Showing papers by "Medical Research Council published in 2019"
TL;DR: Approaches used for drug repurposing (also known as drug repositioning) are presented, the challenges faced by the repurpose community are discussed, and innovative ways by which these challenges could be addressed are recommended to help realize the full potential of drugRepurposing.
Abstract: Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.
2,365 citations
Royal Edinburgh Hospital1, Centre for Mental Health2, King's College London3, University of Glasgow4, University of Edinburgh5, Medical Research Council6, University of Münster7, University of Melbourne8, University of Freiburg9, University of Queensland10, Charité11, Broad Institute12, Harvard University13, Karolinska Institutet14, University of North Carolina at Chapel Hill15
TL;DR: A genetic meta-analysis of depression found 269 associated genes that highlight several potential drug repositioning opportunities, and relationships with depression were found for neuroticism and smoking.
Abstract: Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.
1,312 citations
TL;DR: Profiling of single epithelial cells in healthy and inflamed colons identifies specialized cellular subpopulations, including a type of goblet cell that secretes the antibacterial protein WFDC2, which preserves the integrity of the epithelial barrier layer.
Abstract: The colonic epithelium facilitates host–microorganism interactions to control mucosal immunity, coordinate nutrient recycling and form a mucus barrier. Breakdown of the epithelial barrier underpins inflammatory bowel disease (IBD). However, the specific contributions of each epithelial-cell subtype to this process are unknown. Here we profile single colonic epithelial cells from patients with IBD and unaffected controls. We identify previously unknown cellular subtypes, including gradients of progenitor cells, colonocytes and goblet cells within intestinal crypts. At the top of the crypts, we find a previously unknown absorptive cell, expressing the proton channel OTOP2 and the satiety peptide uroguanylin, that senses pH and is dysregulated in inflammation and cancer. In IBD, we observe a positional remodelling of goblet cells that coincides with downregulation of WFDC2—an antiprotease molecule that we find to be expressed by goblet cells and that inhibits bacterial growth. In vivo, WFDC2 preserves the integrity of tight junctions between epithelial cells and prevents invasion by commensal bacteria and mucosal inflammation. We delineate markers and transcriptional states, identify a colonic epithelial cell and uncover fundamental determinants of barrier breakdown in IBD. Profiling of single epithelial cells in healthy and inflamed colons identifies specialized cellular subpopulations, including a type of goblet cell that secretes the antibacterial protein WFDC2, which preserves the integrity of the epithelial barrier layer.
415 citations
University of Oslo1, University College Hospital2, Dalhousie University3, Leiden University4, Children's Oncology Group5, University of Texas MD Anderson Cancer Center6, Harvard University7, Semmelweis University8, Mayo Clinic9, University of British Columbia10, University Hospital Bonn11, Boston Children's Hospital12, Ghent University13, Lund University14, Royal National Orthopaedic Hospital15, Leiden University Medical Center16, University of California, San Francisco17, University of Washington18, Oslo University Hospital19, University Hospital of Basel20, Community College of Rhode Island21, University of Vienna22, Baylor College of Medicine23, Children's Medical Center of Dallas24, Nationwide Children's Hospital25, University of Southern California26, Memorial Sloan Kettering Cancer Center27, Cincinnati Children's Hospital Medical Center28, University of Utah29, Katholieke Universiteit Leuven30, University of Copenhagen31, Medical Research Council32
TL;DR: Survival rates from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials, and known prognostic factors were reaffirmed.
308 citations
TL;DR: In persons with rifampin‐resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety.
Abstract: Background Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommend...
244 citations
University of Amsterdam1, VU University Amsterdam2, Harvard University3, Broad Institute4, Medical Research Council5, University of Copenhagen6, University of Miami7, Karolinska Institutet8, University of Gothenburg9, University of North Carolina at Chapel Hill10, NorthShore University HealthSystem11, University of Chicago12, University of Queensland13
TL;DR: This genome-wide association study of same-sex sexual behavior identifies loci associated with human sexual orientation that suggest links to biological pathways that involve sex hormone regulation and olfaction and investigates the biology and complexity of the trait.
