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排序方式: 共有1835条查询结果,搜索用时 78 毫秒
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Dr. David Xu Dr. Khuchtumur Bum-Erdene Julie M. Leth Mona K. Ghozayel Prof. Michael Ploug Prof. Samy O. Meroueh 《ChemMedChem》2021,16(2):377-387
The urokinase receptor (uPAR) is a cell surface receptor that binds to the serine protease urokinase-type plasminogen activator (uPA) with high affinity. This interaction is beneficial for extravascular fibrin clearance, but it has also been associated with a broad range of pathological conditions including cancer, atherosclerosis, and kidney disease. Here, starting with a small molecule that we previously discovered by virtual screening and cheminformatics analysis, we design and synthesize several derivatives that were tested for binding and inhibition of the uPAR ⋅ uPA interaction. To confirm the binding site and establish a binding mode of the compounds, we carried out biophysical studies using uPAR mutants, among them uPARH47C−N259C, a mutant previously developed to mimic the structure of uPA-bound uPAR. Remarkably, a substantial increase in potency is observed for inhibition of uPARH47C−N259C binding to uPA compared to wild-type uPAR, consistent with our use of the structure of uPAR in its uPA-bound state to design small-molecule uPAR ⋅ uPA antagonists. Combined with the biophysical studies, molecular docking followed by extensive explicit-solvent molecular dynamics simulations and MM-GBSA free energy calculations yielded the most favorable binding pose of the compound. Collectively, these results suggest that potent inhibition of uPAR binding to uPA with small molecules will likely only be achieved by developing small molecules that exhibit high-affinity to solution apo structures of uPAR, rather than uPA-bound structures of the receptor. 相似文献
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Brian Lawn David Marshall Rishi Raj Greg Hirth Trevor Page Julie Yeomans 《Journal of the American Ceramic Society》2021,104(1):23-26
Crystalline quartz has long been identified as among the weakest of abundant crustal minerals. This weakness is particularly evident around the α–β phase inversion at 573°C, in which Si–O bonds undergo a displacive structural transformation from trigonal to hexagonal symmetry. Here we present data using indentation testing methodologies that highlight the precipitous extent of the transformational weakening. Although the indentations are localized over relatively small specimen contact areas, the data quantify the essential deformation and fracture properties of quartz in a predominantly (but not exclusively) compressive stress field, at temperatures and pressures pertinent to conditions in the earth's crust. 相似文献
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Sophia X. Sui Lana J. Williams Kara L. Holloway-Kew Natalie K. Hyde Julie A. Pasco 《International journal of molecular sciences》2021,22(1)
Sarcopenia is the loss of skeletal muscle mass and function with advancing age. It involves both complex genetic and modifiable risk factors, such as lack of exercise, malnutrition and reduced neurological drive. Cognitive decline refers to diminished or impaired mental and/or intellectual functioning. Contracting skeletal muscle is a major source of neurotrophic factors, including brain-derived neurotrophic factor, which regulate synapses in the brain. Furthermore, skeletal muscle activity has important immune and redox effects that modify brain function and reduce muscle catabolism. The identification of common risk factors and underlying mechanisms for sarcopenia and cognition may allow the development of targeted interventions that slow or reverse sarcopenia and also certain forms of cognitive decline. However, the links between cognition and skeletal muscle have not been elucidated fully. This review provides a critical appraisal of the literature on the relationship between skeletal muscle health and cognition. The literature suggests that sarcopenia and cognitive decline share pathophysiological pathways. Ageing plays a role in both skeletal muscle deterioration and cognitive decline. Furthermore, lifestyle risk factors, such as physical inactivity, poor diet and smoking, are common to both disorders, so their potential role in the muscle–brain relationship warrants investigation. 相似文献
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Mariana Tasso Thomas Pons Nicolas Lequeux Julie Nguyen Zsolt Lenkei Diana Zala 《Small (Weinheim an der Bergstrasse, Germany)》2019,15(47)
Single‐particle tracking with quantum dots (QDs) constitutes a powerful tool to track the nanoscopic dynamics of individual cell membrane components unveiling their membrane diffusion characteristics. Here, the nano‐resolved population dynamics of QDs is exploited to reconstruct the topography and structural changes of the cell membrane surface with high temporal and spatial resolution. For this proof‐of‐concept study, bright, small, and stable biofunctional QD nanoconstructs are utilized recognizing the endogenous neuronal cannabinoid receptor 1, a highly expressed and fast‐diffusing membrane protein, together with a commercial point‐localization microscope. Rapid QD diffusion on the axonal plasma membrane of cultured hippocampal neurons allows precise reconstruction of the membrane surface in less than 1 min with a spatial resolution of tens of nanometers. Access of the QD nanoconstructs to the synaptic cleft enables rapid 3D topological reconstruction of the entire presynaptic component. Successful reconstruction of membrane nano‐topology and deformation at the second time‐scale is also demonstrated for HEK293 cell filopodia and axons. Named “nanoPaint,” this super‐resolution imaging technique amenable to any endogenous transmembrane target represents a versatile platform to rapidly and accurately reconstruct the cell membrane nano‐topography, thereby enabling the study of the rapid dynamic phenomena involved in neuronal membrane plasticity. 相似文献
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Anton Polotai Julie Voak Jim Henry David Thoss Yi Yang Sanjay Chitale 《International Journal of Applied Ceramic Technology》2020,17(2):728-733
The need for electronics to operate at temperatures of 200°C and above continues to grow. These applications include avionics, aerospace, automotive, downhole drilling, mining, and many others. To satisfy this demand, a significant amount of research and development has been conducted. Despite the efforts, the number of new electronic components designed specifically for high-temperature operation is still relatively limited. In Low Temperature Co-fired Ceramic (LTCC) packages, LTCC materials are generally used as the host media for a number of pre-fabricated semiconductor components. As a result, reliability of the entire LTCC package largely depends on the performance of the least robust component. Ferro A6M-E and Ferro L8 are the two well-established and recognized LTCC dielectrics widely used for mid and high frequency LTCC applications, including several high reliability aerospace and defense applications that require demanding Mil-Spec qualifications. This study is our first attempt to characterize and understand basic high-temperature dielectric properties of these two commercial LTCC materials. The secondary objective is to initiate a dialogue in attempt to establish reliability requirements for LTCC packages dedicated for high-temperature operation. 相似文献
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