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Background:Intra-articular injection of hyaluronan (HA) has been suggested to have a disease-modifying effect in osteoarthritis, but little is known about the possible mechanisms.Objective:To investigate the effects of HA species of different molecular mass, including 800 kDa (HA800) and 2700 kDa (HA2700), on the expression of aggrecanases (ie, ADAMTS species), which play a key role in aggrecan degradation.Methods:The effects of HA species on the expression of ADAMTS1, 4, 5, 8, 9 and 15 in interleukin 1α (IL1α)-stimulated osteoarthritic chondrocytes were studied by reverse transcription PCR and real-time PCR. Expression of ADAMTS4 protein and aggrecanase activity and signal transduction pathways of IL1, CD44 and intracellular adhesion molecule 1 (ICAM1) were examined by immunoblotting.Results:IL1α treatment of chondrocytes induced ADAMTS4, and HA800 and HA2700 significantly decreased IL1α-induced expression of ADAMTS4 mRNA and protein. IL1α-stimulated aggrecanase activity in osteoarthritic chondrocytes was reduced by treatment with HA2700 or transfection of small interfering RNA for ADAMTS4. A similar result was obtained when HA2700 was added to explant cultures of osteoarthritic cartilage. HA2700 neither directly inhibited nor bound to ADAMTS4. Downregulation of ADAMTS4 expression by HA2700 was attenuated by treatment of IL1α-treated chondrocytes with antibodies to CD44 and/or ICAM1. The increased phosphorylation of IL1 receptor-associated kinase-1 and extracellular signal-regulated protein kinase1/2 induced by the IL1α treatment was downregulated by enhanced IRAK-M expression after HA2700 treatment.Conclusion:These data suggest that HA2700 suppresses aggrecan degradation by downregulating IL1α-induced ADAMTS4 expression through the CD44 and ICAM1 signalling pathways in osteoarthritic chondrocytes.

In 2008, Nuclear and Industrial Safety Agency (NISA) (currently integrated to the Nuclear Regulatory Authority) launched a project to develop a soundness assessment method for concrete members subject to a radiation environment. Presently, the soundness of concrete members subject to radiation is evaluated based on whether the predicted fast neutron fluence and gamma-ray dose values are lower than specific reference values in Japan, which are 1×10 20 n/cm 2 and 2×10 5 kGy, respectively. These reference values were determined based on report by Hilsdorf et al. This project begins by reviewing Hilsdorf et al.'s report, and we find that the scientific evidence for the current reference values is weak. We thus conclude that new experimental research is required to assess the current reference values and to propose a new alternative soundness assessment procedure if needed. We quantitatively evaluated the influence of neutrons, gammarays, and the resultant heating and drying processes on the strength of concrete as well as their underlying mechanisms. The irradiation experiments confirmed the degradation mechanism of concrete due to neutron irradiation. The main reason for this degradation is the metamictization of rock-forming minerals, which, in turn, leads to aggregate expansion. Due to aggregate expansion, cracks around aggregates form, which reduce the compressive strength and Young's modulus of concrete. Among the rock-forming minerals, α-quartz is the most sensitive to neutron radiation.60 Co gamma-ray irradiation experiments demonstrated that concrete strength increased as the gamma-ray dose and gammaray flux does not have a dose-rate impact on the first radiolysis of evaporable water in cement paste within the present study. The effect of gamma-ray irradiation on the properties of concrete is equivalent to that of heating and drying. Concrete strength alteration due to heating and drying is attributed to the colloidal and porous nature of hardened cement paste and crack formation around the aggregate due to a mismatch in the volume changes of the mortar and aggregate. In addition, a numerical analysis code called DEVICE (Damage EValuation for Irradiated ConcretE) is developed to harness knowledge obtained from concrete samples to predict the distribution of the physical properties in concrete members and their changes over time. From these fundamental studies, we propose a new soundness assessment procedure for concrete members subject to radiation. We also recommend a new radiation-induced strength-degradation reference value of 1×10 19 n/cm 2 for fast neutron.

Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project.