Abstract: Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.
233 citations
College of William & Mary1, Macquarie University2, University of Kansas3, University of Amsterdam4, Pennsylvania State University5, University at Albany, SUNY6, Oklahoma State University–Stillwater7, University of Maryland, College Park8, University of Arizona9, Purdue University10, University of New South Wales11, Vanderbilt University12, Université de Montréal13, University of South Florida14, University of Utah15, University of Minnesota16, University of Liverpool17, Northwestern University18, Maastricht University19, King's College London20, Emory University21, University of Pittsburgh22, University of Kassel23, University of Toronto24, Southern Methodist University25, University of Hawaii at Manoa26, University of Notre Dame27, Medical Research Council28, University of California, Davis29, University of Vermont30, Georgia State University31, Florida State University32, University of North Texas33, Stony Brook University34
TL;DR: The Hierarchical Taxonomy of Psychopathology (HiTOP) as discussed by the authors is based on empirical patterns of co-occurrence among psychological symptoms, and it has the potential to accelerate and improve research on mental health problems as well as efforts to more effectively assess, prevent, and treat mental illness.
Abstract: For more than a century, research on psychopathology has focused on categorical diagnoses. Although this work has produced major discoveries, growing evidence points to the superiority of a dimensional approach to the science of mental illness. Here we outline one such dimensional system-the Hierarchical Taxonomy of Psychopathology (HiTOP)-that is based on empirical patterns of co-occurrence among psychological symptoms. We highlight key ways in which this framework can advance mental-health research, and we provide some heuristics for using HiTOP to test theories of psychopathology. We then review emerging evidence that supports the value of a hierarchical, dimensional model of mental illness across diverse research areas in psychological science. These new data suggest that the HiTOP system has the potential to accelerate and improve research on mental-health problems as well as efforts to more effectively assess, prevent, and treat mental illness.
225 citations
TL;DR: Advice is presented for optimized nutrition before and during pregnancy, during lactation, infancy and toddlerhood, with special reference to later health outcomes that should contribute to the primary prevention of obesity and associated non-communicable diseases.
Abstract: Background: A considerable body of evidence accumulated especially during the last decade, demonstrating that early nutrition and lifestyle have long-term effects on later health and disease ("developmental or metabolic programming"). Methods: Researchers involved in the European Union funded international EarlyNutrition research project consolidated the scientific evidence base and existing recommendations to formulate consensus recommendations on nutrition and lifestyle before and during pregnancy, during infancy and early childhood that take long-term health impact into account. Systematic reviews were performed on published dietary guidelines, standards and recommendations, with special attention to long-term health consequences. In addition, systematic reviews of published systematic reviews on nutritional interventions or exposures in pregnancy and in infants and young children aged up to 3 years that describe effects on subsequent overweight, obesity and body composition were performed. Experts developed consensus recommendations incorporating the wide-ranging expertise from additional 33 stakeholders. Findings: Most current recommendations for pregnant women, particularly obese women, and for young children do not take long-term health consequences of early nutrition into account, although the available evidence for relevant consequences of lifestyle, diet and growth patterns in early life on later health and disease risk is strong. Interpretation: We present updated recommendations for optimized nutrition before and during pregnancy, during lactation, infancy and toddlerhood, with special reference to later health outcomes. These recommendations are developed for affluent populations, such as women and children in Europe, and should contribute to the primary prevention of obesity and associated non-communicable diseases. (c) 2019 S. Karger AG, Basel
178 citations
Institute of Cancer Research1, Western General Hospital2, University of Birmingham3, University of Edinburgh4, Trinity College, Dublin5, John Radcliffe Hospital6, University of Oxford7, Medical Research Council8, University of Helsinki9, National Institutes of Health10, University of Tampere11, Broad Institute12, Harvard University13, University of Melbourne14, Mayo Clinic15, Fred Hutchinson Cancer Research Center16, Lunenfeld-Tanenbaum Research Institute17, Translational Genomics Research Institute18, University of Virginia19, University of Basel20, University of Bonn21, University of Duisburg-Essen22, University of Cambridge23, University of London24, German Cancer Research Center25, University of Manchester26, University College London27, University of Glasgow28, University Hospital Southampton NHS Foundation Trust29, University Hospital Centre Zagreb30, Medical University of Vienna31, Cardiff University32
TL;DR: In this article, the authors reported a genome-wide association analysis of 34,627 colorectal cancer cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci.
