Second generation of Fucose-based DC-SIGN ligands : affinity improvement and specificity versus Langerin

DC-SIGN and Langerin are two C-type lectins involved in the initial steps of HIV infections: the former acts as a viral attachment factor and facilitates viral invasion of the immune system, the latter has a protective effect. Potential antiviral compounds targeted against DC-SIGN were synthesized using a common fucosylamide anchor. Their DC-SIGN affinity was tested by SPR and found to be similar to that of the natural ligand Lewis-X (Le X). The compounds were also found to be selective for DC-SIGN and to interact only weakly with Langerin. These molecules are potentially useful therapeutic tools against sexually transmitted HIV infection

The human NAIP-NLRC4-inflammasome senses the Pseudomonas aeruginosa T3SS inner-rod protein.

While NLRC4-dependent sensing of intracellular Gram-negative pathogens such as Salmonella enterica serovar typhimurium is a beneficial host response, NLRC4-dependent sensing of the Pseudomonas aeruginosa type 3 secretion system (T3SS) has been shown to be involved in pathogenicity. In mice, different pathogen-associated microbial patterns are sensed by the combination of the NLRC4-inflammasome with different neuronal apoptosis inhibitory proteins (NAIPs). NAIP2 is involved in sensing PscI, an inner-rod protein of the P. aeruginosa T3SS. Surprisingly, only a single human NAIP (hNAIP) has been found. Moreover, there is no description of hNAIP-NLRC4 inflammasome recognition of T3SS inner-rod proteins in humans. Here, we show that the P. aeruginosa T3SS inner-rod protein PscI and needle protein PscF are both sensed by the hNAIP-NLRC4 inflammasome in human macrophages and PBMCs from healthy donors, allowing caspase-1 and IL-1β maturation and resulting in a robust inflammatory response. TLR4 and TLR2 are involved in redundantly sensing these two T3SS components

ERA-40 Atlas

Literary and scientific copyrights belong to ECMWF and are reserved in all countries. This publication is not to be reprinted or translated in whole or in part without the written permission of the Director. Appropriate non-commercial use will normally be granted under the condition that reference is made to ECMWF. The information within this publication is given in good faith and considered to be true, but ECMWF accepts no liability for error, omission and for loss or damage arising from its use. ERA-40 Atlas Personal Foreword by Brian Hoskins This atlas is the latest in a sequence that was originally inspired by the diagnostics of the general circulation of the atmosphere produced by Mike Wallace, Maurice Blackmon, Gabriel Lau and collaborators. In the middle and late 1970s they had taken advantage of the availability on magnetic tape of 10 years of routine analyses produced by the US National Meteorological Center for the region 20–90N. The advent and archiving of routine global analyses by the recently established European Centre for Medium-Range Forecasts (ECMWF) in Reading provided the opportunity to diagnose the global circulation. This opportunity was exploited in a Joint Diagnostics project involving the University of Reading, ECMWF and the UK Met Office. The diagnostics of ECMWF data were a crucial part of our activity in the UK Universities Modelling Group. Atlases were produced for the individual years 1980–81, 1981–82 and th

Chemo-Enzymatic Synthesis of S. mansoni O-Glycans and Their Evaluation as Ligands for C-Type Lectin Receptors MGL, DC-SIGN, and DC-SIGNR

Due to their interactions with C-type lectin receptors (CLRs), glycans from the helminth Schistosoma mansoni represent promising leads for treatment of autoimmune diseases, allergies or cancer. We chemo-enzymatically synthesized nine O-glycans based on the two predominant O-glycan cores observed in the infectious stages of schistosomiasis, the mucin core 2 and the S. mansoni core. The O-glycans were fucosylated next to a selection of N-glycans directly on a microarray slide using a recombinant fucosyltransferase and GDP-fucose or GDP-6-azidofucose as donor. Binding assays with fluorescently labelled human CLRs DC-SIGN, DC-SIGNR and MGL revealed the novel O-glycan O8 as the best ligand for MGL from our panel. Significant binding to DC-SIGN was also found for azido-fucosylated glycans. Contrasting binding specificities were observed between the monovalent carbohydrate recognition domain (CRD) and the tetravalent extracellular domain (ECD) of DC-SIGNR

Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor

The C-type lectin receptor DC-SIGN has been highlighted as the coreceptor for the spike protein of the SARS-CoV-2 virus. A multivalent glycomimetic ligand, Polyman26, has been found to inhibit DC-SIGN-dependent trans-infection of SARS-CoV-2. The molecular details underlying avidity generation in such systems remain poorly characterized. In an effort to dissect the contribution of the known multivalent effects ─ chelation, clustering, and statistical rebinding ─ we studied a series of dendrimer constructs related to Polyman26 with a rod core rationally designed to engage simultaneously two binding sites of the tetrameric DC-SIGN. Binding properties of these compounds have been studied with a range of biophysical techniques, including recently developed surface plasmon resonance oriented-surface methodology. Using molecular modeling we addressed, for the first time, the impact of the carbohydrate recognition domains’ flexibility of the DC-SIGN tetramer on the compounds’ avidity. We were able to gain deeper insight into the role of different binding modes, which in combination produce a construct with a nanomolar affinity despite a limited valency. This multifaceted experimental-theoretical approach provides detailed understanding of multivalent ligand/multimeric protein interactions which can lead to future predictions. This work opens the way to the development of new virus attachment blockers adapted to different C-type lectin receptors of viruses

