Background and Purpose: Although the ongoing clinical trials of ABT‐263 and ABT‐199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge.Experimental Approach: The LD₅₀ values of ABT‐737, ABT‐263 and ABT‐199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl‐2 family proteins, including phosphorylated Bcl‐2 (pBcl‐2) and their interactions were measured by immunoblotting and co‐immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed.Key Results: The ratio of (Mcl‐1 + pBcl‐2) to Bcl‐2 expression provided the most significant predictive marker for the cytotoxic potential of ABT‐737, ABT‐263 and ABT‐199 in the panel of CLL samples. Mechanistically, pBcl‐2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl‐2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100–300‐fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl‐2 (T69E, S70E and S87E; EEE‐Bcl‐2). BH3 peptides exhibited different rank orders of binding affinities to full‐length WT‐Bcl‐2 and full‐length EEE‐Bcl‐2.Conclusions and Implications: Our study suggested that a structural alteration in the BH3‐binding groove was induced by phosphorylation of Bcl‐2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl‐2 kinase inhibitors with the ABT compounds.

A novel high-temperature diphenyl sulfone-based phthalonitrile polymer is prepared from bis-[4-(3,4-dicyanophenoxy)phenyl]sulfone (BDS) monomer synthesized with high yield by a simple nucleophilic displacement of a nitro-substituent from 4-nitrophthalonitrile (NPN). The structure of BDS polymer is investigated by Fourier transform infrared spectroscopy and wide-angle X-ray diffraction. Curing behavior of BDS monomer with 1,3-bis(4-aminophenoxy)benzene (APB) is recorded by differential scanning calorimetry. The properties of BDS polymer are evaluated by thermogravimetric analysis, dynamic mechanical analysis, and tensile test. The results reveal that the BDS polymer exhibits excellent thermal and thermo-oxidative stabilities, high glass temperature ( T_g = 337°C), and outstanding mechanical properties (Young’s modulus: 4.02 GPa and tensile strength: 64.16 MPa). Additionally, the BDS polymer exhibits high flame retardance and low water uptake.

SUMMARY: Observer-based two-time scale robust control is proposed for free-flying flexible-joint space manipulators with unknown payload parameters and bounded disturbances. The dynamic equations of a free-flying space manipulator with two flexible revolute joints were derived by the momentum conservation law and the Lagrange equations. A flexibility compensator was introduced to make the equivalent joint stiffness large enough, which made traditional singular perturbation approach applicable. Then, a singular perturbation model was formulated and a reduced-order controller is proposed. This controller consisted of a slow sub-controller and a fast flexible-joint sub-controller. To the slow subsystem, a sliding observer based robust slow sub-controller was proposed. By optimal linear quadratic regulator method, the fast sub-controller was designed with the estimated velocity by linear observer. This fast sub-controller could stabilize the fast subsystem around the equilibrium trajectory created by the slow subsystem under the effect of the slow control. Finally the numerical simulations were carried out, which showed that elastic joint vibrations had been stabilized effectively and good tracking performances had been achieved.

The flexibility of the free-floating flexible space manipulator system’s link and joint may affect the control accuracy and cause vibrations. We studied the dynamics modeling, joint trajectory tracking control, and vibration suppressing problem of free-floating flexible-link and flexible-joints space manipulator system with external interference and uncertain parameter. The system’s dynamic equations are established using linear momentum conservation, angular momentum conservation, assumed mode method, and Lagrange equation. Then, the system’s singular perturbation model is established, and a hybrid control is presented. For the slow subsystem, a robust fuzzy sliding mode control is proposed to realize the joint desired trajectory tracking. For the fast subsystem, a speed difference feedback control and a linear-quadratic optimal control are designed to suppress the vibration caused by the flexible joints and the flexible link separately. The simulation comparison experiments under different conditions are taken. The simulate results demonstrate the proposed hybrid control’s validity.

Singular perturbation adaptive control is designed for free-flying space manipulators with multiple flexible links and unknown physical parameters. The dynamical Lagrange equation was established based on assumed mode technique and linear momentum conservation theory. A singular perturbation model has been formulated and used for designing a reduced-order controller. This controller consisted of a slow control component and a fast control component. An adaptive control law was constructed for the slow counterpart of the flexible manipulator. The flexible-link fast subsystem controller would damp out the vibrations of flexible links by optimal linear quadratic regulator method. Numerical simulations by undertaking a computer simulation of a two-flexible-link space manipulator using the fourth-order Runge–Kutta integration method showed that the link vibrations had been stabilized effectively with good tracking performance.