Abstract: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
151 citations
University of Southern Denmark1, University of Sydney2, Minia University3, Odense University Hospital4, Nottingham University Hospitals NHS Trust5, University of Nottingham6, Medical Research Council7, Kurume University8, Westmead Hospital9, Fiona Stanley Hospital10, University of Western Australia11
TL;DR: A PRO‐C3‐based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB‐4, and NFS in most comparisons.
150 citations
University of Cambridge1, University of Milan2, Medical Research Council3, NHS Blood and Transplant4, University of Pisa5, University of Barcelona6, National Institute for Health Research7, Wellcome Trust Sanger Institute8, University of Florence9, Ruhr University Bochum10, Karolinska University Hospital11, University of Lübeck12, University of Melbourne13, Tallaght Hospital14, University of St. Gallen15, Lund University16, University of Jena17, Vita-Salute San Raffaele University18, Jagiellonian University Medical College19, University of Erlangen-Nuremberg20, Charles University in Prague21, University of East Anglia22, Suffolk University23
TL;DR: A genome-wide association study of EGPA is described that reveals clinical and genetic differences between subgroups stratified by autoantibody status (ANCA), and four candidate genes are targets of therapies in development, supporting their exploration in EGPA.
Abstract: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.
TL;DR: There is evidence of differential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age, and it is shown that an inflammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function.
Abstract: The link between mutations in collagen genes and the development of Alport Syndrome has been clearly established and a number of animal models, including knock-out mouse lines, have been developed that mirror disease observed in patients. However, it is clear from both patients and animal models that the progression of disease can vary greatly and can be modified genetically. We have identified a point mutation in Col4a4 in mice where disease is modified by strain background, providing further evidence of the genetic modification of disease symptoms. Our results indicate that C57BL/6J is a protective background and postpones end stage renal failure from 7 weeks, as seen on a C3H background, to several months. We have identified early differences in disease progression, including expression of podocyte-specific genes and podocyte morphology. In C57BL/6J mice podocyte effacement is delayed, prolonging normal renal function. The slower disease progression has allowed us to begin dissecting the pathogenesis of murine Alport Syndrome in detail. We find that there is evidence of differential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an inflammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function.
University of British Columbia1, Telethon Institute for Child Health Research2, Boston Children's Hospital3, Harvard University4, Medical Research Council5, Ludwig Maximilian University of Munich6, Papua New Guinea Institute of Medical Research7, University of Melbourne8, University of London9, University of Western Australia10, BC Cancer Agency11, Broad Institute12
TL;DR: Extracting multi-omic data from small volumes of blood is extracted to study the dynamic molecular changes during the first week of life, revealing a robust developmental trajectory common to different populations.
Abstract: Systems biology can unravel complex biology but has not been extensively applied to human newborns, a group highly vulnerable to a wide range of diseases. We optimized methods to extract transcriptomic, proteomic, metabolomic, cytokine/chemokine, and single cell immune phenotyping data from <1 ml of blood, a volume readily obtained from newborns. Indexing to baseline and applying innovative integrative computational methods reveals dramatic changes along a remarkably stable developmental trajectory over the first week of life. This is most evident in changes of interferon and complement pathways, as well as neutrophil-associated signaling. Validated across two independent cohorts of newborns from West Africa and Australasia, a robust and common trajectory emerges, suggesting a purposeful rather than random developmental path. Systems biology and innovative data integration can provide fresh insights into the molecular ontogeny of the first week of life, a dynamic developmental phase that is key for health and disease.
