Search

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5%; t1/2 = 2.47 h). Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the “tunnel” allosteric site of SHP2. TK-642 could effectively suppress cell proliferation (KYSE-520 cells IC50 = 5.73 μmol/L) and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways. Additionally, oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model, with a T/C value of 83.69%. Collectively, TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

Electrochemical noise (EN) signals generated during corrosion fatigue (CF) process of friction stir welded (FSW) AA6061-T6 joints in 3.5 wt% NaCl solution under different loading conditions were monitored. Wavelet analysis and cumulative probability calculations showed that the increase in peak stress, stress ratio and stress frequency all lead to a decrease in Rn and an increase in the incubation rate of local events. Under current experimental conditions, the influence of peak stress is the most significant, while the influence of frequency is the least. The combination of EN signal analysis and transmission electron microscopy (TEM) observations indicates that the coarsening of β′ phase and the extensive dissolution of β'' phase are the main reasons for preferential failure in the weakest heat affected zone. The main contribution of this study is preliminary investigating the CF behavior of FSW AA6061 joints under different low cycle fatigue conditions. Moreover, EN is an effective strategy for monitoring CF process and establishes a connection between an alternative EN technique and in-situ CF behavior research.

The tensile performance of ductile tubes can be enhanced by the application of fillers. Research studies on the mechanical performance of filled tensile tubes have mainly focused on experiments and numerical simulations on concrete-filled steel tube (CFST) components, while the effects of factors such as size, section pattern, and material of filled tensile tubes on their performance have rarely been studied. In this research, the effects of size, section pattern, and material on the tensile performance of filled tubes have been evaluated through theoretical studies, simulations, and experiments. The tensile strength reinforcement and deformation weakening coefficients of filled circular thin-walled tubes corresponding to hollow tubes were theoretically deduced, and the influencing factors of the two were parametrically evaluated. Tensile performances of filled tubes with circular and square sections were compared with each other through numerical methods. In the current research, the circular section was optimized and prestressed circular hollow support section was proposed. Tensile fracture tests were performed on circular thin-walled tubes made of six different materials to determine material effects on the tensile performance of these structures. It was also found that metallic materials with good ductility significantly enhanced the tensile performance, fracture toughness, and energy consumption of test components containing prestressed filler.

In this paper, an elastoplastic analysis model of thin-walled circular tubes under the combined action of axial force and torque is discussed. Based on the von Mises yield criterion and the assumption of isotropic linear hardening, the methods of stress path and strain path loading are analyzed to study the effect of combined tensile-torsional loading path on thin-walled circular tubes. A finite element model is used to analyze the loading path effect on thin-walled circular tubes. A series of tensile and torsional tests are also carried out on 304 stainless steel thin-walled circular tubes using a universal testing machine. In addition, the consistency of the selected material with the von Mises yield criterion, the assumption of isotropic linear hardening, and other classical elastoplastic mechanics are verified. The theoretical calculation results, the numerical analysis results, and the experimental test results are analyzed and compared. The “primary effect” influenced by the stress path and the “recency effect” affected by the strain path are proved, and their application prospects are discussed. The influence of tensile-torsional loading path on the final stress and strain states of thin-walled circular tubes after entering the plastic deformation stage is concretely demonstrated, facilitating the understanding of the principles of the aforementioned two effects. The investigation for a general principle concerning the effect of loading history on the mechanical behavior of engineering materials, based on the classical plastic mechanics, has an important theoretical significance. It is of great theoretical importance for advancements in plastic yield theory and the establishment of more accurate loading conditions suitable for specific materials in engineering practice.

In this study, the microstructure of TC1/1060/6061 composites manufactured by explosive welding was investigated using experiments and numerical simulations. The results showed that the two interfaces of the TC1/1060/6061 composites exhibited an overall linear bonding interface without defects such as macroscopic cracks or pores. A melting layer caused by the adiabatic compression of air was observed, and the overall welding quality of the composites was good. There were no intermetallic compounds observed at the TC1/1060 interface, and the diffusion area was short, which formed a metallurgical bond. After heat treatment, the grains on the base plate and interlayer side of the composites formed a cubic recrystallized texture, while the grains on the flyer plate side developed a fine-grained structure. The microhardness of the base plate and flyer plate was higher closer to the interface due to the process hardening effect, while the microhardness of the interlayer remained stable. The formation process of these two interfaces was analyzed by numerical simulations, and jetting was observed at the 1060/6061 interface. The TC1/1060 interface in the numerical simulations showed a linear morphology, and the 1060/6061 interface showed a microwave morphology.

