Impact of IFNL4 rs12979860 and rs8099917 polymorphisms on response to Peg-Interferon-α and Ribavirin in patients with congenital bleeding disorder and chronic hepatitis C.

BACKGROUND: The aim of this study was to determine whether two polymorphisms of the human interferon lambda 4 (IFNL4) gene (rs12979860 and rs8099917) can predict sustained virologic response (SVR) following antiviral therapy in patients with inherited bleeding disorder and chronic hepatitis C (CHC). METHODS: This retrospective study was conducted on 294 patients with congenital bleeding disorder and CHC who were treated with Peg-Interferon-α (PegIFN) and Ribavirin (RBV). Baseline patient and viral parameters were measured and analyzed statistically to assess their combined and individual contributions to SVR prediction. RESULTS: The most prevalent variants of rs12979860 and rs8099917 identified among the study patients were CT (45.9%) and TT (57.6%), respectively. Overall, SVR was achieved in 69% of the study patients. The rate of SVR was lower in patients with HCV genotype-1 than in those with HCV genotype-3 (62% vs 88%; P<.001; OR=0.23). Multivariate analysis of SVR predictors in patients with HCV genotype-1 infection included age (<24 years), BMI (<25), absence of cirrhosis, HCV RNA level (<400 000 IU/mL), rs8099917 TT and rs12979860 CC, all of which were associated with a higher SVR rate. In HCV genotype-3 infection, only rs12979860 CC was significantly associated with SVR. CONCLUSION: These results demonstrate that polymorphisms of the IFNL4 gene are highly associated with SVR to PegIFN and RBV combination therapy in patients with a congenital bleeding disorder and CHC. Assessment of rs12979860 and rs8099917 genotypes can guide physicians in choosing an optimal treatment regimen, including less expensive therapies that may only be available in many geographic locales.

Brucella melitensis triggers time-dependent modulation of apoptosis and down-regulation of mitochondrion-associated gene expression in mouse macrophages.

Brucella spp. are facultative intracellular bacteria that cause brucellosis in humans and other animals. Brucella spp. are taken up by macrophages, and the outcome of the macrophage-Brucella interaction is a basis for establishment of a chronic Brucella infection. Microarrays were used to analyze the transcriptional response of the murine macrophage-like J774.A1 cell line to infection with virulent Brucella melitensis strain 16M. It was found that most significant changes in macrophage gene transcription happened early following infection, and global macrophage gene expression profiles returned to normal between 24 and 48 h postinfection. These findings support the observation that macrophages kill the majority of Brucella cells at the early infection stage, but the surviving Brucella cells are able to avoid macrophage brucellacidal activity inside replicative phagosomes at the later infection stage. At 4 h postinfection, macrophage genes involved in cell growth, metabolism, and responses to endogenous stimuli were down-regulated, while the inflammatory response (e.g., tumor necrosis factor alpha and Toll-like receptor 2), the complement system, the responses to external stimuli, and other immune responses were up-regulated. It is likely that the most active brucellacidal activity happened between 0 and 4 h postinfection. Mitochondrion-associated gene expression, which is involved in protein synthesis and transport, electron transfer, and small-molecule transfer, and many other mitochondrial functions were significantly down-regulated at 4 h postinfection. Although there were both pro- and antiapoptosis effects, B. melitensis 16M appears to inhibit apoptosis of macrophages by blocking release of cytochrome c and production of reactive oxygen species in the mitochondria, thus preventing activation of caspase cascades.

The xylem and phloem transcriptomes from secondary tissues of the Arabidopsis root-hypocotyl.

The growth of secondary xylem and phloem depends on the division of cells in the vascular cambium and results in an increase in the diameter of the root and stem. Very little is known about the genetic mechanisms that control cambial activity and the differentiation of secondary xylem and phloem cell types. To begin to identify new genes required for vascular cell differentiation and function, we performed genome-wide expression profiling of xylem and phloem-cambium isolated from the root-hypocotyl of Arabidopsis (Arabidopsis thaliana). Gene expression in the remaining nonvascular tissue was also profiled. From these transcript profiles, we assembled three sets of genes with expression significantly biased toward xylem, phloem-cambium, or nonvascular tissue. We also assembled three two-tissue sets of genes with expression significantly biased toward xylem/phloem-cambium, xylem/nonvascular, or phloem-cambium/nonvascular tissues. Localizations predicted by transcript profiles were supported by results from promoter-reporter and reverse transcription-polymerase chain reaction experiments with nine xylem- or phloem-cambium-biased genes. An analysis of the members of the phloem-cambium gene set suggested that some genes involved in regulating primary meristems are also regulators of the cambium. Secondary phloem was implicated in the synthesis of auxin, glucosinolates, cytokinin, and gibberellic acid. Transcript profiles also supported the importance of class III HD ZIP and KANADI transcription factors as regulators of radial patterning during secondary growth, and identified several members of the G2-like, NAC, AP2, MADS, and MYB transcription factor families that may play roles as regulators of xylem or phloem cell differentiation and activity.