During replication, hepatitis delta virus (HDV) switches from production of small to large delta antigen. Both antigen isoforms have an HDV genome binding domain and are packaged into hepatitis B virus (HBV)-derived envelopes but differ at their carboxy termini. The large antigen was shown to contain a terminal CXXX box and undergo prenylation. The large, but not the small, antigen formed secreted particles when expressed singly with HBV surface antigen. Mutation of Cys211 in the CXXX box of the large antigen abolished both prenylation and particle formation, suggesting that this site is important for virion morphogenesis.
In rheumatoid synovium interleukin 6 (IL-6) is the most abundantly expressed cytokine. Increased serum levels have been previously reported in patients with rheumatoid arthritis (RA). In this study serum IL-6 levels were measured in a weli defined cohort using a bioassay (B9 celis) and levels were correlated with conventional clinical and laboratory indices of disease activity.Levels were significantly higher in serum from patients with RA (median 55 IU/ml; interquartile range 28-139) compared with serum from disease (median 7 IU/ml; 1-23) and normal controls (median 10 IU/ml; 7-12). No difference was observed between men and women. Levels did not correlate with disease duration. Significant associations were observed between IL-6 and C reactive protein and between the Ritchie articular index and duration of morning stiffness. No other correlations were observed. The value of these findings in the monitoring ofRA and as an indicator of response to second line treatment needs to be established.
Cyclopamine is a teratogenic steroidal alkaloid that causes cyclopia by blocking Sonic hedgehog (Shh) signal transduction. We have tested whether this activity of cyclopamine is related to disruption of cellular cholesterol transport and putative secondary effects on the Shh receptor, Patched (Ptc). First, we report that the potent antagonism of Shh signaling by cyclopamine is not a general property of steroidal alkaloids with similar structure. The structural features of steroidal alkaloids previously associated with the induction of holoprosencephaly in whole animals are also associated with inhibition of Shh signaling in vitro. Second, by comparing the effects of cyclopamine on Shh signaling with those of compounds known to block cholesterol transport, we show that the action of cyclopamine cannot be explained by inhibition of intracellular cholesterol transport. However, compounds that block cholesterol transport by affecting the vesicular trafficking of the Niemann-Pick C1 protein (NPC1), which is structurally similar to Ptc, are weak Shh antagonists. Rather than supporting a direct link between cholesterol homeostasis and Shh signaling, our findings suggest that the functions of both NPC1 and Ptc involve a common vesicular transport pathway. Consistent with this model, we find that Ptc and NPC1 colocalize extensively in a vesicular compartment in cotransfected cells.
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