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Acute myeloid leukemia (AML) is a malignant proliferative disease of myeloid hematopoietic origin and cannot be treated appropriately at present. This is due to the fact that leukemia cells are not sensitive to some of the traditional chemotherapy drugs. Or some chemotherapeutic drugs are too toxic to normal cells, affecting their wide clinical application. In this study, we identified BAM15 as a novel mitochondrial uncoupling agent by screening a library of small molecule compounds that inhibit AML cell activity. BAM15 significantly inhibited proliferation and promoted apoptosis in AML cells while at the same time being less cytotoxic to normal cells. The mechanism may be related to the disturbance of the ROS production balance. In vivo investigations revealed that BAM15 effectively suppressed AML progression and prolonged the survival time of mice. In addition, we found that BAM15 can be used in combination with cytarabine to enhance its anti-cancer activity and inhibit the activity of primary cells in AML. Therefore, we identified BAM15 as a potential drug candidate for the treatment of AML.

Aberrant activation of receptor tyrosine kinase (RTK) is usually a result of mutation and plays important roles in tumorigenesis. How RTK without mutation affects tumorigenesis remains incompletely understood. Here we show that in human melanomas pro-prion (pro-PrP) is an adaptor protein for an E3 ligase c-Cbl, enabling it to polyubiquitinate activated insulin-like growth factor-1 receptor (IGF-1R), leading to enhanced melanoma metastasis. All human melanoma cell lines studied here express pro-PrP, retaining its glycosylphosphatidylinositol-peptide signal sequence (GPI-PSS). The sequence, PVILLISFLI in the GPI-PSS of pro-PrP, binds c-Cbl, docking c-Cbl to the inner cell membrane, forming a pro-PrP/c-Cbl/IGF-1R trimeric complex. Subsequently, IGF-1R polyubiquitination and degradation are augmented, which increases autophagy and tumor metastasis. Importantly, the synthetic peptide PVILLISFLI disrupts the pro-PrP/c-Cbl/IGF-1R complex, reducing cancer cell autophagy and mitigating tumor aggressiveness in vitro and in vivo. Targeting cancer-associated GPI-PSS may provide a therapeutic approach for treating human cancers expressing pro-PrP.

The expression of normal cellular prion protein (PrP) is required for the pathogenesis of prion diseases. However, the physiological functions of PrP remain ambiguous. Here, we identified PrP as being critical for tumor necrosis factor (TNF) α-triggered signaling in a human melanoma cell line, M2, and a pancreatic ductal cell adenocarcinoma cell line, BxPC-3. In M2 cells, TNFα up-regulates the expression of p-IκB-kinase α/β (p-IKKα/β), p-p65, and p-JNK, but down-regulates the IκBα protein, all of which are downstream signaling intermediates in the TNF receptor signaling cascade. When PRNP is deleted in M2 cells, the effects of TNFα are no longer detectable. More importantly, p-p65 and p-JNK responses are restored when PRNP is reintroduced into the PRNP null cells. TNFα also activates NF-κB and increases TNFα production in wild-type M2 cells, but not in PrP-null M2 cells. Similar results are obtained in the BxPC-3 cells. Moreover, TNFα activation of NF-κB requires ubiquitination of receptor-interacting serine/threonine kinase 1 (RIP1) and TNF receptor–associated factor 2 (TRAF2). TNFα treatment increases the binding between PrP and the deubiquitinase tumor suppressor cylindromatosis (CYLD), in these treated cells, binding of CYLD to RIP1 and TRAF2 is reduced. We conclude that PrP traps CYLD, preventing it from binding and deubiquitinating RIP1 and TRAF2. Our findings reveal that PrP enhances the responses to TNFα, promoting proinflammatory cytokine production, which may contribute to inflammation and tumorigenesis.

Low altitude wind shear badly threatens aircrafts’ flight safety. Since flight states change rapidly during flying through wind shear, it is deficient to design an optimization controller by off-line analyse. A ring-vortex microburst wind shear model and B747 aircraft flight dynamics model were built. For glide slope tracking under wind shear, an off-line controller was designed by linear quadratic method. Furthermore, a model predictive controller with sequential optimization was designed. Simulation results show the on-line sequential optimization controller possess better tracking performance.

The classical mean shift (MS) algorithm is the best color-based method for object tracking. However, in the real environment it presents some limitations, especially under the presence of noise, objects with partial and full occlusions in complex environments. In order to deal with these problems, this paper proposes a reliable object tracking algorithm using corrected background-weighted histogram (CBWH) and the Kalman filter (KF) based on the MS method. The experimental results show that the proposed method is superior to the traditional MS tracking in the following aspects: 1) it provides consistent object tracking throughout the video; 2) it is not influenced by the objects with partial and full occlusions; 3) it is less prone to the background clutter.

This essay stimulates multiple sets of constructional elements and a variety of constraints with the help of ANSYS. Collecting and sorting out the first principal stress simulation of each model which is under the same load .Calculating the theoretical value of each constructional element under the first principal stress by using related formulas in mechanics of materials. The optimal form of constraint was gotten by comparing the simulation value with the theoretical value. The conclusion could provide theoretical basis for simulating structural constraints of ANSYS.

Low altitude microburst wind shear would do harm to aircrafts’ takeoff and landing. In order to analyze flight safety and advise better escape strategies, a mathematical model was built with high fidelity by a vortex ring based microburst model and a flight dynamics model with wind effects. A human pilot model which can describe characteristics of pilots such as skills, experiences, emotion, etc was embedded into the dynamics model. Since the key parameters of the microburst wind shear model and pilot model were set to be stochastic, the Monte Carlo method was adopted to obtain a numerical approximation of the probability density function of the minimum altitude and the F-factors for flight safety analysis.

Pilot should control the aircraft manually when encountering low altitude wind shear during takeoff and landing. For wind shear escape and flight safety research, an effective human pilot model together with wind shear and flight dynamics model should be built with high fidelity. A skill-based human pilot model was built which can describe pilots’ characteristics such as experiences, skills, emotions, reaction abilities, etc. A fuzzy controller was designed for lateral and longitudinal escape control in pilot model. Since single pilot could not represent a group of pilots’ control behavior, some of the model parameters were set to be stochastic, then the Monte Carlo method was adopted to obtain a numerical approximation of safety analysis results. With the probabilistic pilot model, escape strategies and safety analysis can be studied by simulation with high fidelity.

Based on the connection tests of the semi-rigid nodes in the beam-column T-typed member and end plate of steel frame, this paper analyzes the failure phenomena, stiffness, bearing capacity and flexibility of two types of attachments. And according to the tests results, it compares the two types of attachments each other and proposes that T-typed member is a better type of attachment on its bearing capacity and flexibility. Therefore, it provides the experimental basis for the ideal design and application of attachments among the semi-rigid nodes in steel structures.

In this paper, the discrete mean-variance model is considered for portfolio selection under concave transaction costs. By using the Cholesky decomposition technique, the convariance matrix to obtain a separable mixed integer nonlinear optimization problem is decomposed. A brand-and-bound algorithm based on Lagrangian relaxation is then proposed. Computational results are reported for test problems with the data randomly generated and those from the US stock market.