Targeting Mnks for Cancer Therapy

Deregulation of protein synthesis is a common event in human cancer and a key player in translational control is eIF4E. Elevated expression levels of eIF4E promote cancer development and progression. Recent findings suggest that eIF4E activity is a key determinant of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK mediated tumorigenic activity and targeting eIF4E should have a major impact on these pathways in human cancer. The function of eIF4E is modulated through phosphorylation of a conserved serine (Ser209) by Mnk1 and Mnk2 downstream of ERK. While the phosphorylation event is necessary for oncogenic transformation, it seems to be dispensable for normal development. Hence, pharmacologic Mnk inhibitors may provide non-toxic and effective anti-cancer strategy. Strong circumstantial evidence indicates that Mnk inhibition presents attractive therapeutic potential, but the lack of selective Mnk inhibitors has so far confounded pharmacological target validation and clinical development

Robust cross-linked Na3V2(PO4)2F3 full sodium-ion batteries

Sodium-ion batteries (SIBs) have rapidly risen to the forefront of energy storage systems as a promising supplementary for Lithium-ion batteries (LIBs). Na3V2(PO4)2F3 (NVPF) as a common cathode of SIBs, features the merits of high operating voltage, small volume change and favorable specific energy density. However, it suffers from poor cycling stability and rate performance induced by its low intrinsic conductivity. Herein, we propose an ingenious strategy targeting superior SIBs through cross-linked NVPF with multi-dimensional nanocarbon frameworks composed of amorphous carbon and carbon nanotubes (NVPF@C@CNTs). This rational design ensures favorable particle size for shortened sodium ion transmission pathway as well as improved electronic transfer network, thus leading to enhanced charge transfer kinetics and superior cycling stability. Benefited from this unique structure, significantly improved electrochemical properties are obtained, including high specific capacity (126.9 mAh g−1 at 1 C, 1 C = 128 mA g−1) and remarkably improved long-term cycling stability with 93.9% capacity retention after 1000 cycles at 20 C. The energy density of 286.8 Wh kg−1 can be reached for full cells with hard carbon as anode (NVPF@C@CNTs//HC). Additionally, the electrochemical performance of the full cell at high temperature is also investigated (95.3 mAh g−1 after 100 cycles at 1 C at 50 oC). Such nanoscale dual-carbon networks engineering and thorough discussion of ion diffusion kinetics might make contributions to accelerating the process of phosphate cathodes in SIBs for large-scale energy storages

Improving Link Prediction Accuracy of Network Embedding Algorithms via Rich Node Attribute Information

Complex networks are widely used to represent an abundance of real-world relations ranging from social networks to brain networks. Inferring missing links or predicting future ones based on the currently observed network is known as the link prediction task. Recent network embedding based link prediction algorithms have demonstrated ground-breaking performance on link prediction accuracy. Those algorithms usually apply node attributes as the initial feature input to accelerate the convergence speed during the training process. However, they do not take full advantage of node feature information. In this paper, besides applying feature attributes as the initial input, we make better utilization of node attribute information by building attributable networks and plugging attributable networks into some typical link prediction algorithms and name this algorithm Attributive Graph Enhanced Embedding (AGEE). AGEE is able to automatically learn the weighting trades-off between the structure and the attributive networks. Numerical experiments show that AGEE can improve the link prediction accuracy by around 3% compared with SEAL, Variational Graph AutoEncoder (VGAE), and node2vec

Aurora B Inhibitors as Cancer Therapeutics

The Aurora kinases (A, B, and C) are a family of three isoform serine/threonine kinases that regulate mitosis and meiosis. The Chromosomal Passenger Complex (CPC), which contains Aurora B as an enzymatic component, plays a critical role in cell division. Aurora B in the CPC ensures faithful chromosome segregation and promotes the correct biorientation of chromosomes on the mitotic spindle. Aurora B overexpression has been observed in several human cancers and has been associated with a poor prognosis for cancer patients. Targeting Aurora B with inhibitors is a promising therapeutic strategy for cancer treatment. In the past decade, Aurora B inhibitors have been extensively pursued in both academia and industry. This paper presents a comprehensive review of the preclinical and clinical candidates of Aurora B inhibitors as potential anticancer drugs. The recent advances in the field of Aurora B inhibitor development will be highlighted, and the binding interactions between Aurora B and inhibitors based on crystal structures will be presented and discussed to provide insights for the future design of more selective Aurora B inhibitors

Insights into the importance of DFD-motif and insertion I1 in stabilizing the DFD-out conformation of Mnk2 kinase

Human mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special insertions and a DFDmotif that are distinct from other kinases. Crystallographic studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out conformation in which residue F227 flips into the ATP binding pocket. This is rarely observed in other kinases. Although the DFG-out conformation has attracted great interest for designing selective inhibitors, structural requirements for binding and the mechanism governing the DFG-out conformation remain unclear. This work presents for the first time the applicability of 3D models of Mnk2 protein in studying conformational changes by utilizing homology modeling and molecular dynamics simulations. The study reveals that the interactions between residue K234 of insertion I1 and D226 of the DFD motif play a key role in inducing and stabilizing the DFD-out conformation. The structural features will aid in the rational design of Mnk2 inhibitors.

