The acquisition of cell motility is an early step in melanoma metastasis. Here we use intravital imaging of signalling reporter cell-lines combined with genome-wide transcriptional analysis to define ...signalling pathways and genes associated with melanoma metastasis. Intravital imaging revealed heterogeneous cell behaviour in vivo: <10% of cells were motile and both singly moving cells and streams of cells were observed. Motile melanoma cells had increased Notch- and SRF-dependent transcription. Subsequent genome-wide analysis identified an overlapping set of genes associated with high Notch and SRF activity. We identified EZH2, a histone methyltransferase in the Polycomb repressive complex 2, as a regulator of these genes. Heterogeneity of EZH2 levels is observed in melanoma models, and co-ordinated upregulation of genes positively regulated by EZH2 is associated with melanoma metastasis. EZH2 was also identified as regulating the amelanotic phenotype of motile cells in vivo by suppressing expression of the P-glycoprotein Oca2. Analysis of patient samples confirmed an inverse relationship between EZH2 levels and pigment. EZH2 targeting with siRNA and chemical inhibition reduced invasion in mouse and human melanoma cell lines. The EZH2-regulated genes KIF2C and KIF22 are required for melanoma cell invasion and important for lung colonization. We propose that heterogeneity in EZH2 levels leads to heterogeneous expression of a cohort of genes associated with motile behaviour including KIF2C and KIF22. EZH2-dependent increased expression of these genes promotes melanoma cell motility and early steps in metastasis.
The fully printable carbon triple-mesoscopic perovskite solar cell (C-PSC) has already demonstrated good efficiency and long-term stability, opening the possibility of lab-to-fab transition. Modules ...based on C-PSC architecture have been reported and, at present, are achieved through the accurate registration of each of the patterned layers using screen-printing. Modules based on this approach were reported with geometric fill factor (g-FF) as high as 70%. Another approach to create the interconnects, the so-called scribing method, was reported to achieve more than 90% g-FF for architectures based on evaporated metal contacts, i.e., without a carbon counter electrode. Here, for the first time, we adopt the scribing method to selectively remove materials within a C-PSC. This approach allowed a deep and selective scribe to open an aperture from the transparent electrode through all the layers, including the blocking layer, enabling a direct contact between the electrodes in the interconnects. In this work, a systematic study of the interconnection area between cells is discussed, showing the key role of the FTO/carbon contact. Furthermore, a module on 10 × 10 cm2 substrate with the optimised design showing efficiency over 10% is also demonstrated.
Are tundra ecosystems currently a carbon source or sink? What is the future trajectory of tundra carbon fluxes in response to climate change? These questions are of global importance because of the ...vast quantities of organic carbon stored in permafrost soils. In this meta‐analysis, we compile 40 years of CO₂ flux observations from 54 studies spanning 32 sites across northern high latitudes. Using time‐series analysis, we investigated if seasonal or annual CO₂ fluxes have changed over time, and whether spatial differences in mean annual temperature could help explain temporal changes in CO₂ flux. Growing season net CO₂ uptake has definitely increased since the 1990s; the data also suggest (albeit less definitively) an increase in winter CO₂ emissions, especially in the last decade. In spite of the uncertainty in the winter trend, we estimate that tundra sites were annual CO₂ sources from the mid‐1980s until the 2000s, and data from the last 7 years show that tundra continue to emit CO₂ annually. CO₂ emissions exceed CO₂ uptake across the range of temperatures that occur in the tundra biome. Taken together, these data suggest that despite increases in growing season uptake, tundra ecosystems are currently CO₂ sources on an annual basis.
Photovoltaic devices based on perovskite materials have a great potential to become an exceptional source of energy while preserving the environment. However, to enter the global market, they require ...further development to achieve the necessary performance requirements. The environmental performance of a pre-industrial process of production of a large-area carbon stack perovskite module is analyzed in this work through life cycle assessment (LCA). From the pre-industrial process an ideal process is simulated to establish a benchmark for pre-industrial and laboratory-scale processes. Perovskite is shown to be the most harmful layer of the carbon stack module because of the energy consumed in the preparation and annealing of the precursor solution, and not because of its Pb content. This work stresses the necessity of decreasing energy consumption during module preparation as the most effective way to reduce environmental impacts of perovskite solar cells.
Wild fish populations are currently experiencing unprecedented pressures, which are projected to intensify in the coming decades. Developing a thorough understanding of the influences of both biotic ...and abiotic factors on fish populations is a salient issue in contemporary fish conservation and management. During the 50th Anniversary Symposium of The Fisheries Society of the British Isles at the University of Exeter, UK, in July 2017, scientists from diverse research backgrounds gathered to discuss key topics under the broad umbrella of ‘Understanding Fish Populations’. Below, the output of one such discussion group is detailed, focusing on tools used to investigate natural fish populations. Five main groups of approaches were identified: tagging and telemetry; molecular tools; survey tools; statistical and modelling tools; tissue analyses. The appraisal covered current challenges and potential solutions for each of these topics. In addition, three key themes were identified as applicable across all tool‐based applications. These included data management, public engagement, and fisheries policy and governance. The continued innovation of tools and capacity to integrate interdisciplinary approaches into the future assessment and management of fish populations is highlighted as an important focus for the next 50 years of fisheries research.
Simulation offers a simple and flexible way to estimate the power of a clinical trial when analytic formulae are not available. The computational burden of using simulation has, however, restricted ...its application to only the simplest of sample size determination problems, often minimising a single parameter (the overall sample size) subject to power being above a target level. We describe a general framework for solving simulation-based sample size determination problems with several design parameters over which to optimise and several conflicting criteria to be minimised. The method is based on an established global optimisation algorithm widely used in the design and analysis of computer experiments, using a non-parametric regression model as an approximation of the true underlying power function. The method is flexible, can be used for almost any problem for which power can be estimated using simulation, and can be implemented using existing statistical software packages. We illustrate its application to a sample size determination problem involving complex clustering structures, two primary endpoints and small sample considerations.
Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common ...treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone.
Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization.
The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between-group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group.
Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .).
While tissue simulants are considered best practice for ballistic evaluations, there is an ongoing debate about the use of tissue simulant and their relevance and there are calls to improve models by ...making them more anatomically relevant by the introduction of bony structures and organs. Therefore; the aim of this study was to try and determine if sponges and/or ballistic gelatin may be a suitable proxy to porcine lungs using 5.56x45mm (MK262-MOD1). Four sample groups consisting of 10% ballistic gelatin blocks, lungs embedded in gelatin, kitchen sponges and car sponge in gelatin were evaluated. Analysis included determining the onset of yaw, time from impact to the onset of yaw, temporary and permanent cavity characteristics and energy deposition. The results indicated that the kitchen sponge and car sponge may be a suitable proxy to porcine lungs, however there were significant differences between the lung model and plain gelatin blocks and additional work should be carried out to investigate the suitability of sponges as a proxy to porcine lungs further.
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