Direct visualization of superselective colloid-surface binding mediated by multivalent interactions

Reliably distinguishing between cells based on minute differences in receptor density is crucial for cell–cell or virus–cell recognition, the initiation of signal transduction, and selective targeting in directed drug delivery. Such sharp differentiation between different surfaces based on their receptor density can only be achieved by multivalent interactions. Several theoretical and experimental works have contributed to our understanding of this “superselectivity.” However, a versatile, controlled experimental model system that allows quantitative measurements on the ligand–receptor level is still missing. Here, we present a multivalent model system based on colloidal particles equipped with surface-mobile DNA linkers that can superselectively target a surface functionalized with the complementary mobile DNA-linkers. Using a combined approach of light microscopy and Foerster resonance energy transfer (FRET), we can directly observe the binding and recruitment of the ligand–receptor pairs in the contact area. We find a nonlinear transition in colloid-surface binding probability with increasing ligand or receptor concentration. In addition, we observe an increased sensitivity with weaker ligand–receptor interactions, and we confirm that the timescale of binding reversibility of individual linkers has a strong influence on superselectivity. These unprecedented insights on the ligand–receptor level provide dynamic information into the multivalent interaction between two fluidic membranes mediated by both mobile receptors and ligands and will enable future work on the role of spatial–temporal ligand–receptor dynamics on colloid-surface binding.

PILOT STUDY OF TOLL-LIKE RECEPTOR LEVEL 2 AND THYMIC STROMAL LYMPHOPOIETIN IN CHILDREN WITH ATOPIC DERMATITIS

The aim of this study is to assess the level of Toll-like receptor level 2 (TLR-2) and thymic stromal lymphopoietin (TSLP) in the blood serum of children and to establish the relationship between these parameters and the severity of clinical manifestations of atopic dermatitis (AD) and the degree of microbial contamination of the gut. Research materials and methods: 68 children aged from 3 months to 6 years with an AD and 31 conditionally healthy children of the corresponding age were examined. Determination of the level of TLR-2 and TSLP in blood serum was carried out by enzyme immunoassay, and the composition of the intestinal microflora was assessed by MALDITOF mass spectrometry. Results: in children with AD, the median serum TLR-2 level was 2,88 [1,60; 4,91] ng/ml, TSLP – 6,01 [1,11; 9,5] pg/ml, which is statistically significantly higher than in conventionally healthy children (p<0,0001). The highest levels of TLR-2 and TSLP were found in erythematoussquamous with lichenification of the AD form – Me=6,10 [3,55; 10,62] ng/ml and Ме=12,73 [5,81; 22,70] pg/ml respectively. In children with moderate severity of AD, TLR-2 and TSLP values were statistically significantly higher (p<0,0001) compared to mild AD (Me=5,58 [2,29; 8,18] ng/ml versus 0,72 [0,22; 2,02] ng/ml and 7,48 [4,25; 12,95] pg/ml versus 0,64 [0,39; 0,75] pg/ml, respectively). The level of TLR-2 and TSLP increased with the degree of intestinal dysbiosis: Me=6,27 [4,14; 8,02] ng/ml at grade 3 dysbiosis versus 1,25 [0,46; 2,15] ng/ml at the 1st degree of dysbiosis and 16,28 [10,01; 22,6] pg/ml at the 3rd degree of dysbiosis versus 0,63 [1,33; 0,70] pg/ml at the 1st degree of dysbiosis, respectively (p<0,0001). Results: the obtained data on the activation of TLR-2 and TSLP in AD emphasize the systemic nature of the inflammatory response; however, the causal relationship between the level of TLR-2 and TSLP and AD activity requires further verification.

Relationship of Soluble Interleukin-6 Receptors With Asthma: A Mendelian Randomization Study

Purpose: Emerging evidence suggests a potential role of interleukin-6 pathways—trans-signaling with soluble interleukin-6 receptors—in the asthma pathobiology. Despite the evidence for their associations with asthma, the causal role of soluble interleukin-6 receptors remains uncertain. We investigated the relations of soluble interleukin-6 receptors with asthma and its major phenotypes.Methods: We conducted a two-sample Mendelian randomization study. As genetic instruments, we selected 33 independent cis-acting variants strongly associated with the level of plasma soluble interleukin-6 receptor in the INTERVAL study. To investigate the association of variants with asthma and its phenotypes, we used genome-wide association study data from the UK Biobank. We combined variant-specific causal estimates by the inverse-variance weighted method for each outcome.Results: Genetically-instrumented soluble interleukin-6 receptor level was associated with a significantly higher risk of overall asthma (OR per one standard deviation increment in inverse-rank normalized soluble interleukin-6 receptor level, 1.02; 95%CI, 1.01–1.03; P = 0.004). Sensitivity analyses demonstrated consistent results and indicated no directional pleiotropy—e.g., MR-Egger (OR, 1.03; 95%CI, 1.01–1.05; P = 0.002; Pintercept =0.37). In the stratified analysis, the significant association persisted across asthma phenotypes—e.g., childhood asthma (OR, 1.05; 95%CI, 1.02–1.08; P &lt; 0.001) and obese asthma (OR, 1.02; 95%CI 1.01–1.03; P = 0.007). Sensitivity analysis using 16 variants selected with different thresholds also demonstrated significant associations with overall asthma and its phenotypes.Conclusion: Genetically-instrumented soluble interleukin-6 receptor level was causally associated with modestly but significantly higher risks of asthma and its phenotypes. Our observations support further investigations into identifying specific endotypes in which interleukin-6 pathways may play major roles.