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This article aims to describe a novel design method of disturbance compensator in ADRC (Active Disturbance Rejection Control) based on Lyapunov stability theory. Error-based state equation is used to simplify the ADRC structure. The state feedback controller is designed using LQ (Linear Quadratic) method based on a linearized model. The generalized ESO (Extended State Observer) estimates the nonlinear part, model uncertainty, and external disturbance regarded as "total disturbance." Based on the estimate of the disturbance, disturbance compensator is designed using Lyapunov stability theory. In conventional ADRC, after estimating the disturbance compensator rejects the disturbance. But in this paper, it was not simply rejected. Instead the estimate of the disturbance is used in compensator design to make the Lyapunov candidate decrease more quickly. Our method allowed improved the convergence rate of ADRC. A numerical example and IWP (Inertia Wheel Pendulum) stabilization simulation confirmed the new method for effectiveness evaluation.

The feasibility of a machine-learning algorithm is discussed in terms of strain-history prediction and durability evaluation of automotive components. Additionally, an additional benefit using the machine-learning is reported; that is the acquisition of strain histories from sensors other than strain-gages. More specifically, the strain-history prediction performance was compared depending on how to prepare and learn data from each driving event, and the accuracy was analyzed with respect to the dominant direction of wheel-forces. Moreover, detailed information on the strain-history extraction was provided. Consequently, the performance of the network that learned the data generated from whole PG was better than one that learned a single driving data. For better application of machine learning to strain estimation for automotive components, timesteps of 80 were found to be the optimal parameter. And it was suggested that the data ranges for machine-learning training be larger than that in real-application to minimize discrepancies around peaks.

NF-E2-related factor 2 (NRF2) is a master regulator of redox homeostasis and provides cellular protection against oxidants and electrophiles by inducing the expression of a wide array of phase II cytoprotective genes. Until now, a number of NRF2 activators have been developed for treatment of chronic diseases and some are under evaluation in the clinical studies. On the other hand, accumulating evidence indicates that NRF2 confers chemoresistance and radioresistance, and its expression is correlated with poor prognosis in cancer patients. Studies in the last decade demonstrate that diverse mechanisms such as somatic mutations, accumulation of KEAP1 binding proteins, transcriptional dysregulation, oncogene activation, and accumulation of reactive metabolites contribute to NRF2 activation in cancer. In the present review, we illustrate the molecular mechanisms governing the function of NRF2 and explain how they are hijacked in cancer. We also provide some examples of NRF2 inhibitors together with a brief explanation of their mechanisms of action.

5-fluorouracil (5-FU) is a chemotherapeutic agent commonly used for treatment of solid tumors, including colorectal cancer. However, chemoresistance against 5-fluorouracil (5-FU) often limits its success for chemotherapy and, therefore, finding out appropriate adjuvant(s) that might overcome chemoresistance against 5-FU bears a significant importance. In the present study, we have found that α-mangostin can sensitize 5-FU-resistant SNUC5/5-FUR colon cancer cells to apoptosis. Exposure of α-mangostin induced significant DNA damages and increased the intracellular 8-hydroxyguanosine (8-OH-G) and 4-hydroxynonenal (4-HNE) levels in SNUC5 and SNUC5/5-FUR cells. Western blot analysis illustrated that α-mangostin-induced apoptosis was mediated by the activation of the extrinsic and intrinsic pathways in SNUC5/5-FUR cells. In particular, we observed that Fas receptor (FasR) level was lower in SNUC5/5-FUR cells, compared with SNUC5 cells and that silencing FasR attenuated α-mangostin-mediated apoptosis in SNUC5/5-FUR cells. Together, our study illustrates that α-mangostin might be an efficient apoptosis sensitizer that can overcome chemoresistance against 5-FU by activating apoptosis pathway.

Homoharringtonine, known as omacetaxine mepesuccinate, is a pharmaceutical drug substance approved for treatment of chronic myeloid leukemia. Here, we report that homoharringtonine (HHT) is a novel chemical inhibitor of NRF2. HHT significantly suppressed NRF2 and ARE-dependent gene expression in human lung carcinoma A549 cells. HHT stabilized secondary structure of guanine-rich sequence existing in the 5'-untranslated region (5'-UTR) of Nrf2 and sensitized A549 cells to etoposide-induced apoptosis. To the best of our knowledge, HHT is the first type of transcriptional inhibitor of Nrf2 that stabilizes guanine-rich sequence existing in the 5'-UTR. Our study also provides a novel mechanism of action underlying how HHT exerts anti-carcinogenic effects in cancer cells.

