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Pharmacokinetics of Indinavir and Ritonavir Administered at 667 and 100 Milligrams, Respectively, Every 12 Hours Compared with Indinavir Administered at 800 Milligrams Every 8 Hours in Human Immunodeficiency Virus-Infected Patients. Frank S. Rhame, 2004.Human immunodeficiency virus (HIV) patients on nucleoside or nucleotide reverse transcriptase inhibitors with HIV RNA at <1,000 copies/ml were randomized in an open-label study to administration of combined indinavir/ritonavir (IDV/RTV) at 667/100 mg every 12 h (q12h) or IDV alone at 800 mg q8h to determine the regimens' pharmacokinetics . On day 14, plasma IDV and RTV levels were determined over 24 h . Noncompartmental pharmacokinetics (minimum concentration of drug in serum [Cmin], area under the concentration-time curve from 0 to 24 h [AUC0-24], and maximum concentration of drug in serum [Cmax]) were expressed as geometric mean values with 90% confidence intervals (CI) . The primary hypothesis was that the lower bound of the protocol-specified 90% CI for the geometric mean Cmin ratio of the combination compared to IDV alone regimen would be  2 . Twenty-seven patients were enrolled, and 24 (15 male; average age, 42 years) completed the study . The Cmin, AUC0-24, and Cmax for IDV/RTV compared to IDV alone were 1,511 versus 250 nM, 119,557 versus 77,034 nM · h, and 10,428 versus 10,407 nM, respectively . Corresponding relationships for IDV/RTV compared to IDV alone were a 6.0-fold increase in Cmin (90% CI, 4.0, 9.3), an increase in AUC0-24 (1.5-fold, 90% CI, 1.2, 2.0), and no increase in Cmax . Adverse events were similar and generally mild, with no cases of nephrolithiasis . The geometric mean ratio of IDV Cmin for IDV/RTV compared to IDV was at least 2 by a lower bound of the 90% CI, satisfying the primary hypothesis . The Cmax was not increased, suggesting an IDV/RTV 667/100-mg toxicity profile may be similar to that of unboosted IDV .
DNA-Binding Activities of the HilC and HilD Virulence Regulatory Proteins of Salmonella enterica Serovar Typhimurium. Igor N. Olekhnovich, 2002.The HilC and HilD proteins of Salmonella enterica serovar Typhimurium are members of the AraC/XylS family of transcription regulators . They are encoded on Salmonella pathogenicity island 1 (SPI1) and control expression of the hilA gene, which encodes the major transcriptional activator for many genes encoded on SPI1 and elsewhere that contribute to invasion of host cells . Gel electrophoretic shift and DNase footprinting assays revealed that purified HilC and HilD proteins can bind to multiple regions in the hilA and hilC promoters and to a single region in the hilD promoter . Although both HilC and -D proteins can bind to the same DNA regions, they showed different dependencies on the sequence and lengths of their DNA targets . To identify the binding-sequence specificity of HilC and HilD, a series of single base substitutions changing each position in a DNA fragment corresponding to positions -92 to -52 of the hilC promoter was tested for binding to HilC and HilD in a gel shift DNA-binding assay . This mutational analysis in combination with sequence alignments allowed deduction of consensus sequences for binding of both proteins . The consensus sequences overlap but differ so that HilC can bind to both types of sites but HilD only to one . The hilA and hilC promoters contain multiple binding sites of each type, whereas the hilD promoter contains a site that binds HilC but not HilD without additional binding elements . The HilC and HilD proteins had no major effect on transcription from the hilA or hilD promoters using purified proteins in vitro but changed the choice of promoter at hilC . These results are consistent with a model derived from analysis of lacZ fusions stating that HilC and HilD enhance hilA expression by counteracting a repressing activity . ACEI of Trichoderma reesei Is a Repressor of Cellulase and Xylanase Expression. Nina Aro, 2003.We characterized the effect of deletion of the Trichoderma reesei (Hypocrea jecorina) ace1 gene encoding the novel cellulase regulator ACEI that was isolated based on its ability to bind to and activate in vivo in Saccharomyces cerevisiae the promoter of the main cellulase gene, cbh1 . Deletion of ace1 resulted in an increase in the expression of all the main cellulase genes and two xylanase genes in sophorose- and cellulose-induced cultures, indicating that ACEI acts as a repressor of cellulase and xylanase expression . Growth of the strain with a deletion of the ace1 gene on different carbon sources was analyzed . On cellulose-based medium, on which cellulases are needed for growth, the  ace1 strain grew better than the host strain due to the increased cellulase production . On culture media containing sorbitol as the sole carbon source, the growth of the strain with a deletion of the ace1 gene was severely impaired, suggesting that ACEI regulates expression of other genes in addition to cellulase and xylanase genes . A strain with a deletion of the ace1 gene and with a deletion of the ace2 gene coding for the cellulase and xylanase activator ACEII expressed cellulases and xylanases similar to the
ace1 strain, indicating that yet another activator regulating cellulase and xylanase promoters was present .
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