Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene A Disintegrin and Metalloprotease (ADAM)33, acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble (s)ADAM33 is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33 null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances post-natal airway eosinophilia and bronchial hyperresponsiveness following sub-threshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma

Understanding the winners and losers of agricultural expansion in Ghana

Ghana’s population is forecast to double by 2050, resulting in an increased need for food provision. Much of this will be achieved through agricultural expansion. But what are the impacts? Who benefits or loses – and why? How will agricultural expansion ultimately affect food security

Effect of Exposure of Human Monocyte-Derived Macrophages to High, versus Normal, Glucose on Subsequent Lipid Accumulation from Glycated and Acetylated Low-Density Lipoproteins

During atherosclerosis monocyte-derived macrophages accumulate cholesteryl esters from low-density lipoproteins (LDLs) via lectin-like oxidised LDL receptor-1 (LOX-1) and class AI and AII (SR-AI, SR-AII) and class B (SR-BI, CD36) scavenger receptors. Here we examined the hypothesis that hyperglycaemia may modulate receptor expression and hence lipid accumulation in macrophages. Human monocytes were matured into macrophages in 30 versus 5 mM glucose and receptor expression and lipid accumulation quantified. High glucose elevated LOX1 mRNA, but decreased SR-AI, SR-BI, LDLR, and CD36 mRNA. SR-BI and CD36 protein levels were decreased. Normo- and hyperglycaemic cells accumulated cholesteryl esters from modified LDL to a greater extent than control LDL, but total and individual cholesteryl ester accumulation was not affected by glucose levels. It is concluded that, whilst macrophage scavenger receptor mRNA and protein levels can be modulated by high glucose, these are not key factors in lipid accumulation by human macrophages under the conditions examined

Comparison of mouse models reveals a molecular distinction between psychotic illness in PWS and schizophrenia

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by mutations affecting paternal chromosome 15q11-q13, and characterized by hypotonia, hyperphagia, impaired cognition, and behavioural problems. Psychotic illness is a challenging problem for individuals with PWS and has different rates of prevalence in distinct PWS genotypes. Previously, we demonstrated behavioural and cognitive endophenotypes of relevance to psychiatric illness in a mouse model for one of the associated PWS genotypes, namely PWS-IC, in which deletion of the imprinting centre leads to loss of paternally imprinted gene expression and over-expression of Ube3a. Here we examine the broader gene expression changes that are specific to the psychiatric endophenotypes seen in this model. To do this we compared the brain transcriptomic profile of the PWS-IC mouse to the PWS-cr model that carries a deletion of the PWS minimal critical interval spanning the snoRNA Snord116 and Ipw. Firstly, we examined the same behavioural and cognitive endophenotypes of relevance to psychiatric illness in the PWS-cr mice. Unlike the PWS-IC mice, PWS-cr exhibit no differences in locomotor activity, sensory-motor gating, and attention. RNA-seq analysis of neonatal whole brain tissue revealed a greater number of transcriptional changes between PWS-IC and wild-type littermates than between PWS-cr and wild-type littermates. Moreover, the differentially expressed genes in the PWS-IC brain were enriched for GWAS variants of episodes of psychotic illness but, interestingly, not schizophrenia. These data illustrate the molecular pathways that may underpin psychotic illness in PWS and have implications for potential therapeutic interventions

Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia

Background: The majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis. Principal Findings: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D2 (PGD2) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Δ12,14 PGJ2 (15d-PGJ2). BEZ increased PGD2 synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ2 by inhibiting the PGD2 11β -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD2 to 9α11β-PGF2α. B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ2. Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors. Significance: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ2. These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML

