Search Results (33)

Background/Objectives: Oncogenic KRAS drives ~30% of solid tumours, yet the only approved G12C-specific drugs benefit ≈ 13% of KRAS-mutant patients, leaving a major clinical gap. We sought mutation-agnostic natural ligands from Ziziphus lotus, whose stereochemically rich phenolics may overcome this limitation by occupying the SI/II (Switch I/Switch II) groove and locking KRAS in its inactive state. Methods: Phytochemical mining yielded five recurrent phenolics, such as (+)-catechin, hyperin, astragalin, eriodictyol, and the prenylated benzoate amorfrutin A, benchmarked against the covalent inhibitor sotorasib. An in silico cascade combined SI/II docking, multi-parameter ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) filtering, and 100 ns explicit solvent molecular dynamics simulations. Pharmacokinetic modelling predicted oral absorption, Lipinski compliance, mutagenicity, and acute-toxicity class. Results: Hyperin and astragalin showed the strongest non-covalent affinities (−8.6 kcal mol⁻¹) by forging quadridentate hydrogen-bond networks that bridge the P-loop (Asp30/Glu31) to the α3-loop cleft (Asp119/Ala146). Catechin (−8.5 kcal mol⁻¹) balanced polar anchoring with entropic economy. ADME ranked amorfrutin A the highest for predicted oral absorption (93%) but highlighted lipophilic solubility limits; glycosylated flavonols breached Lipinski rules yet remained non-mutagenic with class-5 acute-toxicity liability. Molecular dynamics trajectories confirmed that hyperin clamps the SI/II groove, suppressing loop RMSF below 0.20 nm and maintaining backbone RMSD stability, whereas astragalin retains pocket residence with transient re-orientation. Conclusions: Hyperin emerges as a low-toxicity, mutation-agnostic scaffold that rigidifies inactive KRAS. Deglycosylation, nano-encapsulation, or soft fluorination could reconcile permeability with durable target engagement, advancing Z. lotus phenolics toward broad-spectrum KRAS therapeutics. Full article

The dynamic interactions among the internal components of aero-engine main shaft bearings under unsteady-state conditions are intricate, involving clearance collisions, contact, friction, and lubrication. The dynamic characteristics of bearings significantly influence the performance and stability of mechanical systems. This study establishes a rigid–flexible coupling dynamic model for angular contact ball bearings with two-piece inner rings based on Hertz contact theory and lubrication theory. It systematically analyzes the dynamic characteristics of bearings under the coupling effects of acceleration, deceleration, and impact load. This study explores the influence of various loads, bearing speeds, and groove curvature radius coefficients on the dynamic characteristics of bearings. The findings indicate that the uniform speed phase of a bearing is highly responsive to impact load, followed by the deceleration phase, while the acceleration phase shows lower sensitivity to impact load. The groove curvature radius coefficient significantly affects the contact stress between the ball and its corresponding raceway, with contact stress increasing as the groove curvature radius coefficient rises. As the axial load decreases and the radial load, bearing speed, and groove curvature radius coefficient increase, there is a rise in pocket force, guiding force, and maximum equivalent stress of the flexible cage. Impact load leads to short-term intense fluctuations in the thickness of the bearing oil film, which can be alleviated by an increase in axial load. The oil film thickness firstly increases and then decreases with respect to the groove curvature radius coefficient. Furthermore, variations in bearing speed notably influence the thickness of the bearing oil film. This study analyzes the dynamic characteristics of bearings under the coupling effects of acceleration, deceleration, and impact load, offering insights for the design and optimization of angular contact ball bearings with two-piece inner rings. Full article

