A linear stochastic model is used to simulate the midlatitude storm tracks produced by an atmospheric GCM. A series of six perpetual insolation/SST GCM experiments are first performed for each month. These experiments capture the ''midwinter suppression'' of the Pacific storm track in a particularly clean way. The stochastic model is constructed by linearizing the GCM about its January climatology and finding damping and stirring parameters that best reproduce that model's eddy statistics. The model is tested by examining its ability to simulate other GCM integrations when the basic state is changed to the mean flow of those models, while keeping the stirring and damping unchanged. The stochastic model shows an impressive ability to simulate a variety of eddy statistics. It captures the midwinter suppression of the Pacific storm track qualitatively and is also capable of simulating storm track responses to El Niño. The model results are sensitive to the manner in which the model is stirred. Best results for eddy variances and fluxes are obtained by stirring the temperature and vorticity at low levels. However, a better simulation of the spatial structure of the dominant wave train as defined by covariance maps is obtained by stirring the temperature equation only, and at all levels.

A computational methodology for analysis of spatial flexible multibody systems, considering the effects of the clearances and lubrication in the system spherical joints, is presented. The dry contact forces are evaluated through a Hertzian-based contact law, which includes a damping term representing the energy dissipation. The frictional forces are evaluated using a modified Coulomb's friction law. In the case of lubricated joints, the resulting lubricant forces are derived from the corresponding Reynolds' equation. An absolute nodal formulation is utilized in flexible body formulation. The generalized-α method is used to solve the resulting equations of motion. The effectiveness of the methodology is demonstrated by two numerical examples.

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Modeling of clearance joints plays an important role in the analysis and design of multibody mechanical systems. Based on the absolute nodal coordinate formulation (ANCF), a new computational methodology for modeling and analysis of planar flexible multibody systems with clearance and lubricated revolute joints is presented. A planar absolute nodal coordinate formulation based on the lockingfree shear deformable beam element is implemented to discretize the flexible bodies. A continuous contactimpact model is used to evaluate the contact force, in which energy dissipation in the form of hysteresis damping is considered. A force transition model from hydrodynamic lubrication forces to dry contact forces is introduced to ensure continuity in the joint reaction force. A comprehensive study with different lubrication force models has also been carried out. The generalized-α method is used to solve the equations of motion and several efficient methods are incorporated in the proposed model. Finally, the methodology is validated by two numerical examples.

SUMMARYThis study proposes a new uncertain analysis method for multibody dynamics of mechanical systems based on Chebyshev inclusion functions The interval model accounts for the uncertainties in multibody mechanical systems comprising uncertain‐but‐bounded parameters, which only requires lower and upper bounds of uncertain parameters, without having to know probability distributions. A Chebyshev inclusion function based on the truncated Chebyshev series, rather than the Taylor inclusion function, is proposed to achieve sharper and tighter bounds for meaningful solutions of interval functions, to effectively handle the overestimation caused by the wrapping effect, intrinsic to interval computations. The Mehler integral is used to evaluate the coefficients of Chebyshev polynomials in the numerical implementation. The multibody dynamics of mechanical systems are governed by index‐3 differential algebraic equations (DAEs), including a combination of differential equations and algebraic equations, responsible for the dynamics of the system subject to certain constraints. The proposed interval method with Chebyshev inclusion functions is applied to solve the DAEs in association with appropriate numerical solvers. This study employs HHT‐I3 as the numerical solver to transform the DAEs into a series of nonlinear algebraic equations at each integration time step, which are solved further by using the Newton–Raphson iterative method at the current time step. Two typical multibody dynamic systems with interval parameters, the slider crank and double pendulum mechanisms, are employed to demonstrate the effectiveness of the proposed methodology. The results show that the proposed methodology can supply sufficient numerical accuracy with a reasonable computational cost and is able to effectively handle the wrapping effect, as cosine functions are incorporated to sharpen the range of non‐monotonic interval functions. Copyright © 2013 John Wiley & Sons, Ltd.

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Keywords: MEK/Erk and chemo-resistance, NVP-BEZ235, osteosarcoma, PI3K-Akt-mTOR signaling Abbreviations: mammalian target of rapamycin (mTOR); mTOR complex 1 (mTORC1); mTOR complex 2 (mTORC2); phosphoinositide-dependent protein kinase-1 (PDK1); phosphatidylinositol 3-kinase (PI3K); receptor tyrosine kinases (RTKs).Recent studies have identified that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important feature of osteosarcoma, where it promotes cell proliferation, survival, and chemo-resistance. Here, we studied the therapeutic potential of NVP-BEZ235, a novel dual PI3K/mTOR dual inhibitor, on osteosarcoma cells in vivo and in vitro. NVP-BEZ235 was cytotoxic and cytostatic to a panel of osteosarcoma lines (MG-63, U2OS and SaOs-2), where it induce apoptosis and cell-cycle arrest. At the molecular level, NVP-BEZ235 inhibited PI3K-AKT-mTORC1 activation and downregulated cyclin D1/cyclin B1 expressions, while increasing MEK/Erk phosphorylation in osteosarcoma cells. MEK/Erk inhibitors PD98059 and MEK-162 increased NVP-BEZ235 activity on osteosarcoma cells. In vivo, oral NVP-BEZ235 inhibited U2OS xenograft in SCID mice, and its antitumor efficiency was further enhanced by MEK-162 co-administration. Taken together, our findings indicate that dual inhibition of PI3K and mTOR with NVP-BEZ235, either alone or in combination with MEK/Erk inhibitors, may be an efficient treatment for osteosarcoma.

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