University student attitudes to prosocial bystander behaviours

Purpose: Half of British university students experience assault and harassment behaviours; few report them. Bystander intervention training has been recommended as a means of reducing these behaviours, but there is little evidence about their potential effectiveness in UK contexts. This study sought to understand UK students’ attitudes towards reporting and intervening in sexual assault, harassment, and hate crimes. Design: A mixed methods cross sectional survey (N=201; 75.6% women) was conducted in one British university. Open text data were analysed using thematic analysis. Findings: Students considered harassment and assault unacceptable, and were confident to intervene in and likely to report incidents. However, fear of backlash was a barrier to intervening and reporting, and they felt that victims should decide whether to report incidents. Students perceived perpetrators as being ignorant about what constitutes consent, harassment, and assault. They identified a need for university community education about this and how to report incidents and support peers. Research limitations/implications: This cross sectional survey was conducted at one UK University. The data might not reflect other students’ attitudes, and may be subject to response bias. Practical implications: University community bystander training should be acceptable, report and support systems might be utilised by students. This may have potential to reduce prevalence and increase reporting. Originality: This is the first study to investigate UK student attitudes to prosocial bystander behaviours

Blood eosinophil-guided oral prednisolone for COPD exacerbations in primary care in the UK (STARR2): A non-inferiority, multicentre, double-blind, placebo-controlled, randomised controlled trial

Background: Systemic glucocorticoids are recommended for use in chronic obstructive pulmonary disease (COPD) exacerbations; however, there is increased harm associated with their use. We hypothesised that the use of eosinophil biomarker-directed oral prednisolone therapy at the time of an exacerbation of COPD was effective at reducing prednisolone use without affecting adverse outcomes. Methods: The studying acute exacerbations and response (STARR2) study was a multicentre, randomised, double-blind, placebo-controlled trial conducted in 14 primary care practices in the UK. We included adults (aged ≥ 40 years), who were current or former smokers (with at least a 10 pack year smoking history) with a diagnosis of COPD, defined as a post-bronchodilator FEV1/forced vital capacity ratio of less than 0·7 previously recorded by the primary care physician, and a history of at least one exacerbation in the previous 12 months requiring systemic corticosteroids with or without antibiotics. All study staff and participants were masked to study group allocation and to treatment allocation. Participants were randomly assigned (1:1) to blood eosinophil-directed treatment (BET; to receive oral prednisolone 30 mg once daily if eosinophil count was high [ ≥ 2%] or placebo if eosinophil count was low [ \u3c 2%]) or to standard care treatment (ST; to receive prednisolone 30 mg once daily irrespective of the point-of-care eosinophil result). Treatment was prescribed for 14 days and all patients also received antibiotics. The primary outcome was the rate of treatment failure, defined as any need for re-treatment with antibiotics or steroids, hospitalisation for any cause, or death, assessed at 30 days after exacerbation in the modified intention-to-treat population. Participants were eligible for re-randomisation at further exacerbations (with a maximum of four exacerbations per participant). A safety analysis was conducted on all randomly assigned participants. Although designed as a superiority trial, after identification of an error in the randomisation code before data lock the study converted to show non-inferiority. An upper margin of 1·105 for the 95% CI was defined as the non-inferiority margin. This study was registered with EudraCT, 2017-001586-24, and is complete. Findings: Between Nov 6, 2017, and April 30, 2020, 308 participants were recruited from 14 general practices. 144 exacerbations (73 in the BET group and 71 in the ST group) from 93 participants (mean age 70 years [range 46–84] and mean percent predicted FEV1 60·9% [SD 19·4]; 52 [56%] male and 41 [44%] female; ethnicity data was not collected]) were included in the modified intention-to-treat analysis. There were 14 (19%) treatment failures at 30 days post-exacerbation in the BET group and 23 (32%) in the ST group; we found a large non-significant estimated effect between BET and ST (RR 0·60 [95% CI 0·33–1·04]; p=0·070) in reducing treatment failures after a COPD exacerbation. The non-inferiority analysis supported that BET was non-inferior to ST. Frequency of adverse events were similar between the study groups; glycosuria (2/102 [2%] in BET group and 1/101 [1%] in the ST group) and hospital admission for COPD exacerbation (2/102 [2%] in BET group and 1/101 [1%] in the ST group) were the two most common adverse events in both groups. No deaths occurred in the study. Interpretation: Blood eosinophil-directed prednisolone therapy at the time of an acute exacerbation of COPD is non-inferior to standard care and can be used to safely reduce systemic glucocorticoid use in clinical practice. Funding: National Institute for Health and Care Research