Queen Mary University of London1, University of Bristol2, Imperial College London3, Liverpool School of Tropical Medicine4, University of Southampton5, University of Tasmania6, University of Edinburgh7, Cardiff University8, Medical Research Council9, University of Florida10, University of Sydney11, Janssen Pharmaceutica12, University of Bern13
TL;DR: The guidelines have been updated and information reorganised to facilitate their use in practice and are introduced to help ensure that researchers, reviewers and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
Abstract: Reproducible science requires transparent reporting. The ARRIVE guidelines were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here we introduce ARRIVE 2019. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise the items and split the guidelines into two sets, the ARRIVE Essential 10, which constitute the minimum requirement, and the Recommended Set, which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers to verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document that serves 1) to explain the rationale behind each item in the guidelines, 2) to clarify key concepts and 3) to provide illustrative examples. We aim through these changes to help ensure that researchers, reviewers and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
TL;DR: A nationally representative reflection of the state of mental health spending is offered and inefficiencies and constraints emanating from existing mental health investments in South Africa are elucidated.
Abstract: The inclusion of mental health in the Sustainable Development Goals represents a global commitment to include mental health among the highest health and development priorities for investment. Low- and middle-income countries (LMICs), such as South Africa, contemplating mental health system scale-up embedded into wider universal health coverage-related health system transformations, require detailed and locally derived estimates on existing mental health system resources and constraints. The absence of these data has limited scale-up efforts to address the burden of mental disorders in most LMICs. We conducted a national survey to quantify public expenditure on mental health and evaluate the constraints of the South African mental health system. The study found that South Africa's public mental health expenditure in the 2016/17 financial year was USD615.3 million, representing 5.0% of the total public health budget (provincial range: 2.1-7.7% of provincial health budgets) and USD13.3 per capita uninsured. Inpatient care represented 86% of mental healthcare expenditure, with nearly half of total mental health spending occurring at the psychiatric hospital-level. Almost one-quarter of mental health inpatients are readmitted to hospital within 3 months of a previous discharge, costing the public health system an estimated USD112 million. Crude estimates indicate that only 0.89% and 7.35% of the uninsured population requiring care received some form of public inpatient and outpatient mental healthcare, during the study period. Further, mental health human resource availability, infrastructure and medication supply are significant constraints to the realization of the country's progressive mental health legislation. For the first time, this study offers a nationally representative reflection of the state of mental health spending and elucidates inefficiencies and constraints emanating from existing mental health investments in South Africa. With this information at hand, the government now has a baseline for which a rational process to planning for system reforms can be initiated.
TL;DR: Comparing time series single-cell RNA sequencing of XX and XY somatic cells provides evidence that gonadal supporting cells are specified from these early progenitors by a non-sex-specific transcriptomic program before pre-granulosa and Sertoli cells acquire their sex-specific identity.
TL;DR: Evidence that stunting is in part a biological response to previous episodes of being wasted is provided, suggesting that stunted children are not just short children but are children who earlier were more seriously malnourished and who are survivors of a composite process.
TL;DR: Findings show elevated cytokines in psychosis after accounting for confounds, and that the hypothesis of an immune subgroup is not supported by the variability or modal distribution.
