Suchergebnisse

To overcome the shortcomings of traditional rigid road wheel, such as poor damping effect and low load-bearing efficiency, a new type of flexible road wheel, having a unique suspension-bearing mode, was introduced. The three-dimensional nonlinear finite element model of rigid and flexible road wheel, considering the triple nonlinear characteristics of geometry, material and contact, is established for numerical investigation of static loading performance. The accuracy of the finite element model of the rigid and flexible road wheel is verified by static loading experiment. The static loading performance of the rigid and flexible road wheels is numerically analyzed. The influence of vertical load on maximum stress and deformation of the rigid and flexible wheels is also studied. The results show that the contact pressure uniformity of the flexible road wheel is better than that of the rigid road wheel under the static vertical load, but the maximum stress and deformation of the flexible road wheel are greater than that of the rigid road wheel. However, this problem can be solved by increasing the number of hinge sets and optimising the joints. The research results provide theoretical basis for replacing rigid road wheel with flexible road wheel, and also provide reference for structural optimisation of flexible road wheel.

In addition to oncogenic drivers, signaling nodes can critically modulate cancer-related cellular networks to strength tumor hallmarks. We identify G-protein-coupled receptor kinase 2 (GRK2) as a relevant player in breast cancer. GRK2 is up-regulated in breast cancer cell lines, in spontaneous tumors in mice, and in a proportion of invasive ductal carcinoma patients. Increased GRK2 functionality promotes the phosphorylation and activation of the Histone Deacetylase 6 (HDAC6) leading to de-acetylation of the Prolyl Isomerase Pin1, a central modulator of tumor progression, thereby enhancing its stability and functional interaction with key mitotic regulators. Interestingly, a correlation between GRK2 expression and Pin1 levels and de-acetylation status is detected in breast cancer patients. Activation of the HDAC6-Pin1 axis underlies the positive effects of GRK2 on promoting growth factor signaling, cellular proliferation and anchorage-independent growth in both luminal and basal breast cancer cells. Enhanced GRK2 levels promote tumor growth in mice, whereas GRK2 down-modulation sensitizes cells to therapeutic drugs and abrogates tumor formation. Our data suggest that GRK2 acts as an important onco-modulator by strengthening the functionality of key players in breast tumorigenesis such as HDAC6 and Pin1. ; Our laboratory is funded by grants from Ministerio de Economía y Competitividad (SAF2011-23800 and SAF2014-55511R), the European Union (H2020-MSCA Programme, Grant agreement 64183-ONCORNET), The Cardiovascular Network of Ministerio Sanidad y Consumo-Instituto Carlos III (RD12/0042/0012), Comunidad de Madrid (S-2010/BMD-2332) to F.M and Instituto Carlos III (PI11/00859, PI14-00435, PIE-13-00041), Fundación Ramón Areces and Fundación Rodríguez Pascual to P.P. Dr.MartaMendiola is supported by a postdoctoral research contract of Fondo de Investigación Sanitaria (FIS) ('Sara Borrell' Program), Instituto de Salud Carlos III