A Potent Mimetic of the Siglec-8 Ligand 6’-Sulfo-Sialyl Lewisx

Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewis^x has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewis^x and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.     

Improvement of Aglycone π-Stacking Yields Nanomolar to Sub-nanomolar FimH Antagonists

Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d -mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar K_D values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as ¹H,¹⁵N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.     

Processing and 3D printing of SiCN polymer-derived ceramics

Preceramic polymer resins are attractive for the 3D printing of net-shaped ceramic components. Recently various processes have been demonstrated for 3D printing of polymer-derived ceramics (PDCs). Ultimately in these processes, the process outcomes strongly depend on the process parameters. In particular, for PDCs the ceramic density, and ceramic yield are affected by the catalyst concentration and cross-linking duration. Here, we use thermal analysis and FTIR to quantify the interrelation of the process parameters on the process outcome for polysilazanes and demonstrate 3D printing of PDC components based on the best-identified process parameters. The results of this work can be used as guidelines for future additive manufacturing of PDCs.     

Making urban real estate markets work for the poor: Theory, policy and practice

This paper explores the relationship between theory, policy and practice, linking urban real estate markets and poverty alleviation. The paper argues that the contribution of urban real estate markets to poverty alleviation has not been optimised due, in part, to inadequate or inappropriate policy. The article attributes this to conceptual and methodological problems arising from the traditional neoclassical analysis of urban real estate markets, ambivalence to the idea that freer markets in real estate are a good thing for the urban poor and insufficient regard to lessons of experience from years of implementing urban anti-poverty land projects. Based on new analytical perspectives provided by institutional economics, this paper proposes specific policy interventions more likely to facilitate pro-poor outcomes in urban real estate markets.     

Comparing problem formulations for coupled sets of components

This paper presents several formulations and comparative test results for problems involving the general paradigm of coupled sets of components (CSoC). This paradigm is general enough to include systems of systems (SoS) under any of the various definitions, as well as multidisciplinary design optimization (MDO). It is assumed that a CSoC involves a (potentially inactive) coordinating component, or “Central Authority”, and one or more, potentially interacting, subordinate components. The formulations differ in the amount of control given to the CA versus the autonomy granted to the subordinate components. In this generality, satisfaction of equilibrium conditions replaces the optimality condition in defining a solution. A solution still requires feasibility of all constraints. The desirability of a particular equilibrium point depends on the specific problem being studied and the component algorithms used to obtain that equilibrium. These concepts are illustrated using comparative test results for several of the formulations on a NASA-generated, public domain, aircraft conceptual design problem.     

Reflection mode scanning near-field optical microscopy analyses of integrated devices

Ultra-large-scale integrated devices have been investigated by a reflection mode scanning near-field optical microscope designed for semiconductor analyses. Although it could be found that imaging the reflectivity of metal structures buried underneath thin, optically transparent passivation layers is practicable, shading of the reflected light by the SNOM probe complicated the interpretability of the achieved results. This issue has been overcome by using the SNOM probe as both illumination source and detector, simultaneously. The application of focused ion beam milling to the probes has allowed the increase of the transmittivity of the probes to such an extent that coated fibres could be utilized and the interpretability of the results could be enhanced. Furthermore, the investigated structures are of great interest for an investigation of z -motion artefacts, as the presence of the polished passivation layers allows topographical influences to be distinguished from pure optical contrast.     

SteelStacks艺术文化园区的骨架：胡弗梅森栈桥

正伯利恒钢铁公司是20世纪的一个工业集团,在世界范围内运作工业设施。它于1857年在宾夕法尼亚州里海谷(Lehigh Valley)创立,逐渐占据了里海河沿线1 800英亩(约728hm2)的场地。1995年,伯利恒钢铁公司停止了炼钢业务,关闭了厂房,结束了当地悠久的工业历史,以及成千上万蓝领居民与工厂密不可分的生活模式。