Immediate-early protein ICP0 of herpes simplex virus type 1 (HSV-1) is an E3 ubiquitin ligase of the RING finger class that is required for efficient lytic infection and reactivation from latency. Other alphaherpesviruses also express ICP0-related RING finger proteins, but these have limited homology outside the core RING domain. Existing evidence indicates that ICP0 family members have similar properties, but there has been no systematic comparison of the biochemical activities and biological functions of these proteins. Here, we describe an inducible cell line system that allows expression of the ICP0-related proteins of bovine herpes virus type 1 (BHV-1), equine herpesvirus type 1 (EHV-1), pseudorabies virus (PRV), and varicella-zoster virus (VZV) and their subsequent functional analysis. We report that the RING domains of all the proteins have E3 ubiquitin ligase activity in vitro. The BHV-1, EHV-1, and PRV proteins complement ICP0-null mutant HSV-1 plaque formation and induce derepression of quiescent HSV-1 genomes to levels similar to those achieved by ICP0 itself. VICP0, the ICP0 expressed by VZV, was found to be extremely unstable, which limited its analysis in this system. We compared the abilities of the ICP0-related proteins to disrupt ND10, to induce degradation of PML and Sp100, to affect key components of the interferon signaling pathway, and to interfere with induction of interferon-stimulated genes. We found that the property that correlated most closely with their biological activities was the ability to preclude the recruitment of cellular ND10 proteins to sites closely associated with incoming HSV-1 genomes and early replication compartments.The members of the alphaherpesvirus subfamily are characterized by their ability to establish life-long latent infections in neuronal tissues after the primary infection. Although certain core genes are conserved in all herpesviruses of all subfamilies, there are also genes that are characteristic of particular subfamilies. Among these are the genes that encode the ICP0-related proteins of the alphaherpesviruses, of which the most widely studied is ICP0 of herpes simplex virus type 1 (HSV-1). The interest in ICP0 stems from its biological roles in stimulating lytic infection and reactivation from latency (for reviews, see references 17, 18 and 33). Members of the ICP0 family of proteins are characterized by the presence of a RING finger domain near their N termini, a zinc-stabilized fold that in many other proteins confers E3 ubiquitin ligase activity (43). This has proved to be true of ICP0 (3), and the available evidence indicates that other members of the ICP0 family have similar biochemical functions (13, 61). Although a number of ICP0-related alphaherpesvirus proteins have been studied in a variety of contexts, notably those expressed by bovine herpesvirus 1 (BHV-1), equine herpes virus 1 (EHV-1), pseudorabies virus (PRV), and varicella-zoster virus (VZV), there has been no systematic comparison of their abilities to complement ICP0 null mutant HSV-1 ...

Harpagophytum procumbens (Hp), commonly known as Devil's Claw is a perennial plant which thrives in arid conditions. For centuries, it has been used as a traditional treatment for a variety of illnesses, including fevers, skin complaints, arthritis and diseases of the digestive tract as well as an appetite stimulant. Since its introduction to Europe in the early twentieth century, it has become a popular antiinflammatory and analgesic preparation amongst herbalists for supportive or adjuvant treatment of degenerative joint diseases, tendonitis, headache, backache and menstrual pain. The validity of Hp as an effective antiinflammatory and analgesic preparation, particularly in the relief of arthritic symptoms, has been investigated in numerous animal, clinical and in vitro studies. Although some contradictory evidence exists, the majority of animal studies appear to indicate Hp as an effective antiinflammatory and analgesic preparation in the treatment of acute and subacute inflammation. Clinical trials support Hp as a beneficial treatment for the alleviation of pain and improvement of mobility in a variety of musculoskeletal conditions. Analysis of the in vitro and ex vivo studies that currently exist, indicate that Hp has significant effects on numerous proinflammatory markers. However, the exact mechanism(s) by which Hp may reduce inflammation remain to be elucidated.

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These data suggest that further analysis of these loci may provide a genetic basis for identifying pigs that are less likely to transmit human tropic PERV and would, therefore, be more suitable as source animals for human xenotransplantation.

The emergence of leukemia following gene transfer to restore common cytokine receptor gamma chain (gammaC) function in X-linked severe combined immunodeficiency (SCID-X1) has raised important questions with respect to gene therapy safety. To explore the risk factors involved, we tested the oncogenic potential of human gammaC in new strains of transgenic mice expressing the gene under the control of the CD2 promoter and locus control region (LCR). These mice demonstrated mildly perturbed T-cell development, with an increased proportion of thymic CD8 cells, but showed no predisposition to tumor development even on highly tumor prone backgrounds or after gamma-retrovirus infection. The human CD2-gammaC transgene rescued T and B-cell development in gammaC(-/-) mice but with an age-related delay, mimicking postnatal reconstitution in SCID-X1 gene therapy subjects. However, we noted that gammaC(-/-) mice are acutely susceptible to murine leukemia virus (MLV) leukemogenesis, and that this trait was not corrected by the gammaC transgene. We conclude that the SCID-X1 phenotype can be corrected safely by stable ectopic expression of gammaC and that the transgene is not significantly oncogenic when expressed in this context. However, an underlying predisposition conferred by the SCID-X1 background appears to collaborate with insertional mutagenesis to increase the risk of tumor development.