Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization

Objective: Lumican (LUM) is a major extracellular matrix glycoprotein in adult articular cartilage and its expression is known to be upregulated upon cartilage degeneration. LUM is associated with the pathogen-associated molecular pattern (PAMP) activation of the TLR4 signalling cascade, with TLR4 being highly associated with inflammation in rheumatic diseases. However, the main role of the LUM structural molecule in osteoarthritis (OA) remains elusive. The aim of this study was, therefore, to understand the role of LUM during TLR4-mediated activation in OA. Methods: After measuring LUM levels in synovial fluid (SF) of OA patients and lipopolysaccharide (LPS)-induced TLR4 activation, the role of LUM in the expression of pro-inflammatory molecules and cartilage degradation was assessed in vitro and ex vivo in a cartilage explant model. Primary macrophage activation and polarization were studied upon LUM co-stimulation with LPS. Results: We demonstrate that LUM is not only significantly upregulated in SF from OA patients compared to healthy controls, but also that LUM increases lipopolysaccharide (LPS)-induced TLR4 activation. Furthermore, we show that a pathophysiological level of LUM augments the LPS-induced TLR4 activation and expression of downstream pro-inflammatory molecules, resulting in extensive cartilage degradation. LUM co-stimulation with LPS also provided a pro-inflammatory stimulus, upregulating primary macrophage activation and polarization towards the M1-like phenotype. Conclusions: These findings strongly support the role of LUM as a mediator of PAMP-induced TLR4 activation of inflammation, cartilage degradation, and macrophage polarization in the OA joint and potentially other rheumatic diseases. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Observation of the metallic mosaic phase in 1TT-TaS2_2 at equilibrium

The transition-metal dichalcogenide tantalum disulphide (1$T$-TaS$_2$) hosts a commensurate charge density wave (CCDW) at temperatures below 165$~$K where it also becomes insulating. The low temperature CCDW phase can be driven into a metastable "mosaic" phase by means of either laser or voltage pulses which shows a large density of CDW domain walls as well as a closing of the electronic band gap. The exact origins of this pulse-induced metallic mosaic are not yet fully understood. Here, using scanning tunneling microscopy and spectroscopy (STM/STS), we observe the occurrence of such a metallic mosaic phase on the surface of TaS$_2$ without prior pulse excitation over continuous areas larger than $100 \times 100~$nm$^2$ and macroscopic areas on the millimetre scale. We attribute the appearance of the mosaic phase to the presence of surface defects which arrange into the characteristic dense domain wall network. Based on our STM measurements, we further argue how the appearance of the metallic behaviour in the mosaic phase can be explained by local stacking differences of the top two layers induced by the large number of domain walls. Thus, we provide a potential avenue to explain the origin of the pulse induced mosaic phase.Comment: 10 pages, 8 figures, under review at npj Quantum Material

Hydrophobic Hydration of the Hydrocarbon Adamantane in Amorphous Ice

Hydrophobic molecules are by definition difficult to hydrate. Previous studies in the area of hydrophobic hydration have therefore often relied on using amphiphilic molecules where the hydrophilic part of a molecule enabled the solubility in liquid water. Here we show that the hydrophobic adamantane (C10H16) molecule can be fully hydrated through vapour codeposition with water onto a cryogenic substrate at 80 K resulting in the matrix isolation of adamantane in amorphous ice. Using neutron diffraction in combination with the isotopic substitution method and the empirical potential structure refinement technique, we find that the first hydration shell of adamantane is well structured consisting of a hydrogen-bonded cage of 28 water molecules that is also found in cubic structure II clathrate hydrates. The four hexagonal faces of the 51264 cage are situated above the four methine (CH) groups of adamantane whereas the methylene (CH2) groups are positioned below the edges of two adjoining pentagonal faces. The oxygen atoms of the 28 water molecules can be categorised on the basis of symmetry equivalences as twelve A, twelve B and four C oxygens. The water molecules of the first hydration shell display orientations consistent with those expected for a clathrate-hydrate-type cage, but also unfavourable ones with respect to the hydrogen bonding between the water molecules. Annealing the samples at 140 K, which is just below the crystallisation temperature of the matrix, removes the unfavourable orientations and leads to a slight increase of the structural order of the first hydration shell. The very closest water molecules display a tendency for their dipole moments to point towards the adamantane which is attributed to steric effects. Other than this, no significant polarisation effects are observed which is consistent with weak interactions between adamantane and the amorphous ice matrix. FT-IR spectroscopy shows that the incorporation of adamantane into amorphous ice leads to a weakening of the hydrogen bonds. In summary, the matrix-isolation of the highly symmetric adamantane in amorphous ice provides an interesting test case for hydrophobic hydration. Studying the structure and spectroscopic properties of water at the interface with hydrophobic hydrocarbons is also relevant for astrophysical environments, such as comets or the interstellar medium, where amorphous ice and hydrocarbons have been shown to coexist in large quantities

Subgrid-scale variability of cloud ice in the ICON-AES 1.3.00

This paper presents a stochastic approach for the aggregation process rate in the ICOsahedral Nonhydrostatic general circulation model (ICON-AES), which takes subgrid-scale variability into account. This method creates a stochastic parameterization of the process rate by choosing a new specific cloud ice mass at random from a uniform distribution function. This distribution, which is consistent with the model's cloud cover scheme, is evaluated in terms of cloud ice mass variance with a combined satellite retrieval product (DARDAR) from the satellite cloud radar CloudSat and the Cloud–Aerosol Lidar and Infrared Pathfinder Observations (CALIPSO). The global patterns of simulated and observed cloud ice mixing ratio variance are in a good agreement, despite an underestimation in the tropical regions, especially at lower altitudes, and an overestimation in higher latitudes from the modeled variance. Due to this stochastic approach the yearly mean of cloud ice shows an overall decrease. As a result of the nonlinear nature of the aggregation process, the yearly mean of the process rates increases when taking subgrid-scale variability into account. An increased process rate leads to a stronger transformation of cloud ice into snow and therefore to a cloud ice loss. The yearly averaged global mean aggregation rate is more than 20 % higher at selected pressure levels due to the stochastic approach. A strong interaction of aggregation and accretion, however, lowers the effect of cloud ice loss due to a higher aggregation rate. The new stochastic method presented lowers the bias of the aggregation rate.</p