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Several recent reports have demonstrated that small activating dsRNA [double-stranded RNA; saRNA (small activating dsRNA)] complementary to promoter regions can up-regulate gene expression in mammalian cells, a phenomenon termed RNAa (RNA activation). However, the mechanism of RNAa remains obscure with regard to what is the target molecule for promoter-targeted saRNA and what are the proteins involved in this process. p21Waf1/Cip1 (p21) [CDKN1A (cyclin-dependent kinase inhibitor 1A)], an important tumour suppressor gene, is among the genes that can be activated by RNAa in tumour cells. In the present study, we provide direct evidence that p21 promoter-targeted saRNA interact with its intended target on the p21 promoter to activate p21 expression. This process is associated with recruitment of RNA polymerase II and AGO2 (argonaute 2) protein to the saRNA-target site. Additionally, we found that several hnRNPs (heterogeneous nuclear ribonucleoproteins) (A1, A2/B1 and C1/C2) are associated with saRNA. Further studies show that hnRNPA2/B1 interacts with the saRNA in vivo and in vitro and is required for RNAa activity. These findings indicate that RNAa results from specific targeting of promoters and reveals additional mechanistic details of RNAa.

A new multiscale computational method is developed for the elasto-plastic analysis of heterogeneous continuum materials with both periodic and random microstructures. In the method, the multiscale base functions which can efficiently capture the small-scale features of elements are constructed numerically and employed to establish the relationship between the macroscopic and microscopic variables. Thus, the detailed microscopic stress fields within the elements can be obtained easily. For the construction of the numerical base functions, several different kinds of boundary conditions are introduced and their influences are investigated. In this context, a two-scale computational modeling with successive iteration scheme is proposed. The new method could be implemented conveniently and adopted to the general problems without scale separation and periodicity assumptions. Extensive numerical experiments are carried out and the results are compared with the direct FEM. It is shown that the method developed provides excellent precision of the nonlinear response for the heterogeneous materials. Moreover, the computational cost is reduced dramatically.

An extended multiscale finite element method is developed for small-deformation elasto-plastic analysis of periodic truss materials. The base functions constructed numerically are employed to establish the relationship between the macroscopic displacement and the microscopic stress and strain. The unbalanced nodal forces in the microscale of unit cells are treated as the combined effects of macroscopic equivalent forces and microscopic perturbed forces, in which macroscopic equivalent forces are used to solve the macroscopic displacement field and microscopic perturbed forces are used to obtain the stress and strain in the microscale to make sure the correctness of the results obtained by the downscale computation in the elastic-plastic problems. Numerical examples are carried out and the results verify the validity and efficiency of the developed method by comparing it with the conventional finite element method.

An extended multiscale finite element method (EMsFEM) is developed for solving the mechanical problems of heterogeneous materials in elasticity. The underlying idea of the method is to construct numerically the multiscale base functions to capture the small-scale features of the coarse elements in the multiscale finite element analysis. On the basis of our existing work for periodic truss materials, the construction methods of the base functions for continuum heterogeneous materials are systematically introduced. Numerical experiments show that the choice of boundary conditions for the construction of the base functions has a big influence on the accuracy of the multiscale solutions, thus, different kinds of boundary conditions are proposed. The efficiency and accuracy of the developed method are validated and the results with different boundary conditions are verified through extensive numerical examples with both periodic and random heterogeneous micro-structures. Also, a consistency test of the method is performed numerically. The results show that the EMsFEM can effectively obtain the macro response of the heterogeneous structures as well as the response in micro-scale, especially under the periodic boundary conditions.

Our study demonstrated that knockout exacerbated AngII-induced TAAD formation in mice, which was associated with TGF-β signaling dysfunction. Therapeutic strategies targeting TAAD should consider unexpected side effects associated with alterations in TGF-β signaling.

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