Dendritic cell-mediated viral transfer to T cells is required for human immunodeficiency virus type 1 persistence in the face of rapid cell turnover

Human immunodeficiency virus type 1 (HIV-1)-infected and activated CD4(+) T cells have short half-lives in vivo (<2 days). We have established an in vitro culture system in which infected T cells are turned over frequently to provide a model system that examines this important facet of in vivo HIV-1 replication. We observed that virus replication in T cells under rapid-turnover conditions was possible only when immature dendritic cells or DC-SIGN-expressing cells mediated HIV-1 transmission to T cells. Virus replication was initiated more rapidly in T cells infected with the cell-associated form of virus compared to infection by the cell-free route. This accelerated transfer of virus required adhesion molecule-mediated interactions between the virus-presenting cell and T cell, but surprisingly, HIV-1 transfer could occur independently of DC-SIGN (DC-specific intracellular adhesion molecule 3 [ICAM-3]-grabbing nonintegrin)in the dendritic-cell-T-cell cocultures. These results suggest that dendritic cell-mediated transmission of HIV-1 enables virus replication under conditions of rapid cell turnover in vivo.     

Increased hyperoxia-induced mortality and acute lung injury in IL-13 null mice

IL-13 is a critical effector at sites of Th2 inflammation and remodeling. As a result, anti-IL-13-based therapies are being actively developed to treat a variety of diseases and disorders. However, the beneficial effects of endogenous IL-13 in the normal and diseased lung have not been adequately defined. We hypothesized that endogenous IL-13 is an important regulator of oxidant-induced lung injury and inflammation. To test this hypothesis, we compared the effects of 100% O(2) in mice with wild-type and null IL-13 loci. In this study, we demonstrate that hyperoxia significantly augments the expression of the components of the IL-13R, IL-13Ralpha1, and IL-4Ralpha. We also demonstrate that, in the absence of IL-13, hyperoxia-induced tissue inflammation is decreased. In contrast, in the IL-13 null mice, DNA injury, cell death, caspase expression, and activation and mortality are augmented. Interestingly, the levels of the cytoprotective cytokines vascular endothelial cell growth factor, IL-6, and IL-11 were decreased in the bronchoalveolar lavage fluid. These studies demonstrate that the expression of the IL-13R is augmented and that the endogenous IL-13-IL-13R pathway contributes to the induction of inflammation and the inhibition of injury in hyperoxic acute lung injury.     

Prevalence of duodenal ulcer-promoting gene (dupA) of Helicobacter pylori in patients with duodenal ulcer in North Indian population

BACKGROUND: The duodenal ulcer (DU)-promoting gene (dupA) of Helicobacter pylori has been identified as a novel virulent marker associated with an increased risk for DU. The presence or absence of dupA gene of H. pylori present in patients with DU and functional dyspepsia in North Indian population was studied by polymerase chain reaction (PCR) and hybridization analysis. MATERIALS AND METHODS: One hundred and sixty-six patients (96 DU and 70 functional dyspepsia) were included in this study. In addition, sequence diversity of dupA gene of H. pylori found in these patients was analyzed by sequencing the PCR products jhp0917 and jhp0918 on both strands with appropriate primers. RESULTS: PCR and hybridization analyses indicated that dupA gene was present in 37.5% (36/96) of H. pylori strains isolated from DU patients and 22.86% (16/70) of functional dyspepsia patients (p < or = .05). Of these, 35 patients with DU (97.2%) and 14 patients with functional dyspepsia (81.25%) were infected by H. pylori positive for cagA genotype. Furthermore, the presence of dupA was significantly associated with the cagA-positive genotype (p < or = .02). CONCLUSION: Results of our study have shown that significant association of dupA gene with DU in this population. The dupA gene can be considered as a novel virulent marker for DU in this population.     

Developmental differences in the responses of IL-6 and IL-13 transgenic mice exposed to hyperoxia

Our previous work has shown that adult mice with overexpression of IL-6 and IL-13 in the lung have enhanced survival in hyperoxia associated with reduced hyperoxia-induced lung injury and cell death. We hypothesized that there are developmental differences in these responses in the adult vs. the newborn (NB) animal, and these responses have clinical relevance in the human NB. We compared the responses to 100% O(2) of NB IL-6 and IL-13 transgenic mice with wild-type littermate controls by evaluating mortality, lung tissue TUNEL staining, and mRNA expression using RT-PCR. We used ELISA to measure IL-6 levels in tracheal aspirates from human neonates. Our results show that, in contrast to the cytoprotective effects in mature mice, IL-6 caused significantly increased mortality, DNA injury, caspases, cell death regulator and angiogenic factor expression in hyperoxia in the NB. Furthermore, tracheal aspirate levels of IL-6 were significantly increased in premature neonates with respiratory distress syndrome who had an adverse outcome (bronchopulmonary dysplasia/death). In contrast to the protective effects in adults, there was no survival advantage to the NB IL-13 mice in hyperoxia. These findings imply that caution should be exercised in extrapolating results from the adult to the NB.     

Comparative metagenomics revealed commonly enriched gene sets in human gut microbiomes.

Numerous microbes inhabit the human intestine, many of which are uncharacterized or uncultivable. They form a complex microbial community that deeply affects human physiology. To identify the genomic features common to all human gut microbiomes as well as those variable among them, we performed a large-scale comparative metagenomic analysis of fecal samples from 13 healthy individuals of various ages, including unweaned infants. We found that, while the gut microbiota from unweaned infants were simple and showed a high inter-individual variation in taxonomic and gene composition, those from adults and weaned children were more complex but showed a high functional uniformity regardless of age or sex. In searching for the genes over-represented in gut microbiomes, we identified 237 gene families commonly enriched in adult-type and 136 families in infant-type microbiomes, with a small overlap. An analysis of their predicted functions revealed various strategies employed by each type of microbiota to adapt to its intestinal environment, suggesting that these gene sets encode the core functions of adult and infant-type gut microbiota. By analysing the orphan genes, 647 new gene families were identified to be exclusively present in human intestinal microbiomes. In addition, we discovered a conjugative transposon family explosively amplified in human gut microbiomes, which strongly suggests that the intestine is a 'hot spot' for horizontal gene transfer between microbes.     

N-(1,3-Diaryl-3-oxopropyl)amides as a new template for xanthine oxidase inhibitors

A series of forty two N-(1,3-diaryl-3-oxopropyl)amides were synthesized via an efficient, modified Dakin-West reaction and were evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Structure-activity relationship analyses have been presented. Selected active xanthine oxidase inhibitors (3r, 3s, and 3zh) were assessed in vivo to study their anti-hyperuricemic effect in potassium oxonate induced hyperuricemic mice model. Compound 3s emerged as the most potent xanthine oxidase inhibitor (IC(50)=2.45 μM) as well as the most potent anti-hyperuricemic agent. The basis of significant inhibition of xanthine oxidase by 3s was rationalized by its molecular docking into catalytic site of xanthine oxidase.