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Florian Bauer Claudia Kuntner Jens P. Bankstahl Thomas Wanek Marion Bankstahl Johann Stanek Severin Mairinger Bernd Dörner Wolfgang Löscher Markus Müller Thomas Erker Oliver Langer 《Bioorganic & medicinal chemistry》2010,18(15):5489-5497
The aim of this study was to develop a positron emission tomography (PET) tracer based on the dual P-glycoprotein (P-gp) breast cancer resistance protein (BCRP) inhibitor tariquidar (1) to study the interaction of 1 with P-gp and BCRP in the blood–brain barrier (BBB) in vivo. O-Desmethyl-1 was synthesized and reacted with [11C]methyl triflate to afford [11C]-1. Small-animal PET imaging of [11C]-1 was performed in naïve rats, before and after administration of unlabeled 1 (15 mg/kg, n = 3) or the dual P-gp/BCRP inhibitor elacridar (5 mg/kg, n = 2), as well as in wild-type, Mdr1a/b(?/?), Bcrp1(?/?) and Mdr1a/b(?/?)Bcrp1(?/?) mice (n = 3). In vitro autoradiography was performed with [11C]-1 using brain sections of all four mouse types, with and without co-incubation with unlabeled 1 or elacridar (1 μM). In PET experiments in rats, administration of unlabeled 1 or elacridar increased brain activity uptake by a factor of 3–4, whereas blood activity levels remained unchanged. In Mdr1a/b(?/?), Bcrp1(?/?) and Mdr1a/b(?/?)Bcrp1(?/?) mice, brain-to-blood ratios of activity at 25 min after tracer injection were 3.4, 1.8 and 14.5 times higher, respectively, as compared to wild-type animals. Autoradiography showed approximately 50% less [11C]-1 binding in transporter knockout mice compared to wild-type mice and significant displacement by unlabeled elacridar in wild-type and Mdr1a/b(?/?) mouse brains. Our data suggest that [11C]-1 interacts specifically with P-gp and BCRP in the BBB. However, further investigations are needed to assess if [11C]-1 behaves in vivo as a transported or a non-transported inhibitor. 相似文献
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Background
The species-specificity of male genitalia has been well documented in many insect groups and sexual selection has been proposed as the evolutionary force driving the often rapid, morphological divergence. The internal female genitalia, in sharp contrast, remain poorly studied. Here, we present the first comparative study of the internal reproductive system of Sepsidae. We test the species-specificity of the female genitalia by comparing recently diverged sister taxa. We also compare the rate of change in female morphological characters with the rate of fast-evolving, molecular and behavioral characters. 相似文献887.
Marion Geerligs Gerrit W.M. Peters Paul A.J. Ackermans Cees W.J. Oomens Frank P.T. Baaijens 《Journal of biomechanics》2010,43(6):1153-1159
Although subcutaneous adipose tissue undergoes large deformations on a daily basis, there is no adequate mechanical model to describe the transfer of mechanical load from the skin throughout the tissue to deeper layers. In order to develop such a non-linear model, a set of experimental data is required. Accordingly, this study examines the long term behavior of adipose tissue under small strain and its response to various large strain profiles. The results show that the shear modulus dramatically increases to about an order of magnitude after a loading period between 250 and 1250 s, but returns to its initial value within 3 h of recovery from loading. In addition, it was observed that the stress–strain responses for various large strain history sequences are reproducible up to a strain of 0.15. For increasing strains, the stress decreases for subsequent loading cycles and, above 0.3 strain, tissue structure changes such that the stress becomes independent of the applied strain. From the results, it can be concluded that adipose tissue likely behaves as an (anti-) thixotropic material and that a Mooney–Rivlin model might be appropriate to simulate behavior at physiologically relevant high strains. However, before the model is developed more fully, further experimental research is needed to ratify that the material is (anti-)thixotropic. 相似文献
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Karen Gilio Roger van Kruchten Attila Braun Alejandro Berna-Erro Marion A. H. Feijge David Stegner Paola E. J. van der Meijden Marijke J. E. Kuijpers David Varga-Szabo Johan W. M. Heemskerk Bernhard Nieswandt 《The Journal of biological chemistry》2010,285(31):23629-23638
In platelets, STIM1 has been recognized as the key regulatory protein in store-operated Ca2+ entry (SOCE) with Orai1 as principal Ca2+ entry channel. Both proteins contribute to collagen-dependent arterial thrombosis in mice in vivo. It is unclear whether STIM2 is involved. A key platelet response relying on Ca2+ entry is the surface exposure of phosphatidylserine (PS), which accomplishes platelet procoagulant activity. We studied this response in mouse platelets deficient in STIM1, STIM2, or Orai1. Upon high shear flow of blood over collagen, Stim1−/− and Orai1−/− platelets had greatly impaired glycoprotein (GP) VI-dependent Ca2+ signals, and they were deficient in PS exposure and thrombus formation. In contrast, Stim2−/− platelets reacted normally. Upon blood flow in the presence of thrombin generation and coagulation, Ca2+ signals of Stim1−/− and Orai1−/− platelets were partly reduced, whereas the PS exposure and formation of fibrin-rich thrombi were normalized. Washed Stim1−/− and Orai1−/− platelets were deficient in GPVI-induced PS exposure and prothrombinase activity, but not when thrombin was present as co-agonist. Markedly, , a blocker of (receptor-operated) Ca2+ entry, inhibited Ca2+ and procoagulant responses even in Stim1−/− and Orai1−/− platelets. These data show for the first time that: (i) STIM1 and Orai1 jointly contribute to GPVI-induced SOCE, procoagulant activity, and thrombus formation; (ii) a compensating Ca2+ entry pathway is effective in the additional presence of thrombin; (iii) platelets contain two mechanisms of Ca2+ entry and PS exposure, only one relying on STIM1-Orai1 interaction. SKF96365相似文献
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Recognition by scavenger receptor cysteine-rich domains on membrane proteins regulates innate and adaptive immune responses. Two receptors expressed primarily on T cells, CD5 and CD6, are linked genetically and are structurally similar, both containing three scavenger receptor cysteine-rich domains in their extracellular regions. A specific cell surface interaction for CD5 has been difficult to define at the molecular level because of the susceptibility of CD5 protein to denaturation. By using soluble CD5 purified at neutral pH to preserve biological activity, we show that CD5 mediates species-specific homophilic interactions. CD5 domain 1 only is involved in the interaction. CD5 mAbs that have functional effects in humans, rats, and mice block homophilic binding. Ag-specific responses by mouse T cells in vitro were increased when engagement of human CD5 domain 1 was inhibited by mutation or by IgG or Fab fragment from a CD5 mAb. This showed that homophilic binding results in productive engagement. Enhancement of polyclonal immune responses of rat lymph node cells by a Fab fragment from a CD5 mAb shown to block homophilic interactions provided evidence that the extracellular region of CD5 regulates inhibition in normal cells. These biochemical and in vitro functional assays provide evidence that the extracellular region of CD5 regulates immunity through species-specific homophilic interactions. 相似文献