Daily MODIS 500 m Reflectance Anisotropy Direct Broadcast (DB) Products for Monitoring Vegetation Phenology Dynamics

Land surface vegetation phenology is an efficient bio-indicator for monitoring ecosystem variation in response to changes in climatic factors. The primary objective of the current article is to examine the utility of the daily MODIS 500 m reflectance anisotropy direct broadcast (DB) product for monitoring the evolution of vegetation phenological trends over selected crop, orchard, and forest regions. Although numerous model-fitted satellite data have been widely used to assess the spatio-temporal distribution of land surface phenological patterns to understand phenological process and phenomena, current efforts to investigate the details of phenological trends, especially for natural phenological variations that occur on short time scales, are less well served by remote sensing challenges and lack of anisotropy correction in satellite data sources. The daily MODIS 500 m reflectance anisotropy product is employed to retrieve daily vegetation indices (VI) of a 1 year period for an almond orchard in California and for a winter wheat field in northeast China, as well as a 2 year period for a deciduous forest region in New Hampshire, USA. Compared with the ground records from these regions, the VI trajectories derived from the cloud-free and atmospherically corrected MODIS Nadir BRDF (bidirectional reflectance distribution function) adjusted reflectance (NBAR) capture not only the detailed footprint and principal attributes of the phenological events (such as flowering and blooming) but also the substantial inter-annual variability. This study demonstrates the utility of the daily 500 m MODIS reflectance anisotropy DB product to provide daily VI for monitoring and detecting changes of the natural vegetation phenology as exemplified by study regions comprising winter wheat, almond trees, and deciduous forest

Daily MODIS 500 m Reflectance Anisotropy Direct Broadcast (DB) Products for Monitoring Vegetation Phenology Dynamics

Land surface vegetation phenology is an efficient bio-indicator for monitoring ecosystem variation in response to changes in climatic factors. The primary objective of the current article is to examine the utility of the daily MODIS 500 m reflectance anisotropy direct broadcast (DB) product for monitoring the evolution of vegetation phenological trends over selected crop, orchard, and forest regions. Although numerous model-fitted satellite data have been widely used to assess the spatio-temporal distribution of land surface phenological patterns to understand phenological process and phenomena, current efforts to investigate the details of phenological trends, especially for natural phenological variations that occur on short time scales, are less well served by remote sensing challenges and lack of anisotropy correction in satellite data sources. The daily MODIS 500 m reflectance anisotropy product is employed to retrieve daily vegetation indices (VI) of a 1 year period for an almond orchard in California and for a winter wheat field in northeast China, as well as a 2 year period for a deciduous forest region in New Hampshire, USA. Compared with the ground records from these regions, the VI trajectories derived from the cloud-free and atmospherically corrected MODIS Nadir BRDF (bidirectional reflectance distribution function) adjusted reflectance (NBAR) capture not only the detailed footprint and principal attributes of the phenological events (such as flowering and blooming) but also the substantial inter-annual variability. This study demonstrates the utility of the daily 500 m MODIS reflectance anisotropy DB product to provide daily VI for monitoring and detecting changes of the natural vegetation phenology as exemplified by study regions comprising winter wheat, almond trees, and deciduous forest

The role of temperate bacteriophages in bacterial infection

Bacteriophages are viruses that infect bacteria. There are an estimated 1031 phage on the planet, making them the most abundant form of life. We are rapidly approaching the centenary of their identification, and yet still have only a limited understanding of their role in the ecology and evolution of bacterial populations. Temperate prophage carriage is often associated with increased bacterial virulence. The rise in use of technologies, such as genome sequencing and transcriptomics, has highlighted more subtle ways in which prophages contribute to pathogenicity. This review discusses the current knowledge of the multifaceted effects that phage can exert on their hosts and how this may contribute to bacterial adaptation during infection