The cage strength is a critical factor that constrains performance of high-speed deep groove ball bearing (DGBB) used in the drive motor of new energy vehicles. This paper presents a rigid-flexible coupling dynamic model for high-speed DGBBs, based on interactions dynamic of the flexible crown cage, balls, and rings. This study systematically analyzed the cage weaknesses in strength, and explored how factors such as the pocket clearance, claw length, modification radius and bottom thickness influence cage strength. In addition, an improved design aimed at enhancing cage strength was proposed. The results indicate that the cage strength is more sensitive to the inner-ring speed. Particularly, both the maximum stress and deformation in the radial direction increase sharply when the speed exceeds a threshold of 18,000 r/min. Additionally, an increase in the bearing rotational acceleration leads to a 45.7% rise in the cage stress. Furthermore, the sensitivity of the cage strength to temperature also escalates with bearing speed; the maximum stress and deformation increase by 5% to 16% at 80 °C compared to that obtained at 25 °C. Based on the structural influence on the cage strength, a structural improvement is proposed. With a pocket clearance of 0.23 mm, a claw length of 2.3 mm, a bottom thickness of 2.4 mm, and a shaping radius of 7.0 mm, the strength of the cage was evaluated both before and after the improvements. The results indicated that the enhanced cage exhibited superior strength. Full article

A common approach to optimising hydrodynamic journal bearings for power loss is to reduce the lubricant supply and direct the oil to specific bearing areas where it is needed to guarantee safe operation. This requires information on the processes in the gap and the surrounding pocket areas for both pre-design and simulation. In this paper, a system consisting of a total of eight cameras is used to determine the void fraction in deep grooves outside the lubricant film. The void fraction in the lubrication gap is determined using a novel method for the evaluation of two proximity measurements. While the variation of the deep groove void fraction is realised by a special oil supply and radially adjustable deep groove elements, the gap void fraction is adjusted by the oil supply in the lube oil pockets at the pad leading edges. On the one hand, the experimental investigations show that the void fraction of the deep groove areas has hardly any influence on the general operating behaviour. On the other hand, the void fraction in the lubrication gap can be measured quantitatively for the first time, and the operating point-dependent gas fractions can be visualised. It is also shown that gaseous cavitation is the main mechanism in partially filled regions of the lubrication gap. Full article

Integrated bearings, characterized by their unique structure, feature an inner ring that is seamlessly integrated with the shaft. This study is based on the theoretical framework of rolling bearing dynamics and considers bearing friction, lubrication, and Hertz elastic contact theory. A dynamic simulation model considering the interaction between the components of the rolling bearing is established. Additionally, a subroutine for calculating the interaction forces between the bearing components was written in C and compiled into a dynamic link library, which was then integrated with the dynamic simulation software. To solve and simulate the dynamics of the integrated bearing model, a sophisticated combination of a refined integration method and the predictor-corrector Adams–Bashforth–Moulton multistep technique was employed. The theoretical analysis offers insights into the vibration characteristics of the integrated bearings across different structural and operational parameters. Results indicate that a judicious selection of parameters, such as the curvature radius ratio of the inner and outer grooves and the gap of the cage pockets, can significantly enhance the bearings’ vibration and noise reduction capabilities. Furthermore, the application of an appropriate axial preload effectively reduces bearing vibrations, and there exists an optimal range of rotational speeds that minimizes these vibrations. Full article

A stable attachment between bubbles and solid particles is essential for flotation. Therefore, it is particularly necessary to study the dynamic process that occur in the attachment of bubbles to a solid surface. In this paper, Teflon and plexiglass plates were used as hydrophobic and hydrophilic solid surfaces, respectively, and solid surfaces with roughness of 0.018 μm to 5.33 μm were prepared by polishing with sandpaper. The influence of roughness on the dynamic process in bubble attachment to solid surfaces with different hydrophobicity was studied via a high-speed camera (750 frames per second). It was found that roughness played a positive role in the attachment to the hydrophobic Teflon surface while a negative role in the attachment to the hydrophilic plexiglass surface in terms of the bubble’s attachment to the solid plates. For a smooth Teflon surface, the formation of three–phase contact (i.e., the drainage of wetting film) took up to 95 ms, whereas for a very rough Teflon surface it took only 5 milliseconds. On the contrary, the high roughness prevented the bubble from attaching to the hydrophilic plexiglass surface. It was concluded that the increased roughness of Teflon plates was conductive to air entrapment in surface irregularities, inducing the rapid rupture of the wetting film on a very rough Teflon surface, while the increased roughness of the plexiglass plates resulted in “water pockets” in surface grooves, making the wetting film on the plexiglass surface stable. Full article

