A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN

Dendritic cells (DC) are antigen-presenting cells coordinating the interplay of the innate and the adaptive immune response. The endocytic C-type lectin receptors DC-SIGN and Langerin display expression profiles restricted to distinct DC subtypes and have emerged as prime targets for next-generation immunotherapies and anti-infectives. Using heteromultivalent liposomes copresenting mannosides bearing aromatic aglycones with natural glycan ligands, we serendipitously discovered striking cooperativity effects for DC-SIGN+ but not for Langerin+ cell lines. Mechanistic investigations combining NMR spectroscopy with molecular docking and molecular dynamics simulations led to the identification of a secondary binding pocket for the glycomimetics. This pocket, located remotely of DC-SIGN’s carbohydrate bindings site, can be leveraged by heteromultivalent avidity enhancement. We further present preliminary evidence that the aglycone allosterically activates glycan recognition and thereby contributes to DC-SIGN-specific cell targeting. Our findings have important implications for both translational and basic glycoscience, showcasing heteromultivalent targeting of DCs to improve specificity and supporting potential allosteric regulation of DC-SIGN and CLRs in general

The 1979-2005 Greenland ice sheet melt extent from passive microwave data using an improved version of the melt retrieval XPGR algorithm

Analysis of passive microwave satellite observations over the Greenland ice sheet reveals a significant increase in surface melt over the period 1979-2005. Since 1979, the total melt area was found to have increased +1.22 x 10ˆ7 kmˆ2. An improved version of the cross-polarized gradient ratio (XPGR) technique is used to identify the melt from the brightness temperatures. The improvements in the melt retrieval XPGR algorithm as well as the surface melt acceleration are discussed with results from a coupled atmosphere-snow regional climate model. From 1979 to 2005, the ablation period increases everywhere over the melt zone except in the regions where the model simulates an increased summer snowfall. Indeed, more snowfall in summer decreases the liquid water content of the snowpack, raises the albedo and therefore reduces the melt. Finally, this melt acceleration over the Greenland ice sheet is highly correlated with both Greenland and global warming suggesting a continuing surface melt increase in the future.Peer reviewe

A remote secondary binding pocket promotes heteromultivalent targeting of DC-SIGN

Dendritic cells (DC) are antigen-presenting cells coordinating the interplay of the innate and the adaptive immune response. The endocytic C-type lectin receptors DC-SIGN and Langerin display expression profiles restricted to distinct DC subtypes and have emerged as prime targets for next-generation immunotherapies and anti-infectives. Using heteromultivalent liposomes copresenting mannosides bearing aromatic aglycones with natural glycan ligands, we serendipitously discovered striking cooperativity effects for DC-SIGN+ but not for Langerin+ cell lines. Mechanistic investigations combining NMR spectroscopy with molecular docking and molecular dynamics simulations led to the identification of a secondary binding pocket for the glycomimetics. This pocket, located remotely of DC-SIGN’s carbohydrate bindings site, can be leveraged by heteromultivalent avidity enhancement. We further present preliminary evidence that the aglycone allosterically activates glycan recognition and thereby contributes to DC-SIGN-specific cell targeting. Our findings have important implications for both translational and basic glycoscience, showcasing heteromultivalent targeting of DCs to improve specificity and supporting potential allosteric regulation of DC-SIGN and CLRs in general

The 1958–2009 Greenland ice sheet surface melt and the mid-tropospheric atmospheric circulation

peer reviewedaudience: researcherIn order to assess the impact of the mid-tropospheric circulation over the Greenland ice sheet (GrIS) on surface melt, as simulated by the regional climate model MAR, an automatic Circulation type classification (CTC) based on 500 hPa geopotential height from reanalyses is developed. General circulation correlates significantly with the surface melt anomalies for the summers in the period 1958–2009. The record surface melt events observed during the summers of 2007–2009 are linked to the exceptional persistence of atmospheric circulations favouring warm air advection. The CTC emphasizes that summer 500 hPa circulation patterns have changed since the beginning of the 2000s; this process is partly responsible for the recent warming observed over the GrIS