Abstract: Immune parameters are elevated in psychosis, but it is unclear whether alterations are homogenous across patients or heterogeneity exists, consistent with the hypothesis that immune alterations are specific to a subgroup of patients. To address this, we examine whether antipsychotic-naive first-episode psychosis patients exhibit greater variability in blood cytokines, C-reactive protein, and white cell counts compared with controls, and if group mean differences persist after adjusting for skewed data and potential confounds. Databases were searched for studies reporting levels of peripheral immune parameters. Means and variances were extracted and analyzed using multivariate meta-analysis of mean and variability of differences. Outcomes were (1) variability in patients relative to controls, indexed by variability ratio (VR) and coefficient of variation ratio (CVR); (2) mean differences indexed by Hedges g; (3) Modal distribution of raw immune parameter data using Hartigan's unimodality dip test. Thirty-five studies reporting on 1263 patients and 1470 controls were included. Variability of interleukin-6 (IL6) (VR = 0.19), tumor necrosis factor-α (TNFα) (VR = 0.36), interleukin-1β (VR = 0.35), interleukin-4 (VR = 0.55), and interleukin-8 (VR = 0.28) was reduced in patients. Results persisted for IL6 and IL8 after mean-scaling. Ninety-four percent and one hundred percent of raw data were unimodally distributed in psychosis and controls, respectively. Mean levels of IL6 (g = 0.62), TNFα (g = 0.56), interferon-γ (IFNγ) (g = 0.32), transforming growth factor-β (g = 0.53), and interleukin-17 (IL17) (g = 0.48) were elevated in psychosis. Sensitivity analyses indicated this is unlikely explained by confounders for IL6, IFNγ, and IL17. These findings show elevated cytokines in psychosis after accounting for confounds, and that the hypothesis of an immune subgroup is not supported by the variability or modal distribution.
TL;DR: The VETA model, which integrates values relating to conservation of the status quo and self-enhancement from Schwartz's Theory of Human Values, is developed and introduced and concludes that VETA will be a useful model to researchers studying technology adoption.
Abstract: As technology continues to pervade our lives, the influence of culture on technology adoption is of significant interest to researchers. However, culture, as a group-level construct may not give meaningful results when related to individual-level adoption. Although culture has been integrated into technology adoption models, values are the individual-level representation of culture, and are more appropriate to include in technology adoption models. There have been few studies attempting to explore the influence of values on adoption models, and none within the sphere of digital education. The purpose of this exploratory study is to integrate values with technology adoption models and apply the novel conceptual model to the context of digital education. In this study we investigate the influence of individual-level values on the adoption of e-learning by workers in The Gambia and the UK. Using the Unified Theory of the Acceptance and Use of Technology (UTAUT2) as a base model, we integrate values relating to conservation of the status quo and self-enhancement from Schwartz's Theory of Human Values. Taking this approach, we develop and introduce the Values-Enhanced Technology Adoption (VETA) model. We tested the VETA model on the adoption of e-learning by workers in The Gambia and the UK. Empirical results demonstrated the influence of self-enhancement values in the model via social influence, price value and performance expectancy. The UTAUT2 base model was partially validated in that performance expectancy, price value and habit primarily influenced worker intention to use e-learning. We conclude that VETA will be a useful model to researchers studying technology adoption.
TL;DR: The data support a role for macrophage‐derived IGF‐1 as a key neurotrophic and sensitizing factor in endometriosis, and it is proposed that therapies that modify macrophages phenotype may be attractive therapeutic options for the treatment of women with endometRIosis‐associated pain.
Abstract: Endometriosis is a common incurable inflammatory disorder that is associated with debilitating pelvic pain in women. Macrophages are central to the pathophysiology of endometriosis: they dictate the growth and vascularization of endometriosis lesions and more recently have been shown to promote lesion innervation. The aim of this study was to determine the mechanistic role of macrophages in producing pain associated with endometriosis. Herein, we show that macrophage depletion in a mouse model of endometriosis can reverse abnormal changes in pain behavior. We identified that disease-modified macrophages exhibit increased expression of IGF-1 in an in vitro model of endometriosis-associated macrophages and confirmed expression by lesion-resident macrophages in mice and women. Concentrations of IGF-1 were elevated in peritoneal fluid from women with endometriosis and positively correlate with their pain scores. Mechanistically, we demonstrate that macrophage-derived IGF-1 promotes sprouting neurogenesis and nerve sensitization in vitro. Finally, we show that the Igf-1 receptor inhibitor linsitinib reverses the pain behavior observed in mice with endometriosis. Our data support a role for macrophage-derived IGF-1 as a key neurotrophic and sensitizing factor in endometriosis, and we propose that therapies that modify macrophage phenotype may be attractive therapeutic options for the treatment of women with endometriosis-associated pain.-Forster, R., Sarginson, A., Velichkova, A., Hogg, C., Dorning, A., Horne, A. W., Saunders, P. T. K., Greaves, E. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis.
