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71.
72.
    
Human milk oligosaccharides (HMOs) and their most abundant component, 2′-Fucosyllactose (2′-FL), are known to be immunomodulatory. Previously, it was shown that HMOs and 2′-FL bind to the C-type lectin receptor DC-SIGN. Here we show, using a ligand-receptor competition assay, that a whole mixture of HMOs from pooled human milk (HMOS) and 2′-FL inhibit the binding of the carbohydrate-binding receptor DC-SIGN to its prototypical ligands, fucose and the oligosaccharide Lewis-B, (Leb) in a dose-dependent way. Interestingly, such inhibition by HMOS and 2′-FL was not detected for another C-type lectin, langerin, which is evolutionarily similar to DC-SIGN. The cell-ligand competition assay using DC-SIGN expressing cells confirmed that 2′-FL inhibits the binding of DC-SIGN to Leb. Molecular dynamic (MD) simulations show that 2′-FL exists in a preorganized bioactive conformation before binding to DC-SIGN and this conformation is retained after binding to DC-SIGN. Leb has more flexible conformations and utilizes two binding modes, which operate one at a time via its two fucoses to bind to DC-SIGN. Our hypothesis is that 2′-FL may have a reduced entropic penalty due to its preorganized state, compared to Leb, and it has a lower binding enthalpy, suggesting a better binding to DC-SIGN. Thus, due to the better binding to DC-SIGN, 2′-FL may replace Leb from its binding pocket in DC-SIGN. The MD simulations also showed that 2′-FL does not bind to langerin. Our studies confirm 2′-FL as a specific ligand for DC-SIGN and suggest that 2′-FL can replace other DC-SIGN ligands from its binding pocket during the ligand-receptor interactions in possible immunomodulatory processes.  相似文献   
73.
    
Drugs targeting type 4 dipeptidyl peptidase (DPP-4) are beneficial for glycemic control, whereas fibroblast activation protein alpha (FAP-α) is a potential target for cancer therapies. Unlike other gliptins, linagliptin displays FAP inhibition. We compared biophysical and structural characteristics of linagliptin binding to DPP-4 and FAP to better understand what differentiates linagliptin from other gliptins. Linagliptin exhibited high binding affinity (KD) and a slow off-rate (koff) when dissociating from DPP-4 (KD 6.6 pM; koff 5.1×10−5 s−1), and weaker inhibitory potency to FAP (KD 301 nM; koff>1 s−1). Co-structures of linagliptin with DPP-4 or FAP were similar except for one second shell amino acid difference: Asp663 (DPP-4) and Ala657 (FAP). pH dependence of enzymatic activities and binding of linagliptin for DPP-4 and FAP are dependent on this single amino acid difference. While linagliptin may not display any anticancer activity at therapeutic doses, our findings may guide future studies for the development of optimized inhibitors.  相似文献   
74.
Cluster analysis is sensitive to noise variables intrinsically contained within high dimensional data sets. As the size of data sets increases, clustering techniques robust to noise variables must be identified. This investigation gauges the capabilities of recent clustering algorithms applied to two real data sets increasingly perturbed by superfluous noise variables. The recent techniques include mixture models of factor analysers and auto-associative multivariate regression trees. Statistical techniques are integrated to create two approaches useful for clustering noisy data: multivariate regression trees with principal component scores and multivariate regression trees with factor scores. The tree techniques generate the superior clustering results.  相似文献   
75.
We examine the effect of online Argumentation Vee Diagrams (AVDs) on the quality of students’ argumentation during asynchronous, online discussions. With AVDs, students develop arguments on both sides of a controversial issue and then develop an integrated, overall final conclusion. In this study, students used AVDs individually before composing discussion notes, and then—at the end of the discussion—jointly created a group AVD using Wiki technology. Compared to a control group, the experimental intervention was found to significantly enhance the integration of arguments and counterarguments (specifically, compromises) and fostered opinion change. For AVDs to be effective, however, it was found to be necessary to include specific scaffolds on how to evaluate argument strength and/or to provide practice and feedback in using the AVDs.  相似文献   
76.
A careful study was undertaken of the initial charge developed on the non-metallized surface and of short-circuit thermally stimulated currents (TSCs) in unilaterally metallized polystyrene (PS) films 25 microm thick. The films had been negatively charged by Townsend breakdown at a voltage of −5 kV at various temperatures ranging from 90 to 130°C. The surface charge densities observed were of the order of 10-8 C cm-2, corresponding to full trap densities of the order of 1014 cm−3. The short-circuit TSC spectra of newly charged samples show a single peak at a temperature between 98 and 102°C. The thermal activation energy associated with this peak was found to be 1.2 eV. An analysis of TSCs indicates that electrons are subject to fast retrapping in PS. The ratio of the mean charge depth to the sample thickness is found to increase from 0.069 to 0.12 with the increase in the temperature of polarization, indicating a higher charge accommodation at higher temperatures of polarization. The trap-modulated mobility values for electrons at the TSC peak temperatures are the order of 10−12 cm2 V−1s−1. Such low mobility values at peak temperatures are considered to indicate the excellent charge storage properties of PS.  相似文献   
77.
    
