Interleukin (IL)–12 and IL-23 Are Key Cytokines for Immunity against Salmonella in Humans

Patients with inherited deficiency of the interleukin (IL)–12/IL-23–interferon (IFN)–g axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23–component deficiency had a history of salmonella disease than did those with IFN-g–component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN-g–independent pathways. Investigation of the IL-12/IL-23–IFN-g axis should be considered in patients with invasive salmonella disease

Langerin-Heparin Interaction: Two Binding Sites for Small and Large Ligands as revealed by a combination of NMR Spectroscopy and Cross-Linking Mapping Experiments

Langerin is a C-type lectin present on Langerhans cells that mediates capture of pathogens in a carbohydrate-dependent manner, leading to subsequent internalization and elimination in the cellular organelles called Birbeck granules. This mechanism mediated by langerin was shown to constitute a natural barrier for HIV-1 particle transmission. Besides interacting specifically with high mannose and fucosylated neutral carbohydrate structures, langerin has the ability to bind sulfated carbohydrate ligands as 6-sulfated galactosides in the Ca2+ dependent binding site. Very recently langerin was demonstrated to interact with sulfated glycosaminoglycans (GAGs), in a Ca2+ independent way, resulting in the proposal of a new binding site for GAGs. Based on those results, we have conducted a structural study of the interactions of small heparin (HEP) like oligosaccharides with langerin in solution. Heparin-bead cross-linking experiments, an approach specifically designed to identify HEP/HS binding sites in proteins were first carried out and experimentally validated the previously proposed model for the interaction of Lg ECD with 6 kDa HEP. High-resolution NMR studies of a set of 8 synthetic HEP-like trisaccharides harboring different sulfation patterns demonstrated that all of them bound to langerin in a Ca2+ dependent way. The binding epitopes were determined by STD NMR and the bound conformations by transferred NOESY experiments. These experimental data were combined with docking and molecular dynamics and resulted in the proposal of a binding mode characterized by the coordination of calcium by the two equatorial hydroxyl groups OH3 and OH4 at the non-reducing end. The binding also includes the carboxylate group at the adjacent iduronate residue. Such epitope is shared by all the 8 ligands, explaining the absence of any impact on binding from their differences in substitution pattern. Finally, in contrast to the small trisaccharides, we demonstrated that a longer HEP-like hexasaccharide, bearing an additional O-sulfate group at the non-reducing end, which precludes binding to the Ca2+ site, interacts with langerin in the previously identified Ca2+ independent binding site

Successful treatment of persistent postoperative air leaks following the placement of an endobronchial one-way valve

resection in pathological conditions of the lung involve a very large spectrum of available methods, from chest drainage and placement of Heimlich valves to surgical repair or pleural decortication. However, in some of these patients surgery may be contraindicated. This report describes an endobronchial approach to the control of marked and prolonged air leaks in four patients using a newly designed one-way airway valve (Pulmonx Corporation; Redwood City, Ca.USA) placed into the segmental bronchus that is the source of air leakage. As the device is a one-way inspiratory airway blocker, it can be used to control persistent air leaks while maintaining the drainage of mucus. This approach potentially provides an effective nonsurgical and minimally invasive alternative addition to the armamentarium of treatments for patients who suffer with persistent post-operative air leaks where other methods have failed or in frail patients who are categorised as a high surgical risk

Detection and Quantitative Analysis of Two Independent Binding Modes of a Small Ligand Responsible for DC-SIGN Clustering

DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) is a C-type lectin receptor (CLRs) present, mainly in dendritic cells (DCs), as one of the major pattern recognition receptors (PRRs). This receptor has a relevant role in viral infection processes. Recent approaches aiming to block DC-SIGN have been presented as attractive anti-HIV strategies. DC-SIGN binds mannose or fucose-containing carbohydrates from viral proteins such as the HIV envelope glycoprotein gp120. We have previously demonstrated that multivalent dendrons bearing multiple copies of glycomimetic ligands were able to inhibit DC-SIGN-dependent HIV infection in cervical explant models. Optimization of glycomimetic ligands requires detailed characterization and analysis of their binding modes because they notably influence binding affinities. In a previous study we characterized the binding mode of DC-SIGN with ligand 1, which shows a single binding mode as demonstrated by NMR and X-ray crystallography. In this work we report the binding studies of DC-SIGN with pseudotrisaccharide 2, which has a larger affinity. Their binding was analysed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol and molecular modelling. These studies demonstrate that in solution the complex cannot be explained by a single binding mode. We describe the ensemble of ligand bound modes that best fit the experimental data and explain the higher inhibition values found for ligand

OA011-03. Clusterin, a natural ligand of DC-SIGN present in human semen inhibits HIV capture and transmission by dendritic cells

International audiencen.

The E00-110 experiment in Jefferson Lab's Hall A: Deeply Virtual Compton Scattering off the Proton at 6 GeV

We present final results on the photon electroproduction ($\vec{e}p\rightarrow ep\gamma$) cross section in the deeply virtual Compton scattering (DVCS) regime and the valence quark region from Jefferson Lab experiment E00-110. Results from an analysis of a subset of these data were published before, but the analysis has been improved which is described here at length, together with details on the experimental setup. Furthermore, additional data have been analyzed resulting in photon electroproduction cross sections at new kinematic settings, for a total of 588 experimental bins. Results of the $Q^2$- and $x_B$-dependences of both the helicity-dependent and helicity-independent cross sections are discussed. The $Q^2$-dependence illustrates the dominance of the twist-2 handbag amplitude in the kinematics of the experiment, as previously noted. Thanks to the excellent accuracy of this high luminosity experiment, it becomes clear that the unpolarized cross section shows a significant deviation from the Bethe-Heitler process in our kinematics, compatible with a large contribution from the leading twist-2 DVCS$^2$ term to the photon electroproduction cross section. The necessity to include higher-twist corrections in order to fully reproduce the shape of the data is also discussed. The DVCS cross sections in this paper represent the final set of experimental results from E00-110, superseding the previous publication.Comment: 48 pages, 32 figure

Scaling Tests of the Cross Section for Deeply Virtual Compton Scattering

We present the first measurements of the \vec{e}p->epg cross section in the deeply virtual Compton scattering (DVCS) regime and the valence quark region. The Q^2 dependence (from 1.5 to 2.3 GeV^2) of the helicity-dependent cross section indicates the twist-2 dominance of DVCS, proving that generalized parton distributions (GPDs) are accessible to experiment at moderate Q^2. The helicity-independent cross section is also measured at Q^2=2.3 GeV^2. We present the first model-independent measurement of linear combinations of GPDs and GPD integrals up to the twist-3 approximation.Comment: 5 pages, 4 figures, 2 tables. Text shortened for publication. References added. One figure remove

Deeply Virtual Compton Scattering off the neutron

The present experiment exploits the interference between the Deeply Virtual Compton Scattering (DVCS) and the Bethe-Heitler processes to extract the imaginary part of DVCS amplitudes on the neutron and on the deuteron from the helicity-dependent D$({\vec e},e'\gamma)X$ cross section measured at $Q^2$=1.9 GeV$^2$ and $x_B$=0.36. We extract a linear combination of generalized parton distributions (GPDs) particularly sensitive to $E_q$, the least constrained GPD. A model dependent constraint on the contribution of the up and down quarks to the nucleon spin is deduced.Comment: Published in Phys. Rev. Let