In this study, finite element analysis was performed to investigate the feasibility of multi-layered pyramidal truss structures as a filler material of energy absorbing tubes. Rectangular tubes with the filler and empty tubes were compressed at a constant velocity of 10km/h and their energy absorbing capabilities were compared to demonstrate the structural benefit of filling materials in the tubes. Additionally, the compressive response of the multi-layered pyramidal truss structures without tube wall constraint were observed. The investigations included three tube wall thicknesses and three pyramidal truss structures with three relative densities by varying the inclination angle of the pyramidal truss strut. Those were made of Al6063T5 and 304 stainless steel (SS304) for tube wall and pyramidal truss structure, respectively. The results indicate that the energy absorption capability of the tube with the filling exceeds the simple sum of that of tube and that of the filler, and this is due to the interaction effect between outer tubes and pyramidal truss struts near the tube wall. Furthermore, the inclination angle of pyramidal truss struts influences energy absorption. Thus, the pyramidal truss structures can be potentially applied as a filler material for energy absorbing structures.

NF-E2-related factor 2 (NRF2) regulates transcription of phase II cytoprotective enzymes to protect normal cells against oxidative stress. However, a high level of NRF2 offers a growth advantage, chemoresistance, and radioresistance in cancer. In the present study, we have identified convallatoxin as a novel inhibitor of NRF2/ARE. Suppression of NRF2 by convallatoxin was not transcriptionally mediated, but regulated at the level of proteolysis. Convallatoxin activated GSK-3β and suppression of NRF2 by convallatoxin required the Neh6 domain. Convallatoxin sensitised A549 cells to 5-fluorouracil-mediated cell death by promoting apoptosis. Together, our results provide evidence that convallatoxin might be useful as a chemotherapeutic adjuvant due to its ability to suppress NRF2/ARE.

This research proposed an efficient implicit integration method for the real-time simulation of flexible multi-body vehicle dynamics models. The equations of motion for the flexible bodies were formulated with respect to the moving chassis-body reference frame instead of the fixed inertial reference frame. The proposed approach does not require evaluation of system Jacobian and its LU-decomposition in time loof of simulation. This is one of the key aspects that enable high computational efficiency of the proposed method. The numerical simulation results of the proposed approach were matched up with those of the conventional approach but the computation time can be reduced by applying the proposed method. The joint constraint and generalized force equations are the same as the equations for rigid vehicle dynamics models because the joints and forces between flexible bodies are connected by the RBE (rigid body element). On the various driving conditions, the numerical simulation results show that th...

The purpose of this research is to develop an efficient kinematic formulation for an implicit integration method so that relatively low-cost computers can be used for the real-time simulation of multi-body vehicle dynamics models without sacrificing modelling details. The most time-consuming processes associated with the implicit method are the generation and LU decomposition of the system Jacobian matrix of the augmented equations of motion and the constraints at every time step. In order to save the computation time in these processes, a new kinematic formulation is developed to make the system Jacobian remain nearly constant. This allows us to employ a Newton chord method for implicit integration without the need to update the Jacobian. The formulation is motivated by the idea that relative motions between the chassis and other bodies (e.g. suspension components) are limited. Thus, the equations of motion, as well as the joint constraint equations and the generalized force equations, are formulated with respect to the chassis-body reference frame instead of the inertial reference frame. Consequently, the initial Jacobian can be used for long-term vehicle simulation. A comparison of the proposed approach with the conventional approach shows that the proposed approach drastically improved the computational efficiency; i.e. the computational cost of the proposed method was only 35% of the cost of the conventional method. The proposed algorithm yielded almost exact solutions for a prototype multi-body vehicle model run in real time on a 3.5 GHz personal computer.

Natural compounds are regarded as a rich source for potential anti-inflammatory and anti-carcinogenic agents. Increasing evidence indicates that histone phosphorylation at Ser10 is a marker for cell cycle progression during the mitosis and the induction of immediate pro-inflammatory genes during the interphase. In the present study, we have screened our in-house natural compounds to find out new chemical inhibitor(s) of histone H3 phosphorylation at Ser10. As a result, we observed that α-amyrin, oleanolic acid, marliolide, and 4'-O-β-D-glucosyl-5-O-methylvisamminol decreased the levels of histone H3 phosphorylation at Ser10 and c-Jun. In particular, we observed that 4'-O-β-D-glucosyl-5-O-methylvisamminol suppressed the direct interaction of histone H3 with 14-3-3e, inhibited the aurora B kinase activity and delayed the mitotic cell cycle progression. We reports 4'-O-β-D-glucosyl-5-O-methylvisamminol as the first epigenetic natural chemical inhibitor that can abrogates the mitotic cell cycle progression and immediate pro-inflammatory gene expressions via suppression of histone H3 phosphorylation at Ser10 and its interaction with 14-3-3e.