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1.
Alejandra M. Peter Ventura Dr. Simone Haeberlein Dr. Kerstin Lange-Grünweller Prof. Dr. Arnold Grünweller Prof. Dr. Roland K. Hartmann Prof. Dr. Christoph G. Grevelding Prof. Dr. Martin Schlitzer 《ChemMedChem》2019,14(21):1856-1862
The parasitic disease schistosomiasis is the cause of more than 200 000 human deaths per year. Although the disease is treatable, there is one major shortcoming: praziquantel has been the only drug used to combat these parasites since 1977. The risk of the emergence of resistant schistosomes is known to be increasing, as a reduced sensitivity of these parasites toward praziquantel has been observed. We developed a new class of substances, which are derived from inhibitors of human aldose reductase, and which showed promising activity against Schistosoma mansoni couples in vitro. Further optimisation of the compounds led to an increase in anti-schistosomal activity with observed phenotypes such as reduced egg production, vitality, and motility as well as tegumental damage and gut dilatation. Here, we performed structure–activity relationship studies on the carboxylic acid moiety of biarylalkyl carboxylic acids. Out of 82 carboxylic acid amides, we identified 10 compounds that are active against S. mansoni at 25 μm . The best five compounds showed an anti-schistosomal activity up to 10 μm and induced severe phenotypes. Cytotoxicity tests in human cell lines showed that two derivatives had no cytotoxicity at 50 or 100 μm . These compounds are promising candidates for further optimisation toward the new anti-schistosomal agents. 相似文献
2.
Christine Vssing Marta Owczarek-Lipska Kerstin Nagel-Wolfrum Charlotte Reiff Christoph Jüschke John Neidhardt 《International journal of molecular sciences》2020,21(22)
X-chromosomal retinitis pigmentosa (RP) frequently is caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. We evaluated the potential of PTC124 (Ataluren, TranslamaTM) treatment to promote ribosomal read-through of premature termination codons (PTC) in RPGR. Expression constructs in HEK293T cells showed that the efficacy of read-through reagents is higher for UGA than UAA PTCs. We identified the novel hemizygous nonsense mutation c.1154T > A, p.Leu385* () causing a UAA PTC in RPGR and generated patient-derived fibroblasts. Immunocytochemistry of serum-starved control fibroblasts showed the RPGR protein in a dot-like expression pattern along the primary cilium. In contrast, RPGR was no longer detectable at the primary cilium in patient-derived cells. Applying PTC124 restored RPGR at the cilium in approximately 8% of patient-derived cells. RT-PCR and Western blot assays verified the pathogenic mechanisms underlying the nonsense variant. Immunofluorescence stainings confirmed the successful PTC124 treatment. Our results showed for the first time that PTC124 induces read-through of PTCs in RPGR and restores the localization of the RPGR protein at the primary cilium in patient-derived cells. These results may provide a promising new treatment option for patients suffering from nonsense mutations in RPGR or other genetic diseases. NM_000328.3相似文献
3.
Claudia Pielsticker Martin F. Brodde Lisa Raum Kerstin Jurk Beate E. Kehrel 《International journal of molecular sciences》2020,21(22)
Inflammatory processes are triggered by the fibrinolytic enzyme plasmin. Tissue-type plasminogen activator, which cleaves plasminogen to plasmin, can be activated by the cross-β-structure of misfolded proteins. Misfolded protein aggregates also represent substrates for plasmin, promoting their degradation, and are potent platelet agonists. However, the regulation of plasmin-mediated platelet activation by misfolded proteins and vice versa is incompletely understood. In this study, we hypothesize that plasmin acts as potent agonist of human platelets in vitro after short-term incubation at room temperature, and that the response to thrombospondin-1 and the bona fide misfolded proteins Eap and SCN−-denatured IgG interfere with plasmin, thereby modulating platelet activation. Plasmin dose-dependently induced CD62P surface expression on, and binding of fibrinogen to, human platelets in the absence/presence of plasma and in citrated whole blood, as analyzed by flow cytometry. Thrombospondin-1 pre-incubated with plasmin enhanced these plasmin-induced platelet responses at low concentration and diminished them at higher dose. Platelet fibrinogen binding was dose-dependently induced by the C-terminal thrombospondin-1 peptide RFYVVMWK, Eap or NaSCN-treated IgG, but diminished in the presence of plasmin. Blocking enzymatically catalyzed thiol-isomerization decreased plasmin-induced platelet responses, suggesting that plasmin activates platelets in a thiol-dependent manner. Thrombospondin-1, depending on the concentration, may act as cofactor or inhibitor of plasmin-induced platelet activation, and plasmin blocks platelet activation induced by misfolded proteins and vice versa, which might be of clinical relevance. 相似文献
4.
