702 research outputs found
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
Usefulness of an Intrapartum Ultrasound Simulator (IUSim™) for Midwife Training: Results from an RCT
Introduction: We conducted a randomized study to determine whether a training session on a dedicated simulator (IUSim™) would facilitate the midwives in learning the technique of transperineal intrapartum ultrasound. Methods: Following a 30-min multimedia presentation including images and videos on how to obtain and measure the angle of progression (AoP) and the head-perineum distance (HPD), 6 midwives with no prior experience in intrapartum ultrasound were randomly split into 2 groups: 3 of them were assigned to the "training group"and 3 to the "control group."The midwives belonging to the former group were taught to measure the 2 sonographic parameters during a 3-h practical session conducted on IUSim™ under the supervision of an expert obstetrician. In the following 3 months, all the 6 midwives were asked to independently perform transperineal ultrasound during their clinical practice and to measure on the acquired images either the AoP or the HPD. The sonographic images were examined in blind by the teaching obstetrician who assigned a 0-3 score to the image quality (IQS) and to the measurement quality (MQS). Results: A total of 48 ultrasound images (24 patients) from 5 midwives were acquired and included in the study analysis. A midwife of the "training group"declined participation after the practical session. Independently from the randomization group, the image quality score (IQS + MQS) was significantly higher for the HPD compared with the AoP (2.5 ± 0.66 vs. 1.79 ± 1.14; p = 0.01). In the training group, the MQS of either AoP (2.66 ± 0.5 vs.1.46 ± 1.45. p = 0.038) and the HPD (2.9 ± 0.33 vs. 1.87 ± 0.83 p = 0.002) was significantly higher in comparison with the control group, while the IQS of both measurements was comparable between the 2 groups (1.91 ± 1.24 vs. 2.25 ± 0.865; p = 0.28). Conclusion: The use of a dedicated simulator may facilitate the midwives in learning how to measure the AoP and the HPD on transperineal ultrasound images
Coupling computer-interpretable guidelines with a drug-database through a web-based system – The PRESGUID project
BACKGROUND: Clinical Practice Guidelines (CPGs) available today are not extensively used due to lack of proper integration into clinical settings, knowledge-related information resources, and lack of decision support at the point of care in a particular clinical context. OBJECTIVE: The PRESGUID project (PREScription and GUIDelines) aims to improve the assistance provided by guidelines. The project proposes an online service enabling physicians to consult computerized CPGs linked to drug databases for easier integration into the healthcare process. METHODS: Computable CPGs are structured as decision trees and coded in XML format. Recommendations related to drug classes are tagged with ATC codes. We use a mapping module to enhance computerized guidelines coupling with a drug database, which contains detailed information about each usable specific medication. In this way, therapeutic recommendations are backed up with current and up-to-date information from the database. RESULTS: Two authoritative CPGs, originally diffused as static textual documents, have been implemented to validate the computerization process and to illustrate the usefulness of the resulting automated CPGs and their coupling with a drug database. We discuss the advantages of this approach for practitioners and the implications for both guideline developers and drug database providers. Other CPGs will be implemented and evaluated in real conditions by clinicians working in different health institutions
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
() 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 - and -dependences of both the helicity-dependent and
helicity-independent cross sections are discussed. The -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 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
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