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TGFβ1 plays a regulatory role in the determination of renal cell fate and the progression of renal fibrosis. Here we show an association between SMAD3 and the histone methyltransferase, EZH2, during cell differentiation; ChIP-seq revealed that SMAD3 and EZH2 co-occupy the genome in iPSCs and in iPSC-derived nephron progenitors. Through integration of single cell gene expression and epigenome profiling, we identified de novo ACTA2+ve/POSTN+ve myofibroblasts in kidney organoids treated with TGFβ1, characterised by increased SMAD3-dependent cis chromatin accessibility and gene expression associated with fibroblast activation. We have identified fibrosis-associated regulons characterised by enrichment of SMAD3, AP1, the ETS family of transcription factors, and NUAK1, CREB3L1, and RARG, corresponding to enriched motifs at accessible loci identified by scATACseq. Treatment with the EZH2 specific inhibitor GSK343, blocked SMAD3-dependent cis co-accessibility and inhibited myofibroblast activation. This mechanism, through which TGFβ signals directly to chromatin, represents a critical determinant of fibrotic, differentiated states. Multimodal single-cell analysis on iPSC-derived kidney organoids shows that inhibiting EZH2 attenuates TGFβ1-induced fibrotic gene expression and changes in chromatin accessibility, highlighting a potential therapeutic strategy for renal fibrosis. [ABSTRACT FROM AUTHOR]

Background: Techniques for the accurate identification of activating mutations of BRAF in metastatic melanoma are of great clinical importance, due to the availability of targeted therapies for these tumors. There is uncertainty regarding the frequency with which BRAF status differs between primary and metastatic sites. Methods: Between 2011 and 2016, 219 melanoma cases underwent BRAF testing in our institution. In 53 of these cases, paired primary and metastatic specimens were available for polymerase chain reaction (PCR) and immunohistochemical evaluation. Results: Fifty‐two out of 53 cases (98%) showed concordant BRAF status between primary and metastatic site by immunohistochemistry (IHC). In one case, a metastasis and its matched primary were positive by IHC, but the metastasis was negative on PCR. On further investigation, PCR was positive in the primary, and repeat PCR in the metastasis was positive, following macrodissection. Conclusions: Our results suggest that discordance of BRAF mutational status between primaries and metastases is a rare occurrence. In one case, IHC provided strong evidence that initial PCR testing had provided a false‐negative result due to low tumor volume. Thus, in cases where tissue is difficult to obtain from a metastasis or unavailable, the primary tumor can be used with confidence. [ABSTRACT FROM AUTHOR]

A material model based on the Puck phenomenological failure criteria for fibre and inter-fibre failure of glass-fibre and carbon-fibre reinforced polymer composites is presented. The model is applied through a user-defined material subroutine for 3D shell elements. Sub-modelling is used for detailed analysis of the highest stressed regions in the blades. The material model is incorporated into a methodology for the design and analysis of composite tidal current turbine blades. The methodology employs an iterative design process with respect to a number of failure criteria to ensure optimal structural and material performance of the blade. The methodology is automated using the Python programming language to enable efficient variation of model parameters for various design conditions. The forces acting on the blades are determined from blade element momentum theory for a number of turbine operating conditions. The results of a design case study for a typical horizontal axis device are presented to demonstrate the methodology. [ABSTRACT FROM AUTHOR]

R2854 --> 515.5 --> Differential methylation patterns and changes in post‐translational histone modifications are observed in patients with or without progressive diabetic kidney disease (DKD). TGFβ1 plays a central regulatory role in the determination of renal cell fate and the progression of DKD. Using ChIP‐seq, we identified an association between SMAD3 and the histone methyltransferase, EZH2, in iPSCs and in iPSC derived nephron progenitors. Using the 10X Genomics platform, we performed single cell RNA‐seq and ‐ATAC‐seq on human iPSC‐derived kidney organoids treated with the EZH2 specific inhibitor, GSK343, prior to treatment with TGFβ1. Integration of single cell RNAseq and ‐ATACseq identified de novo ACTA2+ve/POSTN+ve myofibroblasts in TGFβ1‐treated kidney organoids, characterised by increased SMAD3‐dependent cis chromatin accessibility and the expression of genes associated with fibroblast activation, which are similarly overexpressed in DKD patients. This fibrosis‐associated regulon is characterised by enrichment of SMAD3 and AP‐1, corresponding to FOS/JUN motifs at accessible loci identified by scATACseq. Treatment with GSK343 blocked SMAD3‐dependent cis co‐accessibility and inhibited myofibroblast activation. We propose that that the enzymatic function of the polycomb repressive complex is necessary for TGFβ1 induced increase in chromatin accessibility and its subsequent gene regulatory functions. Manipulation of the association between SMAD3 and EZH2 may be a useful therapeutic strategy for the resolution of renal fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: A multiaxial fatigue damage model for fibre reinforced polymer composite materials is presented. The model combines (i) fatigue-induced fibre strength and modulus degradation, (ii) irrecoverable cyclic strain effects and (iii) inter-fibre fatigue. The inter-fibre fatigue aspect is based on a fatigue-modified version of the Puck multiaxial failure criterion for static failure. The model is implemented in a user material finite element subroutine and calibrated against fatigue test data for unidirectional glass fibre epoxy. A programme of uniaxial fatigue tests on quasi-isotropic glass fibre epoxy laminates is presented for validation of the novel fatigue damage methodology. The latter is successfully validated across a range of stress levels. [Copyright &y& Elsevier]

The article discusses the staging of grand opera at The Grand Opera House (GOH) and other venues in Belfast, Northern Ireland between 1945 and 1981. It examines the threats posed by staging of grand opera to the GOH as live venue by the private ownership of the Rank-Odeon cinema chain. It also cites the impacts of the Troubles combined with the unsuitability of the GOH as a cinema on city centre in Belfast.