A Study of the Effect of a Kinematic Pair Containing Clearance on the Dynamic Characteristics of a Tool-Changing Robot

The clearance of a kinematic pair will lead to the contact collision between the joints of the mechanism, which will have a great influence on the dynamic characteristics of a mechanical system with clearance. In order to study the influence of a rotating motion pair with clearance on the dynamic characteristics of a tool changing robot, a contact wear dynamics model of a modular tool changing robot was established based on the three-state model of “free-contact-collision”. Different from analysis of a light linkage structure, this paper takes a solid structure with large mass as the analysis object. Based on the impact contact force model and the improved Coulomb friction model, the effects of clearance size, rotational speed and friction coefficient on the dynamic characteristics of the tool changing robot were analyzed. The Archard wear model was used to predict the wear between the motion pairs with clearance. The analysis results show that, with the increase of clearance size and actuating speed, the fluctuation range of velocity and acceleration increases, and the fluctuation frequency decreases. Under the action of friction, the contact force between components will be reduced due to energy loss so that the kinematic reliability of the mechanism is improved. The wear of the moving pair with clearance is non-uniform. Through the research of this paper, the motion characteristics of the tool-changing robot at low speed and heavy load are clarified. The results show that the established method can realize the dynamic characteristics analysis of low-speed heavy-duty mechanisms with joint gaps, which can be used to guide the design of tool-changing robots, and also has important reference significance for the design of mechanisms containing joint gaps in general

A Study of the Effect of a Kinematic Pair Containing Clearance on the Dynamic Characteristics of a Tool-Changing Robot

The clearance of a kinematic pair will lead to the contact collision between the joints of the mechanism, which will have a great influence on the dynamic characteristics of a mechanical system with clearance. In order to study the influence of a rotating motion pair with clearance on the dynamic characteristics of a tool changing robot, a contact wear dynamics model of a modular tool changing robot was established based on the three-state model of “free-contact-collision”. Different from analysis of a light linkage structure, this paper takes a solid structure with large mass as the analysis object. Based on the impact contact force model and the improved Coulomb friction model, the effects of clearance size, rotational speed and friction coefficient on the dynamic characteristics of the tool changing robot were analyzed. The Archard wear model was used to predict the wear between the motion pairs with clearance. The analysis results show that, with the increase of clearance size and actuating speed, the fluctuation range of velocity and acceleration increases, and the fluctuation frequency decreases. Under the action of friction, the contact force between components will be reduced due to energy loss so that the kinematic reliability of the mechanism is improved. The wear of the moving pair with clearance is non-uniform. Through the research of this paper, the motion characteristics of the tool-changing robot at low speed and heavy load are clarified. The results show that the established method can realize the dynamic characteristics analysis of low-speed heavy-duty mechanisms with joint gaps, which can be used to guide the design of tool-changing robots, and also has important reference significance for the design of mechanisms containing joint gaps in general

Microstructure evolution and mechanical properties during industrial intercritical quenching and partitioning (IQ&P) processing of a low alloy steel

The evolution of the microstructure, texture and mechanical properties of a low alloy steel containing 0.09C-2Mn-0.4Si (wt.%) was investigated during the industrial intercritical quenching & partitioning (IQ&P) process. The steel sheet was thermally treated and characterized by scanning electron microscopy, electron backscatter diffraction, x-ray diffraction, etc. Low alloy steel treated with different processes can reach a tensile strength above 900 MPa. A multiphase structure composed of lath martensite, fine ferrite and retained austenite was obtained after annealing at 770–870 °C, and the retained austenite produced a discontinuous transformation induced plasticity (TRIP) effect and coordinated deformation in the tensile strain. The fractions of the textures {111} 〈112〉 and {111} 〈110〉 were found to gradually abate as the annealing temperature increased, while the textures {100} 〈001〉 and {001} 〈110〉 continuously expanded. The recrystallized texture gradually disappears with decreasing quenching temperature, although the fraction of the texture caused by the martensite transformation increases, and the texture gradually changes from {113} 〈110〉 to {111} 〈110〉. The effect of texture and microstructure evolution on mechanical properties was discussed in terms of character and morphology

Insights into the Importance of DFD-Motif and Insertion I1 in Stabilizing the DFD-Out Conformation of Mnk2 Kinase

Human mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special insertions and a DFD-motif that are distinct from other kinases. Crystallographic studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out conformation in which residue F227 flips into the ATP binding pocket. This is rarely observed in other kinases. Although the DFG-out conformation has attracted great interest for designing selective inhibitors, structural requirements for binding and the mechanism governing the DFG-out conformation remain unclear. This work presents for the first time the applicability of 3D models of Mnk2 protein in studying conformational changes by utilizing homology modeling and molecular dynamics simulations. The study reveals that the interactions between residue K234 of insertion I1 and D226 of the DFD motif play a key role in inducing and stabilizing the DFD-out conformation. The structural features will aid in the rational design of Mnk2 inhibitors

Insights into the Importance of DFD-Motif and Insertion I1 in Stabilizing the DFD-Out Conformation of Mnk2 Kinase

Human mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special insertions and a DFD-motif that are distinct from other kinases. Crystallographic studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out conformation in which residue F227 flips into the ATP binding pocket. This is rarely observed in other kinases. Although the DFG-out conformation has attracted great interest for designing selective inhibitors, structural requirements for binding and the mechanism governing the DFG-out conformation remain unclear. This work presents for the first time the applicability of 3D models of Mnk2 protein in studying conformational changes by utilizing homology modeling and molecular dynamics simulations. The study reveals that the interactions between residue K234 of insertion I1 and D226 of the DFD motif play a key role in inducing and stabilizing the DFD-out conformation. The structural features will aid in the rational design of Mnk2 inhibitors