Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant ( foz/foz ) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a ) vehicle control, b ) ezetimibe (5 mg/kg/day), c ) atorvastatin (20 mg/kg/day), or d ) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFα -positive (activated) KCs forming CLSs ( ≥ 3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation

Power in the Land

In 1542 William Ramsden bought his wife’s family home at Longley and so began a long association between the Ramsdens and Huddersfield which lasted until Sir John Frecheville Ramsden sold his greatly increased Huddersfield estate to the Corporation in 1920. This collection of essays is published to commemorate the centenary of that event. Seven local historians examine different aspects of the Ramsden family’s relationship with the town and its inhabitants, especially in the nineteenth century.  The book incorporates new research and gives fresh insights into the events which led to Huddersfield becoming ‘the town that bought itself’ a century ago

Comparing Water Level Estimation in Coastal and Shelf Seas From Satellite Altimetry and Numerical Models

Accurately resolving coastal Total Water Levels (TWL) is crucial for socio-economic and environmental reasons. Recent efforts in satellite altimetry and numerical modelling have improved accuracy over near-shore areas. In this study we used data from tide gauges (TGs), SAR-mode altimetry from two satellites (Sentinel-3A (S3) and CryoSat-2 (C2)), and a state-of-the-art high-resolution regional coupled environmental prediction model (Amm15) to undertake an inter-comparison between the observations and the model. The aim is to quantify our capability to measure TWL around the UK coast, and to quantify the capacity of the model to represent coastal TWL. Results show good agreement between the satellite and TG data (the mean correlation (R) over seventeen TGs between June 2016 and September 2017 is 0.85 for S3 and 0.80 for C2). The satellite-model comparison shows that the variability is well captured (R=0.98 for both satellite), however there is an offset (-0.23m for S3, -0.15m for C2) between the satellite and model data, that is near-constant across the domain. This offset is partly attributed to the difference in the reference level used by the satellites and the model, and residual differences linked to the temporal resolution of the model. The best agreement between model and satellite is seen away from the coast, further than 3-4km offshore. However, even within the coastal band, R remains high, ~0.95 (S3) and ~0.96 (C2). In conclusion, models are still essential to represent TWL in coastal regions where there is no cover from in-situ observations, but satellite altimeters can now provide valuable observations that are reliable much closer to the coast than before

Automated Single-Particle Reconstruction of Heterogeneous Inorganic Nanoparticles

Single-particle reconstruction can be used to perform three-dimensional (3D) imaging of homogeneous populations of nano-sized objects, in particular viruses and proteins. Here, it is demonstrated that it can also be used to obtain 3D reconstructions of heterogeneous populations of inorganic nanoparticles. An automated acquisition scheme in a scanning transmission electron microscope is used to collect images of thousands of nanoparticles. Particle images are subsequently semi-automatically clustered in terms of their properties and separate 3D reconstructions are performed from selected particle image clusters. The result is a 3D dataset that is representative of the full population. The study demonstrates a methodology that allows 3D imaging and analysis of inorganic nanoparticles in a fully automated manner that is truly representative of large particle populations.Peer reviewe

Epithelialization of hydrogels achieved by amine functionalization and co-culture with stromal cells

The aim of this study was to develop a hydrogel which would be suitable for corneal cell re-epithelialization when used as a corneal implant. To achieve this, a series of hydrogels were functionalized with primary amines by post-polymerization reactions between amine compounds and glycidyl ether groups attached to the hydrogels. We report a strong correlation between the structure of the amine and the viability of stromal cells and epithelial cells cultured on these hydrogels. Subsequent co-culture of epithelial and stromal cells on the amine modified hydrogels allowed successful expansion of epithelial cells on surfaces functionalized with alkyl α–ω diamines with carbon chain lengths of between 3 and 6. Analysis of variance showed that corneal epithelial cells had a strong preference for surfaces functionalized by the reaction of excess 1,3 diaminopropane with units of glycidyl methacrylate compared to the reaction products of other amines (ammonia; 1,2-diaminoethane; 1,4-diaminobutane or 1,6-diaminohexane). We suggest this approach of amine functionalization combined with stromal/epithelial co-culture offers a promising new approach to achieving a secure corneal epithelium. Keywords: Epithelial cell

Natural hazards in Australia : sea level and coastal extremes

The Australian coastal zone encompasses tropical, sub- and extra-tropical climates and accommodates about 80 % of Australia’s population. Sea level extremes and their physical impacts in the coastal zone arise from a complex set of atmospheric, oceanic and terrestrial processes that interact on a range of spatial and temporal scales and will be modified by a changing climate, including sea level rise. This review details significant progress over recent years in understanding the causes of past and projections of future changes in sea level and coastal extremes, yet a number of research questions, knowledge gaps and challenges remain. These include efforts to improve knowledge on past sea level extremes, integrate a wider range of processes in projections of future changes to sea level extremes, and focus efforts on understanding long-term coastline response from the combination of contributing factors

Electron beam and thermal stabilities of MFM-300(M) metal–organic frameworks †

This work reports the thermal and electron beam stabilities of a series of isostructural metal–organic frameworks (MOFs) of type MFM-300(M) (M = Al, Ga, In, Cr). MFM-300(Cr) was most stable under the electron beam, having an unusually high critical electron fluence of 1111 e− Å−2 while the Group 13 element MOFs were found to be less stable. Within Group 13, MFM-300(Al) had the highest critical electron fluence of 330 e− Å−2, compared to 189 e− Å−2 and 147 e− Å−2 for the Ga and In MOFs, respectively. For all four MOFs, electron beam-induced structural degradation was independent of crystal size and was highly anisotropic, although both the length and width of the channels decreased during electron beam irradiation. Notably, MFM-300(Cr) was found to retain crystallinity while shrinking up to 10%. Thermal stability was studied using in situ synchrotron X-ray diffraction at elevated temperature, which revealed critical temperatures for crystal degradation to be 605, 570, 490 and 480 °C for Al, Cr, Ga, and In, respectively. The pore channel diameters contracted by ≈0.5% on desorption of solvent species, but thermal degradation at higher temperatures was isotropic. The observed electron stabilities were found to scale with the relative inertness of the cations and correlate well to the measured lifetime of the materials when used as photocatalysts