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排序方式: 共有351条查询结果,搜索用时 15 毫秒
1.
Dr. Wojciech Schönemann Dr. Jonathan Cramer Tobias Mühlethaler Dr. Brigitte Fiege Marleen Silbermann Dr. Said Rabbani Dr. Philipp Dätwyler Dr. Pascal Zihlmann Dr. Roman P. Jakob Dr. Christoph P. Sager Dr. Martin Smieško Dr. Oliver Schwardt Prof. Dr. Timm Maier Prof. Dr. Beat Ernst 《ChemMedChem》2019,14(7):749-757
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 KD 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. 相似文献
2.
Dr. Blijke S. Kroezen Gabriele Conti Benedetta Girardi Dr. Jonathan Cramer Dr. Xiaohua Jiang Dr. Said Rabbani Jennifer Müller Maja Kokot Enrico Luisoni Prof. Daniel Ricklin Dr. Oliver Schwardt Prof. Beat Ernst 《ChemMedChem》2020,15(18):1706-1719
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 Lewisx 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 Lewisx 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. 相似文献
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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。 相似文献
4.
Mohammadreza Mahmoudi Sungjin Kim Arif M. Arifuzzaman Tomonori Saito Corson L. Cramer Majid Minary-Jolandan 《International Journal of Applied Ceramic Technology》2022,19(2):939-948
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. 相似文献
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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. 相似文献
8.
Sharon F. Arroyo Evin J. Cramer John E. Dennis Jr Paul D. Frank 《Optimization and Engineering》2009,10(4):557-573
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. 相似文献
9.
Digital dermatitis (DD) is a painful infectious foot lesion commonly treated topically with extra-label tetracycline. Our objectives were to determine the concentrations of tetracycline in milk and plasma and to calculate a withdrawal interval following topical application at various doses. Another objective was to evaluate agreement between tests for measuring tetracycline in milk. A randomized block trial was conducted on 2 farms, where 50 cows with active DD lesions on 2 feet were allocated to 1 of 5 treatment groups (n = 10 cows per group). Treatment groups consisted of topical applications of tetracycline hydrochloride, in a paste or as a powdered form under a bandage, at 3 different dosing levels (2, 5, and 25 g) on each of the 2 affected feet. Following enrollment and treatment, samples were collected from milk, teat skin, and blood every 8 to 24 h for up to 7 d postdosing. Concentrations of tetracycline were measured by liquid chromatography-mass spectrometry and milk samples were further tested using the Charm ROSA TET test (Charm Sciences Inc., Lawrence, MA). Tetracycline was present in milk, plasma, and teat skin from all treatment groups. Tetracycline concentrations varied depending on time of sampling, method of application, and dosing level. At 8 h post-treatment, 11% of cows had tetracycline present in milk higher than 100 ng/mL (ppb) but none higher than 300 ng/mL. The 25-g treatment group had the longest estimated withdrawal interval, the highest observed concentrations (210–244 ng/mL) of tetracycline present in milk, and the longest observed consecutive period of tetracycline presence (from 8 to 72 h) among all treatment groups. Compared with liquid chromatography-mass spectrometry, the Charm test had a sensitivity of 77 and 100% for measuring tetracycline in milk at ≥30 and ≥100 ng/mL, respectively. Post-treatment samples of the teat skin were taken from 15 cows on 6 occasions, and every cow had tetracycline present in at least 1 of those 6 samples. This confirms an association between topical DD treatment with tetracycline and contamination of the teat. A total of 22% of blood samples had detectable tetracycline, and the majority (63%) occurred at 8 h post-treatment. At 100 ng/mL, the estimated cow-level milk withdrawal interval ranged from 0 to 70 h. At 300 ng/mL, the estimated cow-level withdrawal interval ranged from 0 to 34 h, and was 0 h at the bulk tank level. We recommend that conservative measures be adopted after extra-label use of topical tetracycline for DD treatment, including using a low dose and strategic post-treatment testing for tetracycline-class drugs in milk. 相似文献
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