Dr. James P. Holt-Martyn Dr. Rasheduzzaman Chowdhury Dr. Anthony Tumber Dr. Tzu-Lan Yeh Dr. Martine I. Abboud Dr. Kerstin Lippl Dr. Christopher T. Lohans Dr. Gareth W. Langley William Figg Jr. Dr. Michael A. McDonough Prof. Dr. Christopher W. Pugh Prof. Dr. Peter J. Ratcliffe Prof. Dr. Christopher J. Schofield 《ChemMedChem》2020,15(3):270-273
The 2-oxoglutarate-dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late stage clinical trials. The number of reported templates for PHD inhibition is limited. We report structure–activity relationship and crystallographic studies on a promising class of 4-hydroxypyrimidine-containing PHD inhibitors. 相似文献
5.
Bunte Olav van Gool Louis C. M. Willemse Tim A. C. 《International Journal on Software Tools for Technology Transfer (STTT)》2022,24(3):441-472
International Journal on Software Tools for Technology Transfer - To aid in making software bug-free, several high-tech companies are moving from coding to modelling. In some cases model checking... 相似文献
6.
Chemikalienfreie Bekämpfung von Holzschädlingen durch dielektrische Erwärmung mit Radiowellen und Mikrowellen 下载免费PDF全文
Christian Hoyer Christian Pfütze Dr. Rudy Plarre Dr. Ulf Trommler Steffen Steinbach Kerstin Klutzny Dr. Frank Holzer Carsten Rabe Björn Höhlig Prof. Frank‐Dieter Kopinke Prof. Detlef Schmidt Dr. Ulf Roland 《化学,工程师,技术》2014,86(8):1187-1197
Thermal pest control requires long treatment times due to the low thermal conductivity of wood and may lead to the formation of cracks. Here, the thermal treatment with radio waves as well as microwaves has been studied. The direct dielectric heating has the advantage of a good homogeneity. The obtained temperature profiles for radio waves were more homogeneous compared to microwaves. Detailed studies showed that elimination of pests was not related to the application of the electromagnetic field itself, but due to the temperature increase. 相似文献
7.
8.
《材料的重要性》是《景观设计理论》的一段节选。《景观设计理论》旨在不使用专业术语或其他领域假说的前提下,结合景观设计过程向学生介绍内在理论思想。《材料的重要性》是本书的五章之一。每一章针对特定理论,解释了其基础和来源,探讨了它对设计的重要性,列举了20—21世纪与其相关的设计案例,整理了该理论的辩论(尤其是有关现代和后现代思想),最后还有相关阅读材料清单和需要学生们思考的问题。本文分为如下3个部分:第一部分,物质性,介绍“辩证唯物主义”“媒介即信息”“物质实践”和“编码”等理论及其在设计中的运用;第二部分,通过“建构表达”“地貌代理人策略”“石材的面层”“材料的暗示”“人造,但不是伪造”等理论,介绍材料的真实性及其在设计中的运用;第三部分,复写理论及应用,包括“剩余物”“复写的展示性”“未来的复写”和“虚构的复写”等内容。 相似文献
9.
通过绿色基础设施途径,处理美国波士顿北部的马萨诸塞州城市流域的水资源规划问题。从多个尺度为风景园林师提供水资源规划的经验与启发,探究公众对新型绿色基础设施解决方案的态度与偏好,以及公众偏好对于整体规划设计的重要作用。 相似文献
10.
Walter Vetter Kerstin Hummert Bernd Luckas Karl Skírnisson 《The Science of the total environment》1995,170(3)
Harbour seals and grey seals from Faxaflói (Western Iceland) were analyzed for contamination with organochlorines (HCB, PCBs, p,p′-DDT, p,p′-DDE, chlordanes and the enantiomers of α-HCH). Although the values strongly varied, both harbour seals and grey seals on average showed comparable levels of PCBs, p,p′-DDT, p,p′-DDE and α-HCH, as well as chlordanes (ΣCD). Differences were measured in the HCB content of the seal species. The HCB/α-HCH ratio in harbour seals was <1 and in grey seals >1. The results from seals on Iceland were compared with data derived from seal samples of the Antarctic, the Arctic (Spitzbergen) and the North Sea (Germany) in order to give an insight into the global distribution of pollution with chlorinated organics. 相似文献