors to forward genetics as well as extremely efficient and precise genome editing. Additionally, careful phylogenetic studies with increased resolution suggest that P. patens emerged from within Physcomitrium. Thus, rather than Physcomitrella patens the species should be named Physcomitrium patens. Here we review these advances and describe the areas where P. patens has had the most impact on plant biology.
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Otto-von-Guericke University Magdeburg1, Paracelsus Private Medical University of Salzburg2, University of Duisburg-Essen3, University of Mainz4, University of Hamburg5, University of Freiburg6, University Hospital Heidelberg7, Gifu Keizai University8, University of Liverpool9, University of Marburg10
TL;DR: The GALAD score can detect patients with early-stage HCC, and might facilitate surveillance of patients with NASH, who are often obese, which limits the sensitivity of detection of liver cancer by ultrasound.
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TL;DR: In this paper, the authors place a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provide a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro inflammatory cytokines and chemokines.
Abstract: Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.
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TL;DR: The current knowledge on the infection strategies and regulatory networks controlling virulence and adaptation mechanisms from Xanthomonas species are summarized and the novel opportunities that this body of work has provided for disease control and plant health are discussed.
Abstract: Xanthomonas is a well-studied genus of bacterial plant pathogens whose members cause a variety of diseases in economically important crops worldwide. Genomic and functional studies of these phytopathogens have provided significant understanding of microbial-host interactions, bacterial virulence and host adaptation mechanisms including microbial ecology and epidemiology. In addition, several strains of Xanthomonas are important as producers of the extracellular polysaccharide, xanthan, used in the food and pharmaceutical industries. This polymer has also been implicated in several phases of the bacterial disease cycle. In this review, we summarise the current knowledge on the infection strategies and regulatory networks controlling virulence and adaptation mechanisms from Xanthomonas species and discuss the novel opportunities that this body of work has provided for disease control and plant health.
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University of Rouen1, University Medical Center Groningen2, Akdeniz University3, Aarhus University Hospital4, Dresden University of Technology5, Rappaport Faculty of Medicine6, University of Reims Champagne-Ardenne7, University Hospital of Bern8, University of Florence9, Tehran University of Medical Sciences10, Post Graduate Institute of Medical Education and Research11, Poznan University of Medical Sciences12, Sofia Medical University13, University of Münster14, University of Parma15, University of Würzburg16, St. John's University17, Medical University of Warsaw18, National Skin Centre19, University of Zagreb20, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico21, University of Milan22, University of Barcelona23, Rabin Medical Center24, St George's Hospital25, University of Modena and Reggio Emilia26, Semmelweis University27, Guy's and St Thomas' NHS Foundation Trust28, Tel Aviv University29, Tel Aviv Sourasky Medical Center30, Karadeniz Technical University31, Boston Children's Hospital32, University of Lübeck33, University of Marburg34
TL;DR: Pemphigus encompasses a group of life‐threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin that was almost always fatal before the era of immunosuppressive treatment.
Abstract: BACKGROUND
Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, pemphigus was almost always fatal. Due to its rarity, only few randomized controlled therapeutic trials are available. Recently, rituximab has been approved as first-line treatment for moderate and severe pemphigus vulgaris in Europe and the United States.
OBJECTIVES
The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated a throughout update of the guideline for the management of patients with pemphigus.
RESULTS
The guidelines for the management of pemphigus were updated, and the degree of consent among all task force members was included. The final version of the guideline was consented by the European Dermatology Forum (EDF) and several patient organizations.