Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal ABSTRACTWe conducted a large-scale survey to determine the frequency and clinical significance of mutations in the pre-core region of hepatitis B virus (HBV). Sera from 263 patients with chronic HBV infection were analyzed by direct sequencing of PCR-amplif ed HBV DNA. Four major missense/nonsense mutations (M) were found: (Ml)

TLR expression patterns were remarkably conserved across the study population and evaluated tissues indicating a predictable responsiveness to STI. The results support cautious use of immortalized cells for genital tract modeling.

Defensins are key participants in mucosal innate defense. The varied antimicrobial activity and differential distribution of defensins at mucosal sites indicate that peptide repertoires are tailored to site-specific innate defense requirements. Nonetheless, few studies have investigated changes in peptide profiles and function after in vivo pathogen challenge. Here, we determined defensin profiles in urethral secretions of healthy men and men with Chlamydia trachomatis-and Neisseria gonorrhoeae-mediated urethritis by immunoblotting for the epithelial defensins HBD1, HBD2, and HD5 and the neutrophil defensins HNP1 to -3 (HNP1-3). HBD1 was not detectable in secretions, and HBD2 was only induced in a small proportion of the urethritis patients; however, HD5 and HNP1-3 were increased in C. trachomatis infection and significantly elevated in N. gonorrhoeae infection. When HNP1-3 levels were low, HD5 appeared mostly as the propeptide; however, when HNP1-3 levels were >10 g/ml, HD5 was proteolytically processed, suggesting neutrophil proteases might contribute to HD5 processing. HD5 and HNP1-3 were bactericidal against C. trachomatis and N. gonorrhoeae, but HD5 activity was dependent upon N-terminal processing of the peptide. In vitro proteolysis of proHD5 by neutrophil proteases and analysis of urethral secretions by surface-enhanced laser desorption ionization substantiated that neutrophils contribute the key convertases for proHD5 in the urethra during these infections. This contrasts with the small intestine, where Paneth cells secrete both proHD5 and its processing enzyme, trypsin. In conclusion, we describe a unique defensin expression repertoire in response to inflammatory sexually transmitted infections and a novel host defense mechanism wherein epithelial cells collaborate with neutrophils to establish an antimicrobial barrier during infection.

Abstract. Benchmarking model performance across large samples of catchments is useful to guide model selection and future model development. Given uncertainties in the observational data we use to drive and evaluate hydrological models, and uncertainties in the structure and parameterisation of models we use to produce hydrological simulations and predictions, it is essential that model evaluation is undertaken within an uncertainty analysis framework. Here, we benchmark the capability of several lumped hydrological models across Great Britain by focusing on daily flow and peak flow simulation. Four hydrological model structures from the Framework for Understanding Structural Errors (FUSE) were applied to over 1000 catchments in England, Wales and Scotland. Model performance was then evaluated using standard performance metrics for daily flows and novel performance metrics for peak flows considering parameter uncertainty. Our results show that lumped hydrological models were able to produce adequate simulations across most of Great Britain, with each model producing simulations exceeding a 0.5 Nash–Sutcliffe efficiency for at least 80 % of catchments. All four models showed a similar spatial pattern of performance, producing better simulations in the wetter catchments to the west and poor model performance in central Scotland and south-eastern England. Poor model performance was often linked to the catchment water balance, with models unable to capture the catchment hydrology where the water balance did not close. Overall, performance was similar between model structures, but different models performed better for different catchment characteristics and metrics, as well as for assessing daily or peak flows, leading to the ensemble of model structures outperforming any single structure, thus demonstrating the value of using multi-model structures across a large sample of different catchment behaviours. This research evaluates what conceptual lumped models can achieve as a performance benchmark and provides interesting insights into where and why these simple models may fail. The large number of river catchments included in this study makes it an appropriate benchmark for any future developments of a national model of Great Britain.

Problem-The endocervix is a major target of Chlamydia trachomatis (CT) infection, but little is known about the immune repertoire in this tissue, or its response to these common bacteria.Method of Study-Using a cytobrush, we isolated cells from the endocervix of 20 women during CT infection, and post-antibiotic treatment. Endocervical swabs and blood were taken in parallel. Endocervical cells were enumerated, and endocervical and blood T cells immunophenotyped. CT was genotyped by sequence analysis of the OmpA gene, and quantified by culture.Results-CT genotypes were D, E, F and Ia, and infectious burden varied considerably. Endocervical T cell and neutrophil numbers were highly elevated during infection, with both CD4 and CD8 T cell subsets accumulating. Regardless of the presence or absence of infection, the endocervical cell infiltrate was dominated by effector memory T cells, and the numbers of CCR5 and CD103 expressing T cells was significantly higher than in the blood. HLA-DR expression by endocervical T cells was significantly increased during infection.Conclusions-The human endocervix exhibits a distinct cellular response to C.trachomatis infection that can be longitudinally evaluated by cytobrush sampling. Infecting organisms can be sampled and analyzed in parallel.