In experiments of aviation motor bearings, when the deep-groove ball bearings are subjected to an overturning moment at high speed, it often happens that the rivet on the cage breaks and the debris invades the raceway, resulting in bearing failure. To address the problem of early failure of deep-groove ball bearing cages and rivets in aviation motors, the causes of early failure were analyzed from the aspect of cage design in this study. The influence of the raceway and cage structure parameters on the dynamic contact characteristics of the rolling element and cage under the action of overturning torque were analyzed, the weak link of the cage was determined, and the cage design parameters were optimized. The results show that with an increase in the cage width and pocket radius, the impact force between the ball and cage first decreases and then increases, and the tilt angle of the cage gradually decreases. A larger channel radius and smaller clearance can slow down the interaction between the cage and the rolling element and make the cage run more smoothly. Increasing the thickness of the cage can ensure that the rivet part of the cage is at a low stress level, and the risk of premature fatigue failure at the rivet part can be reduced by maintaining a small gap–fit relationship between the rivet and rivet holes. The research results indicate that the working condition adaptability of the bearing cage for aviation motors can be improved, and the design method for this type of bearing can be enhanced. Full article

Pyridoxal–S-methyl-isothiosemicarbazone (PLITSC) is a member of an important group of ligands characterized by different complexation modes to various transition metals. In this contribution, a new complex containing two differently protonated PLITSC ligands ([Fe(PLITSC–H)(PLITSC)]SO₄)∙2.5H₂O was obtained. The crystal structure was solved by the X-ray analysis and used further for the optimization at B3LYP/6-311++G(d,p)(H,C,N,O,S)/def2-TZVP(Fe) level of theory. Changes in the interaction strength and bond distance due to protonation were observed upon examination by the Quantum Theory of Atoms in Molecules. The protein binding affinity of [Fe(PLITSC–H)(PLITSC)]SO₄ towards transport proteins (Bovine Serum Albumin (BSA) and Human Serum Albumin (HSA)) was investigated by the spectrofluorimetric titration and molecular docking. The interactions with the active pocket containing fluorescent amino acids were examined in detail, which explained the fluorescence quenching. The interactions between complex and DNA were followed by the ethidium-bromide displacement titration and molecular docking. The binding along the minor groove was the dominant process involving complex in the proximity of DNA. Full article

Protein kinases are key regulators of cell signaling and have been important therapeutic targets for three decades. ATP-competitive drugs directly inhibit the activity of kinases but these enzymes work as part of complex protein networks in which protein–protein interactions (often referred to as kinase docking) may govern a more complex activation pattern. Kinase docking is indispensable for many signaling disease-relevant Ser/Thr kinases and it is mediated by a dedicated surface groove on the kinase domain which is distinct from the substrate-binding pocket. Thus, interfering with kinase docking provides an alternative strategy to control kinases. We describe activity sensors developed for p90 ribosomal S6 kinase (RSK) and mitogen-activated protein kinases (MAPKs: ERK, p38, and JNK) whose substrate phosphorylation is known to depend on kinase-docking-groove-mediated protein–protein binding. The in vitro assays were based on fragment complementation of the NanoBit luciferase, which is facilitated upon substrate motif phosphorylation. The new phosphorylation-assisted luciferase complementation (PhALC) sensors are highly selective and the PhALC assay is a useful tool for the quantitative analysis of kinase activity or kinase docking, and even for high-throughput screening of academic compound collections. Full article

Seizure during ironing negatively affects the quality of parts and die life. To prevent seizures, lubrication has to be improved. In this study, laser-textured dies with lubricant pockets were utilized to improve seizure resistance in the ironing of aluminum alloy sheets and stainless steel cups. The effects of array patterns of micro-pockets, such as grid and crossing array patterns with circular pockets, as well as a grooved array patterns on seizure resistance, were experimentally examined by strip ironing. The sheet and die materials were the A1050-O aluminum alloy and JIS SKD11 tool steel, respectively. Moreover, the underlying physics of the lubricant flow influencing the load-carrying capacity were investigated using three-dimensional computational fluid dynamics simulations. The optimum array patterns of the micro-pockets were then utilized on a tungsten carbide-cobalt (WC-Co) die surface for ironing SUS430 stainless steel cylindrical cups. The strip ironing results showed that the grid array pattern was successful in ironing sheets with a high ironing ratio. The grid array pattern increased the load-carrying capacity of the lubricant more than the crossing pattern, as demonstrated by the simulations, thereby improving the ironing limit. The subsequent ironing of stainless steel cups revealed that when using a textured die with a grid array pattern and lubricant without the extreme pressure additive in comparison to an untextured die, the ironing limit increased by 6% and the average ironing load decreased by 35%. The seizure resistance was improved because the pockets on the surface structured by laser surface texturing improved the load-carrying capacity during ironing. Full article