Background: Smoking is responsible for substantial cardiovascular morbidity and mortality. Electronic cigarettes have been advocated as a means to reduce this disease burden; by reducing exposure to harmful substances in smokers who are unable to quit. Concerns have been raised however, about cardiovascular effects of their use, with inhalants containing carbonyls and fine particulate matter. We systematically reviewed experimental studies of in vitro, animal, and human cardiovascular effects associated with electronic cigarette use.Methods: A literature search was conducted using Ovid MEDLINE & Embase databases, identifying experimental studies investigating cardiovascular effects of electronic cigarette use. Subsequently, Cochrane Risk of Bias tools were used to assess study quality. Any differences in outcomes by conflict of interest and risk of bias status were sought.Results: 38 studies were included, investigating animals (n=6), humans (n=24) and human cardiovascular cells in vitro (n=8). 74.3% of studies found potentially harmful effects. Increased sympathetic nerve activity was observed in human studies, whilst platelet haemostatic processes, reactive oxygen species production and endothelial dysfunction were reported across all study types. Studies with conflicts of interest or median-high risk of bias were less likely to identify potentially harmful effects (p=0.0007, p=0.04 respectively).Discussion: Most studies suggest potential for cardiovascular harm from electronic cigarette use, through mechanisms that increase risk of thrombosis and atherosclerosis. Notably, studies with conflicts of interest are significantly less likely to identify concerning cardiovascular effects. Included studies examine healthy, adult participants, limiting generalisation to potential high-risk groups including individuals with established cardiovascular disease or young, non-smokers. [ABSTRACT FROM AUTHOR]

Recently, tidal energy has gained attention as an attractive renewable source of power generation. In this context, tidal turbine foils must operate in harsh conditions and extremely variable dynamic loads. Considering the expensive dynamic tests required for these large structures, developing validated dynamic models could be valuable for failure prediction and design purposes. In this paper, the free and forced vibration behaviour of the cantilevered part of a non-uniform helical tidal turbine foil made from the composite material is investigated theoretically and experimentally. In this regard, governing vibration equations of the foil with related boundary conditions are presented. The free vibration analysis of the foil is performed by solving a boundary-value problem, where a closed-form solution, based on the mode summation method, for the forced vibration of the foil is employed. Finally, the obtained numerical results (natural frequency and dynamic displacements) are compared with the corresponding results from experiments to validate the vibration equations and the employed solution. Acceptable agreement between numerical and experimental data confirms that the vibration model presented in this study can be employed to predict the dynamic response, parametric study, optimization, and design of the tidal foil without performing costly experiments. • A mathematical model for vibration behaviour of a tidal turbine foil is presented. • The foil has non-uniform helical geometry from fibre-reinforced composite material. • The vibration model is validated against the experimental outputs. • The validated model predicts dynamic response and is useful for design optimization. [ABSTRACT FROM AUTHOR]

Cell differentiation is directed by extracellular cues and intrinsic epigenetic modifications, which control chromatin organization and transcriptional activation. Central to this process is PRC2, which modulates the di- and trimethylation of lysine 27 on histone 3; however, little is known concerning the direction of PRC2 to specific loci. Here, we have investigated the physical interactome of EZH2, the enzymatic core of PRC2, during retinoic acid-mediated differentiation of neuroepithelial, pluripotent NT2 cells and the dedifferentiation of neuroretinal epithelial ARPE19 cells in response to TGF-β. We identified Smad3 as an EZH2 interactor in both contexts. Co-occupation of the CDH1 promoter by Smad3 and EZH2 and the cooperative, functional nature of the interaction were established. We propose that the interaction between Smad3 and EZH2 targets the core polycomb assembly to defined regions of the genome to regulate transcriptional repression and forms a molecular switch that controls promoter access through epigenetic mechanisms leading to gene silencing. [ABSTRACT FROM AUTHOR]

Our objective was to profile genetic pathways whose differential expression correlates with maturation of visual function in zebrafish. Bioinformatic analysis of transcriptomic data revealed Jak-Stat signalling as the pathway most enriched in the eye, as visual function develops. Real-time PCR, western blotting, immunohistochemistry and in situ hybridization data confirm that multiple Jak-Stat pathway genes are up-regulated in the zebrafish eye between 3-5 days post-fertilisation, times associated with significant maturation of vision. One of the most up-regulated Jak-Stat genes is the proto-oncogene Pim1 kinase, previously associated with haematological malignancies and cancer. Loss of function experiments using Pim1 morpholinos or Pim1 inhibitors result in significant diminishment of visual behaviour and function. In summary, we have identified that enhanced expression of Jak-Stat pathway genes correlates with maturation of visual function and that the Pim1 oncogene is required for normal visual function. [ABSTRACT FROM AUTHOR]