Approximately 40% of patients with diabetic macular edema (DME) are resistant to anti-vascular endothelial growth factor (VEGF) therapy (rDME). Here, we demonstrate that significant correlations between inflammatory cytokines and VEGF, as observed in naive DME, are lost in patients with rDME. VEGF overexpression in the mouse retina caused delayed inflammatory cytokine upregulation, monocyte/macrophage infiltration (CD11b 1 Ly6C 1 CCR2 1 cells), macrophage/microglia activation (CD11b 1 CD80 1 cells), and blood-retinal barrier disruption due to claudin-5 redistribution, which did not recover with VEGF blockade alone. Phosphorylated protein analysis of VEGFoverexpressed retinas revealed rho-associated coiled-coilcontaining protein kinase (ROCK) activation. Administration of ripasudil, a selective ROCK inhibitor, attenuated retinal inflammation and claudin-5 redistribution. Ripasudil also contributed to the stability of claudin-5 expression by both transcriptional enhancement and degradation suppression in inflammatory cytokine-stimulated endothelium. Notably, the anti-VEGF agent and the ROCK inhibitor were synergic in suppressing cytokine upregulation, monocyte/macrophage infiltration, macrophage/microglia activation, and claudin-5 redistribution. Furthermore, in vitro analysis confirmed that claudin-5 redistribution depends on ROCK2 but not on ROCK1. This synergistic effect was also confirmed in human rDME cases. Our results suggest that ROCKmediated claudin-5 redistribution by inflammation is a key mechanism in the anti-VEGF resistance of DME.
Spatial isolation of molecules is a powerful strategy for regulating their molecular behavior, but its application has been limited to small molecules. Here, we accurately encapsulated a single molecule of a plastic-degradation enzyme within a synthetic molecular cage and demonstrated that the caged enzyme showed exceptional stability (>1,0003) in organic solvent, as well as stability toward heat and denaturing agents. Most important, we hypothesized that the stabilization was derived from a protein-refolding effect of the cage and directly proved it with reliable spectroscopic analyses.
Fe-25mass%Cr-1.1mass%N alloys with different impurity content were produced by solution nitriding and then subjected to tensile tests at ambient temperature. Yield strength and tensile strength of the alloys are much higher than those of conventional austenitic stainless steels, but the brittle intergranular fracture is caused during uniform deformation without local elongation. It was confirmed that the intergranular fracture takes place at high angle random boundary and that the grain boundary segregation of impurities significantly promotes intergranular fracture. Deformation-induced martensite did not concern the intergranular fracture. In addition, it was suggested that marked stress concentration is caused at grain boundary by the piled-up dislocations in planar array and it would be one of the important factors inducing intergranular fracture.KEY WORDS: high nitrogen steel; austenite; intergranular fracture; grain boundary segregation; impurity; deformation-induced martensite; planar dislocation array; dislocation pile-up; stress concentration. 861© 2008 ISIJ † Throughout this article, the chemical composition is expressed in mass percent, unless otherwise stated.it was reported that a Fe-Cr-Mn-N system austenitic stainless steels produced by the high-pressurized melting exhibit a sufficient ductility with local elongation.11) Although the difference between both cases has not been clarified yet, it is possible that the fracture mode might depend on the susceptibility of deformation-induced martensitic transformation, marked grain coarsening and grain boundary segregation of impurities in the case of solution-nitrided austenitic steels.In this study, two kinds of nickel-free high nitrogen austenitic stainless steel (Fe-25Cr-1N alloy) with different impurity content were produced by solution nitriding, and then the mechanical properties were investigated by means of tensile testing. The contribution of deformation-induced martensite, stress concentration at grain boundary caused by the piled-up dislocations in planar array and grain boundary segregation of impurity was then discussed for clarifying the mechanism of the occurrence of intergranular fracture. Experimental ProcedureAs the base materials for solution nitriding, two kinds of ferritic stainless steel (Fe-25Cr alloy) with different impurity content were prepared in this study. The chemical compositions of these steels are listed in Table 1. The low purity steel, Fe-25Cr-LP, contains phosphorus of 270 ppm and sulfur of 32 ppm, while the high purity steel, Fe-25Cr-HP, contains less phosphorus and sulfur contents, which are below 50 ppm and 4 ppm, respectively. The ingots (50 kg) were produced by induction melting in a vacuum and then casting into metallic molds. The ingots were homogenized by annealing at 1 473 K and then followed by hot forging to make bars of 50 mm in diameter. The specimens cut from the hot-forged bars (40 mmϫ15 mmϫ1 mm) were wet-polished and then electrically polished with a solution of phosphoric acid and chromic oxide (H 3 PO ...
A 2-biphenylacetylene was fixed into a specific conformation within the confined cavity of a hollow cage, where it underwent a regioselective spirocyclization in the presence of an electrophile. A 5-endo-dig cyclization proceeded selectively in the cage, which stands in sharp contrast to the 6-endo-dig cyclization that normally occurs in common organic media. The folded conformation adopted by the substrate within the cage was examined by 1 H NMR spectroscopy and X-ray crystallographic analysis.
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