The corrosion fatigue properties and fracture characteristics of friction stir welding joints of 7075 aluminum alloys were studied via corrosion fatigue tests, electrochemical measurements, and corrosion fatigue morphology and microstructure observations. The results show that the corrosion fatigue crack of the friction stir welding (FSW) joint of 7075 aluminum alloys originated in the junction zone between the thermomechanically affected zone and the weld nugget zone. The corrosion fatigue life of the joint decreased with increasing stress amplitude, with an S–N curve equation of lgN = 5.845 − 0.014S. Multiple crack sources were observed in the corrosion fatigue fracture. The main crack source originated from the corrosion pits at the interface between the thermomechanically affected zone and the weld nugget zone due to the influence of the coarse microstructure and the large potential difference between both zones. Corrosion morphologies of a rock candy block and an ant nest appeared in the crack propagation zone and the grain boundary of the weld nugget zone. In addition, fatigue speckles and intergranular fractures were observed, as well as brittle fracture characterized by cleavage steps and secondary cracks in the final fracture zone.

BS700 high-strength steel is widely used in engineering. Welding residual stress during the manufacturing process has a significant influence on the structural safety and service life of steel structures. In this study, the residual stress of a BS700 butt-welded box section axial compression member was studied by the blind-hole method, its distribution law was summarized, and a residual stress distribution model was established. By establishing a finite element model considering initial geometric imperfection and residual stress, the influence of residual stress on the stability of axial compression members was analyzed. The results illustrated that the residual tensile stress near the weld in the welded box section axial compression members was the largest: the average residual tensile stress reached 76.6% of the measured steel yield strength, the residual tensile stress at the roof and web were almost the same, and the residual tensile stress at the corner was approximately 11.6% of the measured yield strength. The residual stress had a different influence on the stability factor of the axial compression members with different width-thickness ratios, and the influence decreased with the increase in the width-thickness ratio. In addition, when the slenderness ratio of members ranged between 20 and 70, the residual stress had a significant influence on the stability of members, while outside that interval, the influence was relatively small.

To study the influence of residual stress on the corrosion behavior of welded structures, methods such as residual stress measurement, microstructure observation, and corrosion morphology observation were used. The energy transformation model and corrosion-resistance constant model were utilized to reveal the mechanism of residual stress on the welded structures’ corrosion behavior. The results show that the fusion line was the region that is most heavily affected by corrosion and sustains more serious corrosion damage than other areas, resulting in the welded structure becoming a high-incidence area for corrosion cracking and failure. Residual tensile stress could reduce the activation energy and surface atomic density, and therefore decrease the corrosion resistance of the welded structures. The residual compressive stress decreased the activation energy needed by metal atoms to convert into metal ions in welded structures, and simultaneously increased the surface atomic density. The corrosion resistance of the welded structures ultimately increased owing to the combined influence of changes in activation energy and surface atomic density.

The nucleation mechanism of corrosion cracks in welded structures in natural seawater has been revealed through investigation on the corrosion behavior of X65-welded structures in natural seawater. The evolution laws of surface corrosion morphology, residual stress, and areas of welded structures with the most serious corrosion damage were analyzed by microstructure observation, corrosion morphology observation, residual stress detection, and magnetic field detection. The results show that the main factors of determining surface corrosion morphology evolution law of welded structures are microstructures of the weld joint, heat-affected zone (HAZ), and the fusion line. Due to the difference of corrosion rates between the weld joint, HAZ, and the coarse Widmänstatten structure in fusion line, the fusion line of welded structures receives the most serious damage while being corroded. Meanwhile, mutual reinforcement of residual stress and corrosion damage on the surface of welded structures further accelerate the nucleation of corrosion cracks. Under the influences of microstructure, residual stress, and corrosion, corrosion cracks that are parallel to weld joints generate first in the fusion line of welded structures. Therefore, it makes welded structures the source of marine steel structures’ corrosion failure.