Abstract Characteristics of deformation and alteration of the 1140 m deep fracture zone of the Nojima Fault are described based on mesoscopic (to the naked eye) and microscopic (by both optical and scanning electron microscopes) observations of the Hirabayashi National Research Institute for Earth Science and Disaster Prevention (NIED) drill core. Three types of fault rocks; that is, fault breccia, fault gouge and cataclasite, appear in the central part of the fault zone and two types of weakly deformed and/or altered rocks; that is, weakly deformed and altered granodiorite and altered granodiorite, are located in the outside of the central part of the fault zone (damaged zone). Cataclasite appears occasionally in the damaged zone. Six distinct, thin foliated fault gouge zones, which dip to the south‐east, appear clearly in the very central part of the fracture zone. Slickenlines plunging to the north‐east are observed on the surface of the newest gouge. Based on the observations of XZ thin sections, these slickenlines and the newest gouge have the same kinematics as the 1995 Hyogo‐ken Nanbu earthquake (Kobe earthquake), which was dextral‐reverse slip. Scanning electron microscopy observations of the freeze‐dried fault gouge show that a large amount of void space is maintained locally, which might play an important role as a path for fluid migration and the existence of either heterogeneity of pore fluid pressure or strain localization.
The serine/threonine protein phosphatase (PP) 2A inhibitor, microcystin-LR, selectively induces liver damage and promotes hepatocarcinogenesis. It is thought that microcystin-LR affects hepatocellular viability mainly through inhibition of PP2A, partially through PP1, and, in addition, by generation of reactive oxygen species (ROS). However, the molecular basis of the selective liver damage and the balance between cell death and survival remained unclear. We analyzed the cytotoxicity of low doses of microcystin-LR using HEK293 cells stably expressing the human hepatocyte uptake transporters, organic anion transporting polypeptide (OATP)1B1 (HEK293-OATP1B1 cells) and OATP1B3 (HEK293-OATP1B3 cells). HEK293-OATP1B1 (IC50 6.6nM) and HEK293-OATP1B3 cells (IC50 6.5nM) were equally very sensitive to microcystin-LR. In contrast, control-vector–transfected (HEK293-CV) cells were resistant to microcystin-LR. Using HEK293-OATP1B3 cells, the cytotoxicity was attenuated by substrates and inhibitors of OATP1B3, including bromosulfophthalein, rifampicin, and cyclosporin A. Microcystin-LR was transported into HEK293-OATP1B3 cells with 1.2μM Km value, and its uptake was inhibited by above substances. Accumulation of microcystin-LR in the HEK293-OATP1B1 and HEK293-OATP1B3 cells was increased in a dose-dependent manner but not in HEK293-CV cells. Cellular serine/threonine PP activity of HEK293-OATP1B3 cells was decreased by microcystin-LR but not in HEK293-CV cells. Apoptotic changes were observed after incubation of the HEK293-OATP1B3 cells with microcystin-LR. We found by FACS analysis that microcystin-LR induced apoptosis but not necrosis in HEK293-OATP1B3 cells. Microcystin-LR activated several mitogen-activated protein kinases (MAPKs) including ERK1/2, JNK, and p38 through inhibition of PP2A. In addition, the cytotoxicity of microcystin-LR was attenuated by the inhibitors of MAPK pathways, including U0126, SP600125, and SB203580. The ROS scavenger N-acetyl-L-cysteine partially attenuated the cytotoxicity of microcystin-LR. Thus, the present study demonstrates that microcystin-LR induces apoptosis through activation of multiple MAPK pathways subsequent to its selective uptake via OATP1B1 and OATP1B3 and followed by inhibition of PP2A, in addition to the ROS generation which might contribute to apoptosis.
Thymidine phosphorylase (TP) is a rate-limiting enzyme in the thymidine catabolic pathway. TP is identical to platelet-derived endothelial cell growth factor and contributes to tumour angiogenesis. TP induces the generation of reactive oxygen species (ROS) and enhances the expression of oxidative stress-responsive genes, such as interleukin (IL)-8. However, the mechanism underlying ROS induction by TP remains unclear. In the present study, we demonstrated that TP promotes NADPH oxidase-derived ROS signalling in cancer cells. NADPH oxidase inhibition using apocynin or small interfering RNAs (siRNAs) abrogated the induction of IL-8 and ROS in TP-expressing cancer cells. Meanwhile, thymidine catabolism induced by TP increased the levels of NADPH and intermediates of the pentose phosphate pathway (PPP). Both siRNA knockdown of glucose 6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme in PPP, and a G6PD inhibitor, dihydroepiandrosterone, reduced TP-induced ROS production. siRNA downregulation of 2-deoxy-D-ribose 5-phosphate (DR5P) aldolase, which is needed for DR5P to enter glycolysis, also suppressed the induction of NADPH and IL-8 in TP-expressing cells. These results suggested that TP-mediated thymidine catabolism increases the intracellular NADPH level via the PPP, which enhances the production of ROS by NADPH oxidase and activates its downstream signalling.
Abstract In situ stress was measured close to the fault associated with the 1995 Kobe Earthquake (Hyogo‐ken Nanbu earthquake; January 1995; M 7.2) using the hydraulic fracturing method. The measurements were made approximately 2 years after the earthquake. The measured points were approximately 40 m from the fault plane at depths of about 1500 m. The maximum and the minimum horizontal compressive stresses were 45 MPa and 31 MPa, respectively. The maximum compressive stress and the maximum shear stress are very small in comparison with those of other seismically active areas. The azimuth of the maximum horizontal compressive stress was estimated from the observed azimuths of well bore breakouts at depths between 1400 m and 1600 m and was found to be N135° (clockwise). The maximum stress axis is perpendicular to the fault strike, N45°. These features are interpreted in terms of a small frictional coefficient of the fault. The shear stress on the fault was released and dropped almost to zero during the earthquake and it has not yet recovered. Zero shear stress on the fault plane resulted from the perpendicular orientation of one of the principal stress to the fault plane.
