Description: We have performed 2D and 3D gas hydrate (GH) petroleum systems modeling for the Pleistocene turbiditic sedimentary sequences distributed in the Daini-Atsumi area in the eastern Nankai Trough to understand the accumulation mechanisms and their spatial distribution related to geologic and geochemical processes. High-resolution seismic facies analysis and interpretations were used to define facies distributions in the models. We have created a new biogenic methane generation model based on the biomarker analysis using core samples and incorporated it into our model. Our 2D models were built and simulated to confirm the parameters to be used for 3D modeling. Global sea level changes and paleogeometry estimated from 3D structural restoration results were taken into account to determine the paleowater depth of the deposited sedimentary sequences. Pressure and temperature distributions were modeled because they are the basic factors that control the GH stability zone. Our 2D modeling results suggested that the setting of biogenic methane generation depth is one of the most important controlling factors for GH accumulation in the Nankai Trough, which may be related to the timing of methane upward migration (expulsion) and methane solution process in pore water. Our 3D modeling results suggested that the distribution of sandy sediments and the formation dip direction are important controlling factors in the accumulation of GHs. We also found that the simulated amount of GH accumulation from the petroleum systems modeling compares well with independent estimations using 3D seismic and well data. This suggests that the model constructed in this study is valid for this GH system evaluation and that this type of evaluation can be useful as a supplemental approach to resource assessment.

Description: Mitogen-activated protein kinase (MAPK) signaling in the liver occurs in response to physical and chemical stress, including alterations in nutrients, growth factors, cytokines, extracellular matrix, DNA damage, drugs and toxins. This signaling pathway plays a role in liver injury and diseases such as drug induced hepatotoxicity, viral hepatitis, infection and inflammation, NAFLD, NASH, ALD, ischemia/reperfusion, fibrosis, regeneration, and carcinogenesis (1-4). In mammals, three major groups of MAPK have been identified. Each of these groups of MAPK is activated by a protein kinase cascade. MAPK signaling cascades consist of at least three components, or tiers: MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK. The groups are named according to their executing downstream MAPK, such as the extracellular signal-regulated kinase (ERK), the p38 kinase, and the c-Jun N-terminal kinase (JNK) families. In the liver, JNK is a dominant effector MAPK which catalyzes the phosphorylation of numerous substrate proteins including nuclear AP1 transcription factors (c-Jun, etc) as well as protein kinases and phosphatases, scaffold proteins, and other functional proteins (4, 5). JNK activation and substrate phosphorylation has two major direct consequences: regulation of gene expression through AP1 transcription factors and direct activation or inhibition of protein targets (Fig.1). The liver expresses both JNK1 and JNK2. In this review we will focus on recent studies from many different laboratories in the past 5 years which have improved our understanding of the role of JNK signaling pathway in the pathogenesis of liver diseases and promise to lead to exciting therapeutic applications. Because of the broad nature of this subject, we have selected specific areas which illustrate the important recent conceptual advances. This article is protected by copyright. All rights reserved.

Description: Sustained JNK activation has been implicated in many models of cell death and tissue injury. P-JNK interacts with the mitochondrial outer membrane protein, Sab (SH3BP5). Using knockdown or liver specific deletion of Sab we aimed to elucidate the consequences of this interaction on mitochondrial function in isolated mitochondria and liver injury models in vivo. Respiration in isolated mitochondria was directly inhibited by P-JNK+ATP. Knockdown or liver specific knockout of Sab abrogated this effect and markedly inhibited sustained JNK activation and liver injury from acetaminophen (APAP) or TNF/galactosamine. We then elucidated an intramitochondrial pathway in which interaction of JNK and Sab on the outside of the mitochondria released SHP1 (PTPN6) from Sab in the inside of the mitochondrial outer membrane leading to its activation and transfer to the inner membrane where it dephosphorylates P-Y419Src (active) which required a platform protein, DOK4, on the inner membrane. Knockdown of mitochondrial DOK4 or SHP1 inhibited the inactivation of mitochondrial P-Src and the effect of P-JNK on mitochondria. Conclusions; the binding to and phosphorylation of Sab by P-JNK on the outer mitochondrial membrane leads to SHP1 and DOK4 dependent inactivation of P-Src on the inner membrane. Inactivation of mitochondrial Src inhibits electron transport and increases ROS release, which sustains JNK activation and promotes cell death and organ injury. This article is protected by copyright. All rights reserved.