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Oral Treatment of Murine Cytomegalovirus Infections with Ether Lipid Esters of Cidofovir. Earl R. Kern, 2004.To improve the oral bioavailability of cidofovir (CDV), a series of ether lipid ester prodrugs were synthesized and evaluated for activity against murine cytomegalovirus (MCMV) infection . Four of these analogs, hexadecyloxypropyl (HDP)-CDV, octadecyloxyethyl (ODE)-CDV, oleyloxyethyl (OLE)-CDV, and oleyloxypropyl (OLP)-CDV, were found to have greater activity than CDV against human CMV and MCMV in vitro . The efficacy of oral treatment with these compounds against MCMV infections in BALB/c mice was then determined . Treatment with HDP-CDV, ODE-CDV, OLE-CDV, or OLP-CDV at 2.0 to 6.7 mg/kg of body weight provided significant protection when daily treatments were initiated 24 to 48 h after viral inoculation . Additionally, HDP-CDV or ODE-CDV administered twice weekly or as a single dose of 1.25 to 10 mg/kg was effective in reducing mortality when treatment was initiated at 24 h, 48 h, or, in some cases, 72 h after viral inoculation . In animals treated daily with HDP-CDV or ODE-CDV, virus titers in lung, liver, spleen, kidney, pancreas, salivary gland, and blood were reduced 3 to 5 log10-fold, which was comparable to CDV given intraperitoneally . These results indicated that HDP-CDV or ODE-CDV given orally was as effective as parenteral CDV for the treatment of experimental MCMV infection and suggest that further evaluation for use in CMV infections in humans is warranted . Benzoic Acid, a Weak Organic Acid Food Preservative, Exerts Specific Effects on Intracellular Membrane Trafficking Pathways in Saccharomyces cerevisiae. Reut Hazan, 2004.Microbial spoilage of food causes losses of up to 40% of all food grown for human consumption worldwide . Yeast growth is a major factor in the spoilage of foods and beverages that are characterized by a high sugar content, low pH, and low water activity, and it is a significant economic problem . While growth of spoilage yeasts such as Zygosaccharomyces bailii and Saccharomyces cerevisiae can usually be retarded by weak organic acid preservatives, the inhibition often requires levels of preservative that are near or greater than the legal limits . We identified a novel synergistic effect of the chemical preservative benzoic acid and nitrogen starvation: while exposure of S . cerevisiae to either benzoic acid or nitrogen starvation is cytostatic under our conditions, the combination of the two treatments is cytocidal and can therefore be used beneficially in food preservation . In yeast, as in all eukaryotic organisms, survival under nitrogen starvation conditions requires a cellular response called macroautophagy . During macroautophagy, cytosolic material is sequestered by intracellular membranes . This material is then targeted for lysosomal degradation and recycled into molecular building blocks, such as amino acids and nucleotides . Macroautophagy is thought to allow cellular physiology to continue in the absence of external resources . Our analyses of the effects of benzoic acid on intracellular membrane trafficking revealed that there was specific inhibition of macroautophagy . The data suggest that the synergism between nitrogen starvation and benzoic acid is the result of inhibition of macroautophagy by benzoic acid and that a mechanistic understanding of this inhibition should be beneficial in the development of novel food preservation technologies . NhaR and RcsB Independently Regulate the osmCp1 Promoter of Escherichia coli at Overlapping Regulatory Sites. Rachel Sturny, 2003.Transcription of the Escherichia coli osmC gene is induced by several stress conditions . osmC is expressed from two overlapping promoters, osmCp1 and osmCp2. The proximal promoter, osmCp2, is transcribed at the entry into the stationary phase by the  s sigma factor . The distal promoter, osmCp1, is activated by NhaR and RcsB . NhaR is a positive regulator of the LysR family and is known to be an activator of the nhaA gene encoding an Na+/H+ antiporter . RcsB is the response regulator of the RcsCDB His-Asp phosphorelay signal transduction system . Genetic data indicated that activation of osmCp1 by both NhaR and RcsB requires the same short sequences upstream of the -35 region of the promoter . Accordingly, DNase I footprint analysis indicated that both activators protect an overlapping region close to the -35 box of the promoter and suggested that the regulatory effect is direct . Despite the overlap of the binding sites, each activator acts independent of the other and is specific for a particular stress . NhaR can stimulate osmCp1 in response to an osmotic signal even in the absence of RcsB . RcsB is responsible for the induction of osmCp1 by alteration of the cell envelope, even in the absence of NhaR . osmCp1 as an example of multiple-stress-responsive promoter is discussed in light of a comparison of the NhaR and RcsB target regions in the Enterobacteriaceae .
Lysine-2,3-Aminomutase and ß-Lysine Acetyltransferase Genes of Methanogenic Archaea Are Salt Induced and Are Essential for the Biosynthesis of N  -Acetyl-ß-Lysine and Growth at High Salinity.K. Pflüger, 2003.The compatible solute N -acetyl-ß-lysine is unique to methanogenic archaea and is produced under salt stress only . However, the molecular basis for the salt-dependent regulation of N-acetyl-ß-lysine formation is unknown . Genes potentially encoding lysine-2,3-aminomutase (ablA) and ß-lysine acetyltransferase (ablB), which are assumed to catalyze N-acetyl-ß-lysine formation from
 -lysine, were identified on the chromosomes of the methanogenic archaea Methanosarcina mazei Gö1, Methanosarcina acetivorans, Methanosarcina barkeri, Methanococcus jannaschii, and Methanococcus maripaludis . The order of the two genes was identical in the five organisms, and the deduced proteins were very similar, indicating a high degree of conservation of structure and function . Northern blot analysis revealed that the two genes are organized in an operon (termed the abl operon) in M . mazei Gö1 . Expression of the abl operon was strictly salt dependent . The abl operon was deleted in the genetically tractable M . maripaludis .
 abl mutants of M . maripaludis no longer produced N-acetyl-ß-lysine and were incapable of growth at high salt concentrations, indicating that the abl operon is essential for N-acetyl-ß-lysine synthesis . These experiments revealed the first genes involved in the biosynthesis of compatible solutes in methanogens .
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