Feedbacks of dust and boundary layer meteorology during a dust storm in the eastern Mediterranean

Aerosols affect the atmosphere through direct interaction with short-wave and long-wave radiation and the microphysical properties of clouds. In this paper we report in detail on several mechanisms by which the short-term impact of dust on surface radiative fluxes can affect the dust loading of the atmosphere via modification of boundary-layer meteorology. This in turn affects the aerosol radiative forcing itself. Examples of these feedbacks between dust and boundary layer meteorology were observed during a series of dust storms in the Sahara and the eastern Mediterranean in April 2012. These case studies have been analysed using the Monitoring Atmospheric Composition and Climate – Interim Implementation (MACC-II) system. The radiative fluxes in the short-wave and long-wave spectra were both significantly affected by the prognostic aerosol–radiation interaction, which in turn impacted the meteorological simulation. Reduced incoming solar radiation below the aerosol layers led to a decrease in maximum surface temperatures and to a more stable thermal stratification of the lower atmosphere. This in turn forced weaker surface wind speeds and eventually smaller dust emissions. Moreover, we also observed a secondary impact of the aerosol radiative forcing, whereby horizontal gradients of surface temperature were increased at the edge of the dust plume, which led to local increases of surface wind speeds due to the thermal wind effect. The differentiated impact of the aerosol layer on surface pressure also contributed to the increase in surface wind speed and dust production in the same area. Enhanced long-wave radiative fluxes by the dust mass were associated with opposite processes. Less stable thermal stratification at night, brought mainly by higher minimum temperatures at the surface, caused stronger surface winds. At the edge of the dust storm, weaker horizontal temperature and pressure gradients forced lower winds and reduced dust production. Regarding dust emissions, short-wave radiative forcing had a larger impact than long-wave radiative forcing, corroborating several previous studies. For surface temperature, short-wave and long-wave contribution were close in intensity. These feedbacks were amplified when using data assimilation to build the aerosol analysis of the MACC-II global system. This led to an improvement in the short-term forecasts of thermal radiative fluxes and surface temperatures

Precision Glycodendrimers for DC-SIGN Targeting**

Multivalent ligands of the C-type lectin receptor DC-SIGN have emerged as effective antiadhesive agents against various pathogens. Some years ago, we described a hexavalent DC-SIGN ligand, Polyman-26, designed to bridge two of the four binding sites displayed by the receptor. In this work, we present our efforts to accomplish simultaneous coordination of all four carbohydrate binding sites of DC-SIGN through the synthesis of cross-shaped glycodendrimers. The tailored rigid scaffold allowed multivalent presentation of glycomimetics in a spatially defined fashion, while providing good water solubility to the constructs. Evaluation of the biological activity by SPR assays revealed strong binding avidity towards DC-SIGN and increased selectivity over langerin. Inhibition of DC-SIGN binding to SARS-CoV-2 spike protein and of DC-SIGN mediated Ebola virus trans-infection testifies for the glycodendrimers potential application in infection diseases. The tetravalent platform described here is easily accessible and can be used in modular fashion with different ligands, thus lending itself to multiple applications

Structural studies of langerin and birbeck granule: a macromolecular organization model

International audienc

Human Macrophage Galactose-Type Lectin (MGL) Recognizes the Outer Core of Escherichia coli Lipooligosaccharide

Carbohydrate-lectin interactions intervene in and mediate most biological processes, including a crucial modulation of immune responses to pathogens. Despite growing interest in investigating the association between host receptor lectins and exogenous glycan ligands, the molecular mechanisms underlying bacterial recognition by human lectins are still not fully understood. Herein, a novel molecular interaction between the human macrophage galactose-type lectin (MGL) and the lipooligosaccharide (LOS) of Escherichia coli strain R1 is described. Saturation transfer difference NMR spectroscopy analysis, supported by computational studies, demonstrated that MGL bound to the purified deacylated LOSR1 mainly through recognition of its outer core and established crucial interactions with the terminal Galα(1,2)Gal epitope. These results assess the ability of MGL to recognise glycan moieties exposed on Gram-negative bacterial surfaces

A comparison of two methods for developing the linearization of a shallow-water model

We develop the linearization of a semi-implicit semi-Lagrangian model of the one-dimensional shallow-water equations using two different methods. The usual tangent linear model, formed by linearizing the discrete nonlinear model, is compared with a model formed by first linearizing the continuous nonlinear equations and then discretizing. Both models are shown to perform equally well for finite perturbations. However, the asymptotic behaviour of the two models differs as the perturbation size is reduced. This leads to difficulties in showing that the models are correctly coded using the standard tests. To overcome this difficulty we propose a new method for testing linear models, which we demonstrate both theoretically and numerically. © Crown copyright, 2003. Royal Meteorological Societ