TL;DR: It is shown that lung neutrophils in mice exposed to three distinct pro-allergic conditions release neutrophil extracellular traps that potentiate allergen uptake by dendritic cells and type 2 allergic inflammation.
Abstract: Low exposure to microbial products, respiratory viral infections and air pollution are major risk factors for allergic asthma, yet the mechanistic links between such conditions and host susceptibility to type 2 allergic disorders remain unclear. Through the use of single-cell RNA sequencing, we characterized lung neutrophils in mice exposed to a pro-allergic low dose of lipopolysaccharide (LPS) or a protective high dose of LPS before exposure to house dust mites. Unlike exposure to a high dose of LPS, exposure to a low dose of LPS instructed recruited neutrophils to upregulate their expression of the chemokine receptor CXCR4 and to release neutrophil extracellular traps. Low-dose LPS–induced neutrophils and neutrophil extracellular traps potentiated the uptake of house dust mites by CD11b+Ly-6C+ dendritic cells and type 2 allergic airway inflammation in response to house dust mites. Neutrophil extracellular traps derived from CXCR4hi neutrophils were also needed to mediate allergic asthma triggered by infection with influenza virus or exposure to ozone. Our study indicates that apparently unrelated environmental risk factors can shape recruited lung neutrophils to promote the initiation of allergic asthma. Marichal and colleagues show that lung neutrophils in mice exposed to three distinct pro-allergic conditions release neutrophil extracellular traps that potentiate allergen uptake by dendritic cells and type 2 allergic inflammation.
TL;DR: It is suggested that affective WM capacity may be a transdiagnostic mechanism associated with poor mental health and the importance of integrating behavioral and neural levels of analysis is highlighted.
Abstract: Everyday life is defined by goal states that are continuously reprioritized based on available, often affective information. To pursue these goals, individuals need to process and maintain goal-relevant information, while ignoring potentially salient information that distracts resources from these goals. Empirically, this ability has typically been operationalized as working memory (WM) capacity. A growing body of research is investigating the impact of information's affective salience on WM capacity. In the present review we address this question by exploring the potential differential impact of affective compared with neutral information on WM, and the underlying neural substrates. One-hundred and 65 studies (N = 7,433) were included in the meta-analysis. Results showed negligible to small (d = -.07-.20) effects of affective information on behavioral measures of WM in healthy individuals (n = 4,936) that varied as a function of valence and task-relevance. Heterogeneity analyses were significant, demonstrating the need to identify further study-specific factors and individual differences that moderate affective WM. At the neural level (33 studies; n = 683), processing affective versus neutral material during WM tasks was associated with more frequent recruitment of the vlPFC, the amygdala, and the temporo-occipital cortex. In contrast to healthy individuals, across behavioral studies those suffering from mental health problems (n = 2,041) showed impaired WM accuracy (d = -0.21) in the presence of affective material. These findings highlight the importance of integrating behavioral and neural levels of analysis. Finally, these findings suggest that affective WM capacity may be a transdiagnostic mechanism associated with poor mental health. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
TL;DR: Further studies are needed to strengthen the retrieved association between anthocyanins consumption and decreased risk of hypertension and clarify whether total flavonoids or rather individual subclasses may exert beneficial effects on blood pressure.
