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Despite pathophysiological similarities to alcoholic liver disease, susceptibility to acetaminophen hepatotoxicity in metabolic syndrome-related nonalcoholic steatohepatitis (NASH) has not been well elucidated. In this study, therefore, we investigated acetaminophen-induced liver injury in KK-[A.sup.y] mice, an animal model of metabolic syndrome. Twelve-week-old male KK-[A.sup.y] and C57B1/6 mice were injected intraperitoneally with 300 or 600 mg/kg acetaminophen, and euthanized 6 h later. Liver histology was assessed, and hepatic expression of 4-hydroxy-2-nonenal was detected by immunohistochemistry. Levels of reduced glutathione were determined spectrophotometrically. Phosphorylation of c-Jun N[H.sub.2]-terminal kinase (JNK) was analyzed by Western blotting. Hepatocytes were isolated from both strains by collagenase perfusion, and cell death and oxidative stress were measured fluorometrically by use of propidium iodide and 5-(and-6)-chloromethyl-2'7'-dichlorodihydrofluorescein diacetate acetyl ester, respectively. Acetaminophen induced more severe necrosis and apoptosis of hepatocytes in KK-[A.sup.y] mice than in C57B1/6 mice and significantly increased serum alanine aminotransferase levels in KK-[A.sup.y] mice. Acetaminophen-induction of 4-hydroxy-2-nonenal in the liver was potentiated, whereas the levels of reduced glutathione in liver were lower in KK-[A.sup.y] mice. Acetaminophen-induced phosphorylation of JNK in the liver was also enhanced in KK-[A.sup.y] mice. Exposure to 20 [micro]M tert-butyl hydroperoxide did not kill hepatocytes isolated from C57B1/6 mice but induced cell death and higher oxidative stress in hepatocytes from KK-[A.sup.y] mice. These results demonstrated that acetaminophen toxicity is increased in diabetic KK-[A.sup.y] mice mainly due to enhanced oxidative stress in hepatocytes, suggesting that metabolic syndrome-related steatohepatitis is an exacerbating factor for acetaminophen-induced liver injury. drug-induced liver injury; metabolic syndrome; steatohepatitis; oxidative stress; hepatotoxicity doi: 10.1152/ajpgi.00361.2009.

TGF-[beta]--activated kinase 1 (TAK1) is a MAP3K family member that activates NF-[kappa]B and JNK via Toll-like receptors and the receptors for IL-1, TNF-[alpha], and TGF-[beta]. Because the TAK1 downstream molecules NF-[kappa]B and JNK have opposite effects on cell death and carcinogenesis, the role of TAK1 in the liver is unpredictable. To address this issue, we generated hepatocyte-specific Tak1-deficient (Tak1[DELTA]HEP) mice. The Tak1[DELTA]HEP mice displayed spontaneous hepatocyte death, compensatory proliferation, inflammatory cell infiltration, and perisinusoidal fibrosis at age 1 month. Older Tak1[DELTA]HEP mice developed multiple cancer nodules characterized by increased expression of fetal liver genes including [alpha]-fetoprotein. Cultures of primary hepatocytes deficient in Tak1 exhibited spontaneous cell death that was further increased in response to TNF-[alpha]. TNF-[alpha] increased caspase-3 activity but activated neither NF-[kappa] nor JNK in Tak1-deficient hepatocytes. Genetic abrogation of TNF receptor type I (TNFRI) in Tak1[DELTA]HEP mice reduced liver damage, inflammation, and fibrosis compared with unmodified Tak1[DELTA]HEP mice. In conclusion, hepatocyte-specific deletion of TAK1 in mice resulted in spontaneous hepatocyte death, inflammation, fibrosis, and carcinogenesis that was partially mediated by TNFR signaling, indicating that TAK1 is an essential component for cellular homeostasis in the liver. apoptosis | JNK | liver cancer | NF-[kappa]B | TNF-[alpha] www.pnas.org/cgi/doi/10.1073/pnas.0909781107

Chronic cholestasis often results in premature death from liver failure with fibrosis; however, the molecular mechanisms contributing to biliary cirrhosis are not demonstrated. In this article, we show that the death signal mediated by TNF-related apoptosisinducing ligand (TRAIL) receptor 2/death receptor 5 (DRS) may be a key regulator of cholestatic liver injury. Agonistic anti-DR5 monoclonal antibody treatment triggered cholangiocyte apoptosis, and subsequently induced cholangitis and cholestatic liver injury in a mouse strain-specific manner. TRAIL- or DR5-deficient mice were relatively resistant to common bile duct ligation-induced cholestasis, and common bile duct ligation augmented DR5 expression on cholangiocytes, sensitizing mice to DR5-mediated cholangitis. Notably, anti-DR5 monoclonal antibody-induced cholangitis exhibited the typical histological appearance, reminiscent of human primary sclerosing cholangitis. Human cholangiocytes constitutively expressed DR5, and TRAIL expression and apoptosis were significantly elevated in cholangiocytes of human primary sclerosing cholangitis and primary biliary cirrhosis patients. Thus, TRAIL/ DR5-mediated apoptosis may substantially contribute to chronic cholestatic disease, particularly primary sclerosing cholangitis. cholangitis | primary sclerosing cholangitis

The study report of the impact of polarity of gate bias and Hf concentration on HfSiON/Si[O.sub.2] gate dielectric breakdown (DB) with time-zero DB (TZDB) and time-dependent DB (TDDB) is presented.

The article analyzed the gate depletion in poly-Si/HfSiON stacks by the C-V differentiation analysis.

Byline: Tomoko Itao (1), Satoshi Tanaka (1), Tatsuya Suda (2), Tomonori Aoyama (3) Keywords: ubiquitous computing; mobile agent; relationship; user preferences; service emergence Abstract: The Jack-in-the-Net Architecture (Ja-Net) that we present in this paper provides a unique and promising approach to design ubiquitous computing applications that can scale, self-organize, and adapt to short- and long-term changes in network conditions and user preferences. In Ja-Net, network applications are implemented by a group of distributed, autonomous entities called the cyber-entities. Each cyber-entity implements a function component related to its service and follows simple behavior rules (such as migration, replication, energy exchange, death, and relationship establishment with other cyber-entities). They form organizations or communities by establishing and learning useful relationships with a number of other cyber-entities and collectively provide higher level services through interactions among them. Consequently, desirable services and characteristics emerge in network applications through autonomous and self-organizing interactions among cyber-entities (service emergence). In this paper, we discuss the design and implementation of Ja-Net platform software that achieves dynamic and adaptive provision of network applications through service emergence. We also built an application for Ja-Net that features service emergence and we empirically verified that the application can adapt itself to user preferences. Author Affiliation: (1) NTT Network Innovation Laboratories, 3-9-11 Midori-cho, Musashino-shi, Tokyo, 180-8585, Japan (2) Department of Information and Computer Science, University of California, Irvine, CA, 92697-3425, USA (3) Department of Information and Communication Engineering, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8656, Japan Article History: Registration Date: 03/10/2004

The influences of nitrogen on the change of effective work function with impurity segregation is elucidated by examining the effective work function at arsenic (As) and boron (B) segregated NiSi/Si[O.sub.2] and NiSi/SiON interfaces. The studies have shown that the precise control of B configuration, meaning low B concentration in SiON as well as high concentration at the NiSi/SiON interface, is needed for larger positive effective work function modulation in NiSi/SiON system.