Hardware tracing has emerged as a low‐cost technique to analyze systems at a very fine granularity, thus mitigating the need for software‐only trace approaches for performance analysis. State‐of‐the‐art trace hardware on modern Intel and ARM processors allows recording change‐of‐flow instructions in executable binaries, such as branches, for off‐line reconstruction. This conventional userspace–based trace reconstruction, however, is not robust enough in the common scenarios where runtime code is being generated, compiled, and executed. We therefore propose a novel kernel‐assisted mechanism called FlowJIT to reconstruct hardware traces with a low overhead of around 1.3 μs per code page modification event. We further show the efficacy or our technique with the help of 2 illustrative usecases that cover the JIT compiled code scenario and a same‐page instruction modification scenario. Our implementation has been open sourced as a patch for the Linux kernel.  相似文献   
78.
Non-alcoholic steatohepatitis (NASH) represents a risk factor for the development of hepatocellular carcinoma (HCC) and is characterized by quantitative and qualitative changes in hepatic lipids. Since elongation of fatty acids from C16 to C18 has recently been reported to promote both hepatic lipid accumulation and inflammation we aimed to investigate whether a frequently used mouse NASH model reflects this clinically relevant feature and whether C16 to C18 elongation can be observed in HCC development. Feeding mice a methionine and choline deficient diet to model NASH not only increased total hepatic fatty acids and cholesterol, but also distinctly elevated the C18/C16 ratio, which was not changed in a model of simple steatosis (ob/ob mice). Depletion of Kupffer cells abrogated both quantitative and qualitative methionine-and-choline deficient (MCD)-induced alterations in hepatic lipids. Interestingly, mimicking inflammatory events in early hepatocarcinogenesis by diethylnitrosamine-induced carcinogenesis (48 h) increased hepatic lipids and the C18/C16 ratio. Analyses of human liver samples from patients with NASH or NASH-related HCC showed an elevated expression of the elongase ELOVL6, which is responsible for the elongation of C16 fatty acids. Taken together, our findings suggest a detrimental role of an altered fatty acid pattern in the progression of NASH-related liver disease.  相似文献   
79.
80.
Alicyclobacillus spoilage and isolation--a review   总被引:2,自引:0,他引:2  
Until recently, acidic products such as fruit juice and fruit based products were generally thought to be susceptible to spoilage by yeasts, mycelia fungi and lactic acid bacteria, as the low pH of these products acts as natural control measures against spoilage by most bacteria. Alicyclobacillus seem to be prevalent in fruit based products as they survive the acidic fruit juice environment, even when they are exposed to pasteurisation temperatures during production. In this review the historical background of the discovery of these bacteria is summarised. The bacterial characteristics and the reported spoilage incidences caused by members of this genus are discussed. As the isolation methods for these bacteria are controversial, this review includes a discussion of the various media that have been reported in the literature for the use in the isolation and enumeration of members of the genus Alicyclobacillus.  相似文献   
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