ABSTRACT
Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r2=0.98-1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml-1 of IL-18 after adjusting for covariates (rs80011693; rs111311302 ß=-0.06, P-value=2.7 × 10-4). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections.
Subject(s)
Coinfection/immunology , HIV Infections/immunology , HIV-1/physiology , Hepatitis C, Chronic/immunology , Interleukin-18/blood , Interleukin-18/genetics , Adult , Dioxygenases/genetics , Female , HIV Infections/blood , Hepatitis C, Chronic/blood , Humans , Inflammasomes/immunology , Male , Polymorphism, Single NucleotideABSTRACT
The directional distribution of the ambient neutron dose equivalent from 145-MeV (19)F projectiles bombarding a thick aluminium target is measured and analysed. The measurements are carried out with a commercially available dose equivalent meter at 0°, 30°, 60° and 90° with respect to the beam direction. The experimental results are compared with calculated doses from EMPIRE nuclear reaction code and different empirical formulations proposed by others. The results are also compared with the measured data obtained from an earlier experiment at a lower projectile energy of 110 MeV for the same target-projectile combination.
Subject(s)
Aluminum/chemistry , Fluorine Radioisotopes , Neutrons , Particle Accelerators , Algorithms , Computer Simulation , Radiation DosageABSTRACT
A mobilizable suicide vector, pSUP5011, was used to introduce Tn5-mob in a new facultative sulfur lithotrophic bacterium, KCT001, to generate mutants defective in sulfur oxidation (Sox(-)). The Sox(-) mutants were unable to oxidize thiosulfate while grown mixotrophically in the presence of thiosulfate and succinate. The mutants were also impaired in oxidizing other reduced sulfur compounds and elemental sulfur as evident from the study of substrate oxidation by the whole cells. Sulfite oxidase activity was significantly diminished in the cell extracts of all the mutants. A soxA gene was identified from the transposon-adjacent genomic DNA of a Sox(-) mutant strain. The sequence analysis revealed that the soxA open reading frame (ORF) is preceded by a potential ribosome binding site and promoter region with -10- and -35-like sequences. The deduced nucleotide sequence of the soxA gene was predicted to code for a protein of 286 amino acids. It had a signal peptide of 26 N-terminal amino acids. The amino acid sequence showed similarity with a putative gene product of Aquifex aeolicus, soluble cytochrome c(551) of Chlorobium limicola, and the available partial SoxA sequence of Paracoccus denitrificans. The soxA-encoded product seems to be a diheme cytochrome c for KCT001 and A. aeolicus, but the amino acid sequence of C. limicola cytochrome c(551) revealed a single heme-binding region. Another transposon insertion mutation was mapped within the soxA ORF. Four other independent transposon insertion mutations were mapped in the 4.4-kb soxA contiguous genomic DNA region. The results thus suggest that a sox locus of KCT001, essential for sulfur oxidation, was affected by all these six independent insertion mutations.