Abstract: Background: Dietary polyphenols, including flavonoids, have been the focus of major recent attentions due to their wide content in a variety of foods commonly consumed and the findings from numerous studies showing evidence of an association with positive outcomes on human health. Methods: A systematic search using electronic databases PubMed and EMBASE was performed to retrieve English language studies published from the earliest indexing year of each database to April 2019, reporting on the association between dietary flavonoids intake and hypertension. Results: The search strategy resulted in the final selection of 20 studies including 15 cross-sectional investigations and 7 prospective cohorts (1 study reported on 3 prospective cohorts). 5 prospective cohorts, comprising 200,256 individuals and 45,732 cases of hypertension were included in the quantitative analysis. Analysis by extreme quantiles of intake of flavonoid showed a non-significant association with decreased risk of hypertension (RR (risk ratio): 0.96, 95% CI (confidence interval): 0.89, 1.03). Taking into consideration individual flavonoid subclasses, dietary anthocyanins intake was associated with 8% reduction in risk of hypertension, when comparing highest vs. lowest exposure (RR: 0.92, 95% CI: 0.88, 0.97). Conclusions: Further studies are needed to strengthen the retrieved association between anthocyanins consumption and decreased risk of hypertension and clarify whether total flavonoids or rather individual subclasses may exert beneficial effects on blood pressure.
Mayo Clinic1, Erasmus University Rotterdam2, University of California, San Francisco3, University of British Columbia4, University of Western Ontario5, Karolinska Institutet6, University of Tübingen7, German Center for Neurodegenerative Diseases8, University of Rostock9, Ludwig Maximilian University of Munich10, Technische Universität München11, University of Texas Southwestern Medical Center12, King's College London13, University of Cambridge14, Northwestern University15, University of Texas Health Science Center at San Antonio16, University of Arizona17, Columbia University18, Indiana University – Purdue University Indianapolis19, Medical Research Council20, University of Pennsylvania21, University of Manchester22, University of Sydney23, United States Department of Veterans Affairs24, University of Toronto25, University Health Network26, Washington University in St. Louis27, University of Pittsburgh28, University of New South Wales29, Emory University30, University College London31
TL;DR: A possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP is discovered and strongly implicates the immune pathway in FTLD/TDP pathogenesis.
Abstract: Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e − 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e − 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e − 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
TL;DR: This pilot study supports high-dose simvastatin as an adjuvant therapy for CAP + S in an older and milder disease cohort than assessed previously and indicates that a definitive multicenter study is now warranted in this population to assess the likelihood of benefit and harm.
Abstract: Rationale: Population studies suggest improved sepsis outcomes with statins but randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly bee...
TL;DR: This study exemplifies the combination of HaloPROTACs with CRISPR/Cas9 endogenous protein tagging as a useful method to induce rapid and reversible degradation of endogenous proteins to interrogate their function.
Abstract: Inducing post-translational protein knockdown is an important approach to probe biology and validate drug targets. An efficient strategy to achieve this involves expression of a protein of interest fused to an exogenous tag, allowing tag-directed chemical degraders to mediate protein ubiquitylation and proteasomal degradation. Here, we combine improved HaloPROTAC degrader probes with CRISPR/Cas9 genome editing technology to trigger rapid degradation of endogenous target proteins. Our optimized probe, HaloPROTAC-E, a chloroalkane conjugate of high-affinity VHL binder VH298, induced reversible degradation of two endosomally localized proteins, SGK3 and VPS34, with a DC50 of 3-10 nM. HaloPROTAC-E induced rapid (∼50% degradation after 30 min) and complete ( Dmax of ∼95% at 48 h) depletion of Halo-tagged SGK3, blocking downstream phosphorylation of the SGK3 substrate NDRG1. HaloPROTAC-E more potently induced greater steady state degradation of Halo tagged endogenous VPS34 than the previously reported HaloPROTAC3 compound. Quantitative global proteomics revealed that HaloPROTAC-E is remarkably selective inducing only degradation of the Halo tagged endogenous VPS34 complex (VPS34, VPS15, Beclin1, and ATG14) and no other proteins were significantly degraded. This study exemplifies the combination of HaloPROTACs with CRISPR/Cas9 endogenous protein tagging as a useful method to induce rapid and reversible degradation of endogenous proteins to interrogate their function.
