Variation of Neisseria gonorrhoeae Lipooligosaccharide Directs Dendritic Cell–Induced T Helper Responses

Gonorrhea is one of the most prevalent sexually transmitted diseases in the world. A naturally occurring variation of the terminal carbohydrates on the lipooligosaccharide (LOS) molecule correlates with altered disease states. Here, we investigated the interaction of different stable gonoccocal LOS phenotypes with human dendritic cells and demonstrate that each variant targets a different set of receptors on the dendritic cell, including the C-type lectins MGL and DC-SIGN. Neisseria gonorrhoeae LOS phenotype C constitutes the first bacterial ligand to be described for the human C-type lectin receptor MGL. Both MGL and DC-SIGN are locally expressed at the male and female genital area, the primary site of N. gonorrhoeae infection. We show that targeting of different C-type lectins with the N. gonorrhoeae LOS variants results in alterations in dendritic cell cytokine secretion profiles and the induction of distinct adaptive CD4+ T helper responses. Whereas N. gonorrhoeae variant A with a terminal N-acetylglucosamine on its LOS was recognized by DC-SIGN and induced significantly more IL-10 production, phenotype C, carrying a terminal N-acetylgalactosamine, primarily interacted with MGL and skewed immunity towards the T helper 2 lineage. Together, our results indicate that N. gonorrhoeae LOS variation allows for selective manipulation of dendritic cell function, thereby shifting subsequent immune responses in favor of bacterial survival

Human Milk Oligosaccharide 2′-Fucosyllactose Inhibits Ligand Binding to C-Type Lectin DC-SIGN but Not to Langerin

Human milk oligosaccharides (HMOs) and their most abundant component, 2′-Fucosyllactose (2′-FL), are known to be immunomodulatory. Previously, it was shown that HMOs and 2′-FL bind to the C-type lectin receptor DC-SIGN. Here we show, using a ligand-receptor competition assay, that a whole mixture of HMOs from pooled human milk (HMOS) and 2′-FL inhibit the binding of the carbohydrate-binding receptor DC-SIGN to its prototypical ligands, fucose and the oligosaccharide Lewis-B, (Leb) in a dose-dependent way. Interestingly, such inhibition by HMOS and 2′-FL was not detected for another C-type lectin, langerin, which is evolutionarily similar to DC-SIGN. The cell-ligand competition assay using DC-SIGN expressing cells confirmed that 2′-FL inhibits the binding of DC-SIGN to Leb. Molecular dynamic (MD) simulations show that 2′-FL exists in a preorganized bioactive conformation before binding to DC-SIGN and this conformation is retained after binding to DC-SIGN. Leb has more flexible conformations and utilizes two binding modes, which operate one at a time via its two fucoses to bind to DC-SIGN. Our hypothesis is that 2′-FL may have a reduced entropic penalty due to its preorganized state, compared to Leb, and it has a lower binding enthalpy, suggesting a better binding to DC-SIGN. Thus, due to the better binding to DC-SIGN, 2′-FL may replace Leb from its binding pocket in DC-SIGN. The MD simulations also showed that 2′-FL does not bind to langerin. Our studies confirm 2′-FL as a specific ligand for DC-SIGN and suggest that 2′-FL can replace other DC-SIGN ligands from its binding pocket during the ligand-receptor interactions in possible immunomodulatory processes

The changing face of major trauma in the UK

Aim Major trauma (MT) has traditionally been viewed as a disease of young men caused by high-energy transfer mechanisms of injury, which has been reflected in the configuration of MT services. With ageing populations in Western societies, it is anticipated that the elderly will comprise an increasing proportion of the MT workload. The aim of this study was to describe changes in the demographics of MT in a developed Western health system over the last 20 years. Methods The Trauma Audit Research Network (TARN) database was interrogated to identify all cases of MT (injury severity score >15) between 1990 and the end of 2013. Age at presentation, gender, mechanism of injury and use of CT were recorded. For convenience, cases were categorised by age groups of 25 years and by common mechanisms of injury. Longitudinal changes each year were recorded. Results Profound changes in the demographics of recorded MT were observed. In 1990, the mean age of MT patients within the TARN database was 36.1, the largest age group suffering MT was 0–24 years (39.3%), the most common causative mechanism was road traffic collision (59.1%), 72.7% were male and 33.6% underwent CT. By 2013, mean age had increased to 53.8 years, the single largest age group was 25–50 years (27.1%), closely followed by those >75 years (26.9%), the most common mechanism was low falls (39.1%), 68.3% were male and 86.8% underwent CT. Conclusions This study suggests that the MT population identified in the UK is becoming more elderly, and the predominant mechanism that precipitates MT is a fall from <2 m. Significant improvements in outcomes from MT may be expected if services targeting the specific needs of the elderly are developed within MT centres

Strategies to improve the signal and noise performance of active matrix, flatâ panel imagers for diagnostic xâ ray applications

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134928/1/mp8831.pd