Purpose: To conduct a phase I clinical trial with a second-generation oncolytic herpes simplex virus (HSV) expressing granulocyte macrophage colony-stimulating factor (Onco VEX GM-CSF

Organic chemistry Z 0200 Furans, Thiophenes and Related Heterocycles in Drug Discovery -[35 refs.]. -(SPERRY, J. B.; WRIGHT, D. L.; Curr. Opin. Drug Discovery Dev. 8 (2005) 6, 723-740; Dep. Chem., Dartmouth Coll., Hanover, NH 03755, USA; Eng.) -Lindner 15-242

[reaction: see text] An approach to the spirocyclic core of halichlorine and pinnaic acid has been designed around an imine allylation/ring-closing metathesis sequence. This sequence has been used to generate several azabicylo[n.5] model systems. A newly reported metathesis catalyst was show to be highly effective for cyclization of these systems.

Considers the reasons for a high turnover of staff in different industries before looking at the nature of commitment. Provides some areas where improvements can lead to enhanced employee commitment and briefly looks at these issues in turn, e.g. pay, benefits, flexible work options and career development and training. Concludes that policies to encourage commitment need to become inherent within the culture of the organization to be successful.

No abstract

Highlights d Inhibitors of the folate pathway in Mycobacterium tuberculosis have been identified d These molecules are dual inhibitors of dihydrofolate reductase and Rv2671 d para-Aminosalicylic acid metabolite inhibits flavindependent thymidylate synthase d Antifolates decrease the level of precursors of mycolic acids in M.

The Herpes simplex virus type I alkaline nuclease, UL12, has 5' to 3' exonuclease activity and shares homology with nucleases from other members of the Herpesviridae family. We previously reported that a UL12 null virus exhibits a severe defect in viral growth. To determine whether the growth defect was a result of loss of nuclease activity or another function of UL12, we introduced an exonuclease-inactivating mutation into the viral genome. The recombinant virus, UL12-D340E (D340E), behaved identically to the null virus (AN-1) in virus yield experiments, exhibiting a 4-log decrease in the production of infectious virus. Furthermore, both viruses were severely defective in cell-to-cell spread and produced fewer DNA containing capsids and more empty capsids than wild type virus. In addition, DNA packaged by the viral mutants was aberrant as determined by infectivity assays and pulsed-field gel electrophoresis. We conclude that UL12 exonuclease activity is essential for the production of viral DNA that can be packaged to produce infectious virus. This conclusion was bolstered by experiments showing that a series of natural and synthetic α-hydroxytropolones recently reported to inhibit HSV replication also inhibit the nuclease activity of UL12. Taken together, our results demonstrate that the exonuclease activity of UL12 is essential for the production of infectious virus and may be considered as a target for development of antiviral agents. Herpes Simplex Virus is a major pathogen, and although nucleoside analogs such as acyclovir are highly effective in controlling HSV1/2 infections in immunocompetent individuals, their use in immunocompromised patients is complicated by the development of resistance. Identification of additional proteins essential for viral replication is necessary to develop improved therapies. In this communication, we confirm that the exonuclease activity of UL12 is essential for viral replication through the analysis of a nuclease-deficient viral mutant. We demonstrate that the exonuclease activity of UL12 is essential for the production of viral progeny and thus provides an attractive, druggable enzymatic target.

[formula: see text] Compounds that induce the synthesis of nerve growth factor (NGF) are of interest as alternatives to the administration of the native peptide. We have initiated a program to study the NGF synthesis stimulating activity of the erinacine and scabronine diterpenes. Herein, we report an approach to the core cyathin system by sequential application of an oxidative coupling and [4 + 3] cycloaddition.