Evaluation of a high-resolution regional climate simulation over Greenland

A simulation of the 1991 summer has been performed over south Greenland with a coupled atmosphere–snow regional climate model (RCM) forced by the ECMWF re-analysis. The simulation is evaluated with in-situ coastal and ice-sheet atmospheric and glaciological observations. Modelled air temperature, specific humidity, wind speed and radiative fluxes are in good agreement with the available observations, although uncertainties in the radiative transfer scheme need further investigation to improve the model’s performance. In the sub-surface snow-ice model, surface albedo is calculated from the simulated snow grain shape and size, snow depth, meltwater accumulation, cloudiness and ice albedo. The use of snow metamorphism processes allows a realistic modelling of the temporal variations in the surface albedo during both melting periods and accumulation events. Concerning the surface albedo, the main finding is that an accurate albedo simulation during the melting season strongly depends on a proper initialization of the surface conditions which mainly result from winter accumulation processes. Furthermore, in a sensitivity experiment with a constant 0.8 albedo over the whole ice sheet, the average amount of melt decreased by more than 60%, which highlights the importance of a correctly simulated surface albedo. The use of this coupled atmosphere–snow RCM offers new perspectives in the study of the Greenland surface mass balance due to the represented feedback between the surface climate and the surface albedo, which is the most sensitive parameter in energy-balance-based ablation calculations.Peer reviewe

A mixed methods pilot study with a cluster randomized control trial to evaluate the impact of a leadership intervention on guideline implementation in home care nursing

Abstract Background Foot ulcers are a significant problem for people with diabetes. Comprehensive assessments of risk factors associated with diabetic foot ulcer are recommended in clinical guidelines to decrease complications such as prolonged healing, gangrene and amputations, and to promote effective management. However, the translation of clinical guidelines into nursing practice remains fragmented and inconsistent, and a recent homecare chart audit showed less than half the recommended risk factors for diabetic foot ulcers were assessed, and peripheral neuropathy (the most significant predictor of complications) was not assessed at all. Strong leadership is consistently described as significant to successfully transfer guidelines into practice. Limited research exists however regarding which leadership behaviours facilitate and support implementation in nursing. The purpose of this pilot study is to evaluate the impact of a leadership intervention in community nursing on implementing recommendations from a clinical guideline on the nursing assessment and management of diabetic foot ulcers. Methods Two phase mixed methods design is proposed (ISRCTN 12345678). Phase I: Descriptive qualitative to understand barriers to implementing the guideline recommendations, and to inform the intervention. Phase II: Matched pair cluster randomized controlled trial (n = 4 centers) will evaluate differences in outcomes between two implementation strategies. Primary outcome: Nursing assessments of client risk factors, a composite score of 8 items based on Diabetes/Foot Ulcer guideline recommendations. Intervention: In addition to the organization's 'usual' implementation strategy, a 12 week leadership strategy will be offered to managerial and clinical leaders consisting of: a) printed materials, b) one day interactive workshop to develop a leadership action plan tailored to barriers to support implementation; c) three post-workshop teleconferences. Discussion This study will provide vital information on which leadership strategies are well received to facilitate and support guideline implementation. The anticipated outcomes will provide information to assist with effective management of foot ulcers for people with diabetes. By tracking clinical outcomes associated with guideline implementation, health care administrators will be better informed to influence organizational and policy decision-making to support evidence-based quality care. Findings will be useful to inform the design of future multi-centered trials on various clinical topics to enhance knowledge translation for positive outcomes. Trial Registration Current Control Trials ISRCTN0691089

Modelling of large-scale melt parameters with a regional climate model in South-Greenland during the 1991 melt season

Large-scale positive degree-day based melt parameterisations for the Greenland ice sheet are highly sensitive to their parameters (standard temperature deviation, snow and ice degree-day factors). In this article, these parametrs have been simulated with a coupled atmosphere-snow regional climate model for the southern part of Greenland during the summer of 1991 forced at the lateral boundaries with ECMWF re-analysis. The calculated (from net ablation, i.e. ablation without refreezing) snow and ice positive degree-day factors vary considerably over the ice sheet. At low elevations, the modelled snow degree-day factor approaches closely the generally accepted value of 3 mm WE d-1 °C-1. Higher up the ice sheet, large values up to 15 mm WE d-1 °C-1 are simulated. In case of ice melt, maximum values until 40 mm WE d-1 °C-1 are found. The snow and ice positive degree-day factor distributions peak respectively at 3 and 8 mm WE d-1 °C-1. Refreezing is of small importance close to the ice sheet margin. Higher up the ice sheet, refreezing considerably lowers the amount of net ablation. The monthly simulated 2m air temperature standard deviation exhibits a strong seasonal cycle with the highest (between 3.0° and 5.0°C) values in May and June. July shows the lowest temperature fluctuations due to melting of the surface

Climate-fit.city Deliverable 5.1 Urban primary data need analysis

nrpages: 97status: publishe