TL;DR: In this paper, the role of prostaglandin E2-EP2/EP4 signaling in the induction of pathogenic helper T (TH17) cells was examined.
Abstract: Background IL-23 is the key cytokine for generation of pathogenic IL-17–producing helper T (TH17) cells, which contribute critically to autoimmune diseases. However, how IL-23 generates pathogenic TH17 cells remains to be elucidated. Objectives We sought to examine the involvement, molecular mechanisms, and clinical implications of prostaglandin (PG) E2–EP2/EP4 signaling in induction of IL-23–driven pathogenic TH17 cells. Methods The role of PGE2 in induction of pathogenic TH17 cells was investigated in mouse TH17 cells in culture in vitro and in an IL-23–induced psoriasis mouse model in vivo. Clinical relevance of the findings in mice was examined by using gene expression profiling of IL-23 and PGE2-EP2/EP4 signaling in psoriatic skin from patients. Results IL-23 induces Ptgs2, encoding COX2 in TH17 cells, and produces PGE2, which acts back on the PGE receptors EP2 and EP4 in these cells and enhances IL-23–induced expression of an IL-23 receptor subunit gene, Il23r, by activating signal transducer and activator of transcription (STAT) 3, cAMP-responsive element binding protein 1, and nuclear factor κ light chain enhancer of activated B cells (NF-κB) through cyclic AMP–protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in TH17 cell–mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A+ and IL-17A+IFN-γ+ pathogenic Th17 cells and abolished skin inflammation in an IL-23–induced psoriasis mouse model. Analysis of human psoriatic skin biopsy specimens shows positive correlation between PGE2 signaling and the IL-23/TH17 pathway. Conclusions T cell–intrinsic EP2/EP4 signaling is critical in IL-23–driven generation of pathogenic TH17 cells and consequent pathogenesis in the skin.
TL;DR: The development of SGK3-PROTAC1, a PROTAC conjugate of the 308-R SGK inhibitor with the VH032 VHL binding ligand, targetingSGK3 for degradation underscores the benefit of the PROTAC approach in targeting protein kinase signaling pathways with greater efficacy and selectivity than can be achieved with conventional inhibitors.
Abstract: SGK3 is a PX domain containing protein kinase activated at endosomes downstream of class 1 and 3 PI3K family members by growth factors and oncogenic mutations. SGK3 plays a key role in mediating re...
TL;DR: Fetal PreProB- upstream of ProB-progenitors are identified as the first B-lymphoid restricted progenitor in human fetal life, and it is suggested that this fetal-restricted committed B-pro genitor might provide a permissive cellular context for prenatal B- Progenitor leukemia initiation.
TL;DR: Early events leading to gonad formation, including the identity of gonadal progenitors, the genetic networks involved in cell lineage specification, the mutual antagonism of the pro-testis and pro-ovary networks and the importance of timing of developmental events orchestrating testis and ovary development are focused on.
Abstract: Primary sex determination is the decision by which the bipotential embryonic gonad commits to either the testicular or ovarian fate. The developing gonad constitutes a unique paradigm for the study of lineage specification, cell fate commitment and the exploration of how distinct cell populations diverge from multipotent progenitors. After the separation of the adreno-gonadal primordium into two distinct primordia, somatic progenitor cells of the gonadal primordium undergo several cell fate decisions and sex-specific cell differentiation. The specification of the supporting and steroidogenic cell lineages into either Sertoli and Leydig cells in the testis, or granulosa and theca cells in the ovary is essential for germ cell development and endocrine function of the gonads. In this review, we focus on the early events leading to gonad formation, including the identity of gonadal progenitors, the genetic networks involved in cell lineage specification, the mutual antagonism of the pro-testis and pro-ovary networks and the importance of timing of developmental events orchestrating testis and ovary development. We discuss, and put into perspective, a number of experiments performed in mice or humans that have shed light on sex-determining mechanisms and, where possible, the clinical significance and limitations of such model organism data.