MicroRNA miR-196a is a central regulator of HOX-B7 and BMP4 expression in malignant melanoma

Since bone morphogenetic proteins (BMPs) play an important role in melanoma progression, we aimed to determine the molecular mechanisms leading to overexpression of BMP4 in melanoma cells compared to normal melanocytes. With our experimental approach we revealed that loss of expression of a microRNA represents the starting point for a signaling cascade finally resulting in overexpression of BMP4 in melanoma cells. In detail, strongly reduced expression of the microRNA miR-196a in melanoma cells compared to healthy melanocytes leads to enhanced HOX-B7 mRNA and protein levels, which subsequently raise Ets-1 activity by inducing basic fibroblast growth factor (bFGF). Ets-1 finally accounts for induction of BMP4 expression. We were furthermore able to demonstrate that bFGF-mediated induction of migration is achieved via activation of BMP4, thus determining BMP4 as major modulator of migration in melanoma. In summary, our study provides insights into the early steps of melanoma progression and might thereby harbor therapeutic relevance.     

Identification of a virus similar to hepatitis B virus in non-A non-B hepatitis]

Hepatitis B virus-like particles (including DANE particles) with DNA polymerase activity but negative for HBs Ag have been identified in NON-A, NON-B hepatitis sera positive for HC Ag. Although specifically associated with the particles, HC Ag is not a surface antigen of the hepatitis C virus identified here for the first time. The relationship of this agent with HBV seems obvious, and deserves further study.     

The replication of a xenotropic murine C type virus in some mammalian cells. Definition of a specific antigen]

The use of our mink cell line maintained in vitro infected with the murine xenotropic AT 124 virus, and that of a (W/Fu x bn) f1 rat anti-124 serum allow us to define a new cell surface antigen specific of murine xenotropic type C viruses.     

RNA-dependent RNA polymerase encoded by hepatitis C virus: biomedical applications

The hepatitis C viruses (HCVs) are a group of small enveloped RNA viruses that have been viewed as a leading cause of chronic hepatitis in humans. Infections by HCV represent a serious global health problem, because millions of people worldwide are infected and no efficient treatment is available at the present time. Since HCV was identified in 1989, considerable effort has been devoted to the discovery and development of novel molecules to treat HCV-related diseases. One of the approaches is the development of novel inhibitors that interrupt the normal functions of HCV NS5B, an RNA-dependent RNA polymerase essential to HCV replication. This review summarizes recent advances in the biochemical and structural understanding of HCV NS5B polymerase as well as in the development of antiviral agents targeting this important enzyme. Received 19 March 2002; received after revision 23 April 2002; accepted 23 April 2002     

Non-A non-B hepatitis virus: demonstration of a double antigenic and structural kinship with hepatitis B virus

Major antigenic identity has been demonstrated by immunodiffusion between the Ag described by Shirachi and confirmed by us (NANB/e) in the serum on non A non B hepatitis and the HBe/3 specificity of hepatitis B virus (HBV). A second Ag (NANB/c) linked to the core of a new virion morphologically similar to HBV and also associated with ADN polymerase activity as recently described, has been identified and purified from an infected liver. This NANB/c Ag also cross reacts with HBc Ag. These results confirm that HBV and the NANB virus defined here belong to the same new class of DNA viruses.     

Sequential biogenesis of host cell membrane rearrangements induced by hepatitis C virus infection

Like most positive-strand RNA viruses, hepatitis C virus (HCV) forms a membrane-associated replication complex consisting of replicating RNA, viral and host proteins anchored to altered cell membranes. We used a combination of qualitative and quantitative electron microscopy (EM), immuno-EM, and the 3D reconstruction of serial EM sections to analyze the host cell membrane alterations induced by HCV. Three different types of membrane alteration were observed: vesicles in clusters (ViCs), contiguous vesicles (CVs), and double-membrane vesicles (DMVs). The main ultrastructural change observed early in infection was the formation of a network of CVs surrounding the lipid droplets. Later stages in the infectious cycle were characterized by a large increase in the number of DMVs, which may be derived from the CVs. These DMVs are thought to constitute the membranous structures harboring the viral replication complexes in which viral replication is firmly and permanently established and to protect the virus against double-stranded RNA-triggered host antiviral responses.     

4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-ylurea; Sulbenox,a novel animal growth stimulant

Summary The title compound, a metabolite of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, was synthesized and found to be an effective growth promoter in sheep, mice, and rats. In sheep it gave over a 6-week growth period at 15 and 60 ppm in the diet an economically and statistically significant growth response.United States adopted name (USAN).We thank Dr T.J. Bentley, D.J. France, and Dr L.D. Spicer for synthesis and structural elucidation work, Dr M.W. Bullock and G.W. Cox for metabolism studies, Drs J. Harter, D. Ingle, J.M. Pensack and L. Wozniak and their associates for biological data, and Drs D.J. Thoennes and M.L. Thomson for spectral data and interpretations.     

4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-ylurea; Sulbenox1, a novel animal growth stimulant

The title compound, a metabolite of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, was synthesized and found to be an effective growth promoter in sheep, mice, and rats. In sheep it gave over a 6-week growth period at 15 and 60 ppm in the diet an economically and statistically significant growth response.     

The metabolism, pharmacokinetics and mechanisms of antiviral activity of ribavirin against hepatitis C virus

Ribavirin, a broad spectrum antiviral agent, in conjunction with interferon forms the current standard of treatment for hepatitis C virus (HCV) infection in humans. While ribavirin alone fails to induce a significant antiviral response, in combination with interferon, ribavirin dramatically improves the long-term outcome of therapy. The predominant mechanism(s) of ribavirin action against HCV, are yet to be established. In this review, we examine the current status of our understanding of the metabolism, pharmacokinetics and mechanisms of the antiviral activity of ribavirin against HCV, all of which are central to the rational identification of improved treatment protocols. Received 30 September 2005; received after revision 20 November 2005; accepted 7 December 2005     

Effects of certain hydroxamic acids on virus replication

Résumé L'acide oxamyl-hydroxamique, l'acide salicylhydroxamique et l'acétoxyoxamide inhibent la reproduction du bactériophage T₄ dans l'Escherichia coli B. L'activité de chacun de ces composés était plus grande que celle de l'hydroxyurée dans le même système d'essai. De ce fait, une évaluation plus poussée de ces 3 agents ainsi que d'autres acides hydroxamiques dans une série de systèmes d'essai sur les virus paraît clairement indiquée.     

Ultrastructural and quantitative analysis of the lipid droplet clustering induced by hepatitis C virus core protein

Hepatitis C virus (HCV) release is linked to the formation of lipid droplet (LD) clusters in the perinuclear area of infected cells, induced by the core protein. We used electron microscopy (EM) to monitor and compare the number and size of LD in cells producing the mature and immature forms of the HCV core protein, and 3D EM to reconstruct whole cells producing the mature core protein. Only the mature protein coated the LD and induced their clustering and emergence from endoplasmic reticulum membranes enriched in this protein. We found no particular association between LD clusters and the centrosome in reconstructed cells. The LD clustering induced by the mature core protein was associated with an increase in LD synthesis potentially due, at least in part, to the ability of this protein to coat the LD. These observations provide useful information for further studies of the mechanisms involved in HCV-induced steatosis.