Oxidative stress has been indicated in a variety of pathological processes such as atherosclerosis, diabetes, and neurodegenerative diseases. Understanding how intracellular signaling pathways respond to oxidative insults such as hydrogen peroxide (H 2 O 2 ) would have significant therapeutic implications. Recent genetic studies have placed apoptosis signal-regulating kinase 1 (ASK1) in a pivotal position in transmitting H 2 O 2 -initiated signals. How ASK1 is activated by H 2 O 2 , though, remains a subject of intense investigation. Here we report a mechanism by which H 2 O 2 induces ASK1 activation through dynamic control of its phosphorylation at serine 967. We found that treatment of COS7 cells with H 2 O 2 triggers dephosphorylation of Ser-967 through an okadaic acid-sensitive phosphatase, resulting in dissociation of the ASK1⅐14-3-3 complex with concomitant increase of ASK1 catalytic activity and ASK1-mediated activation of JNK and p38 pathways.

Members of the regulators of G protein signaling (RGS) family modulate Ga-directed signals as a result of the GTPaseactivating protein (GAP) activity of their conserved RGS domain. In addition to its RGS domain, RGS14 contains a Rap binding domain (RBD) and a GoLoco motif. To de®ne the cellular and biochemical properties of RGS14 we utilized two different af®nity puri®ed antisera that speci®cally recognize recombinant and native RGS14. In brain, we observed two RGS14-like immunoreactive bands of distinct size (60 kDa and 55 kDa). Both forms are present in brain cytosol and in two, biochemically distinct, membrane subpopulations: one detergent-extractable and the other detergent-insensitive. Recombinant RGS14 binds speci®cally to activated Ga i/o , but not Ga q/11 , Ga 12/13 , or Ga s in brain membranes. In reconstitution studies, we found that RGS14 is a non-selective GAP for Ga i1 and Ga o and that full-length RGS14 is an approximately 10-fold more potent stimulator of Ga GTPase activity than the RGS domain alone. In contrast, neither fulllength RGS14 nor the isolated RBD domain is a GAP for Rap1. RGS14 is also a highly selective guanine nucleotide dissociation inhibitor (GDI) for Ga i but not Ga o , and this activity is restricted to the C-terminus containing the GoLoco domain. These ®ndings highlight previously unknown biochemical properties of RGS14 in brain, and provide one of the ®rst examples of an RGS protein that is a bifunctional regulator of Ga actions.

Orf virus is a parapoxvirus that infects small ruminants worldwide. We present the case report of a 73-year-old woman with non-Hodgkins lymphoma who developed progressive orf virus lesions that were unresponsive to surgical debridement and to cidofovir therapy. The patient's orf virus infection was successfully treated with topical imiquimod despite progression of her malignancy.

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