Dystrophin is a cytoskeletal protein found at the inner surface of skeletal and cardiac muscle fibers. We hypothesize that deficiency of dystrophin increases muscle compliance and causes an aberrant mechanotransduction in muscle fibers. To test this hypothesis, we measured the length-tension relationships and determined intracellular signaling leading to the activation of mitogen-activated protein (MAP) kinases in diaphragm muscle fibers from dystrophin-deficient mdx mice. Compared with controls, length-tension curves of the mdx mice were shifted to the right. A higher level of activation of extracellular signal-regulated kinase 1/2 (ERK1/2) but not c-Jun N-terminal kinase-1 or p38 MAP kinase was observed in the mdx muscle compared with the normal muscle in response to mechanical stretch. Removal of Ca2+ from the medium inhibited stretch-induced ERK1/2 activation only in mdx muscle fibers but not in the normal fibers. Conversely, pretreatment with TMB-8 (an antagonist of intracellular Ca2+ blocked the mechanical stretch-induced ERK1/2 activation in normal but not in mdx muscle fibers. Pretreatment of muscle with nifedipine (L-type calcium channel antagonist) marginally decreased the activation of ERK1/2 in normal or mdx muscle whereas pretreatment with gadolinium (III) chloride (an inhibitor of stretch-activated channels) only blocked the activation of ERK1/2 in mdx muscle, with no significant effect on normal muscle. A higher basal level of activation of activator protein-1 (AP-1) transcription factor was observed in dystrophin-deficient diaphragm, which was further augmented by mechanical stretch. Mechanical stretch-induced activation of AP-1 was decreased by pretreatment of muscle fibers with PD98059 (ERK1/2 inhibitor) and removal of Ca2+ ions from incubation medium. Our results show that dystrophin is a load-bearing element and its deficiency leads to loss of muscle stiffness and aberrant mechanotransduction in skeletal muscle fibers.

Viruses are obligate intracellular parasites; they heavily depend on the host cell machinery to effectively replicate and produce new progeny virus particles. Following viral infection, diverse cell signaling pathways are initiated by the cells, with the major goal of establishing an antiviral state. However, viruses have been shown to exploit cellular signaling pathways for their own effective replication. Genome-wide siRNA screens have also identified numerous host factors that either support (proviral) or inhibit (antiviral) virus replication. Some of the host factors might be dispensable for the host but may be critical for virus replication; therefore such cellular factors may serve as targets for development of antiviral therapeutics. Mitogen activated protein kinase (MAPK) is a major cell signaling pathway that is known to be activated by diverse group of viruses. MAPK interacting kinase 1 (MNK1) has been shown to regulate both cap-dependent and internal ribosomal entry sites (IRES)-mediated mRNA translation. In this review we have discuss the role of MAPK in virus replication, particularly the role of MNK1 in replication and translation of viral genome.

Background Despite extensive investigation, the cause of liver injury in 14% of acute liver failure patients remains unknown (indeterminate). In a pilot study, using a novel assay, highly specific acetaminophen-cysteine adducts were detected in 7 of 36 (19%) indeterminate patients. Methods To extend these observations, sera from 110 subjects enrolled in the Acute Liver Failure Study Group registry with indeterminate acute liver failure were analyzed using a similar but more efficient and sensitive adduct assay. As positive controls, an additional 199 patients with known or presumed acetaminophen-induced liver failure were assessed for the presence and quantity of adducts. Clinical, laboratory and outcome data were compared for the two groups. Results Based on previous data from known therapeutic exposures and acetaminophen overdoses, an adduct concentration of ≥1.0 nmol/mL serum indicated a definite acetaminophen overdose. Among the 110 indeterminate cases, 18% had assay values ≥1.0, with a median level of 9.2 nmol/mL; 94.5 % of the positive control (known APAP) cases had values ≥1.0 nmol/mL. Regardless of initial diagnosis, subjects with elevated adduct levels demonstrated the clinical profile and hyperacute biochemical injury pattern associated with acetaminophen overdose: predominance of female gender, very high aminotransferase levels and low bilirubin levels. Conclusions These data confirm and extend previous observations regarding the high (18%) prevalence of unrecognized or uncertain acetaminophen toxicity among subjects with indeterminate acute liver failure. N-acetylcysteine use was limited in this group, presumably because of the lack of a specific diagnosis of acetaminophen toxicity.

No abstract