The flow through the stator vanes of a variable geometry turbocharger turbine can reach supersonic conditions and generates a shock wave on the stator vanes, which has a potential impact on the flow loss as well as on unsteady aerodynamic interaction. The shock wave causes a sudden increase in pressure and can lead to boundary separation and strong excitation force, besides pressure fluctuation in the rotor blades. Thus, in this study, the flat surface of the vanes of a commercial variable geometry turbocharger turbine has been modified to analyze the effects of two grooved surfaces configuration using CFD simulations. The results reveal that the grooves change the turbine efficiency, especially at higher speed, where the increase in the efficiency is between 2% and 6% points. Additionally, the load fluctuation around the rotor leading edge can be reduced and minimize the factors that compromise the integrity of the turbine. Furthermore, the grooves reduce the supersonic pocket developed on the suction side of the vane and diminish the shock wake intensity. Evaluating the effectiveness of the available energy usage in the turbine, on the one hand, at lower speed, the fraction of energy at the inlet destinated to produce power does not change significantly with a grooved surface on the stator vanes. On the other hand, at higher speed and higher pressure ratio with 5 grooves occurs the most effective approach of the maximum energy. Full article

The protein PARP1, which plays a crucial role in DNA repair processes, is an attractive target for cancer therapy, especially for BRCA-deficient cancers. To overcome the acquired drug resistance of PARP1, PARP1 G-quadruplex (G4) identified in the PARP1-promotor region is gaining increasing attention. Aiming to explore the molecular mechanism of PARP1 inhibition with PARP1 G4 and PARP1 as potential targets, a comparative investigation of the binding characteristics of the newly identified G4 stabilizer MTR-106, which showed modest activity against talazoparib-resistant xenograft models and the FDA-approved PARP1 inhibitor (PARPi) talazoparib, were performed through molecular simulations. Combined analyses revealed that, relative to the groove binding of talazoparib, MTR-106 induced the formation of a sandwich framework through stacking with dT₁ and the capping G-pair (dG₂ and dG₁₄) of PARP1 G4 to present largely enhanced binding affinity. For the binding with PARP1, although both were located in the catalytic pocket of PARP1, MTR-106 formed more extensive interactions with the surrounding PARP1 residues compared to talazoparib, in line with its increased binding strength. Importantly, vdW interaction was recognized as a decisive factor in the bindings with PARP1 G4 and PARP1. Collectively, these findings demonstrated the ascendancy of MTR-106 over talazoparib at the atomic level and revealed that the dual targeting of PARP1 G4 and PARP1 might be pivotal for PARPi that is capable of overcoming acquired drug resistance, providing valuable information for the design and development of novel drugs. Full article

Oil lubrication is widely adopted in rolling bearings, the characteristics of which affect the oil film formation and friction state, and also the heat generation and dissipation characteristics. However, it is difficult to measure the internal lubrication of rolling bearings in practice, which is of great importance for lubrication and structure design. In this work, one measurement system for lubricant distribution was built and installed on a test rig to obtain original pictures of the lubricant in bearings. Grayscale images were obtained by picture processing to characterize the lubricant distribution, and the image pixels were evaluated for the characterization of lubricant volume. Finally, the measurement of the lubricant distribution in the angular ball bearing was carried out under different lubrication and cage groove conditions, and their influences were investigated. The results show that the lubricant distribution is affected by the oil jet nozzle angle, operating speed, and cage structure. The lubricant capacity among balls and the cage pocket in bearings gradually increased with the increase in the nozzle angle and the depth of the cage grooves, but decreased with the increasing operating speed. The experimental results are helpful to provide a basis for the structure and lubrication design of ball bearings. Full article

Influenza A viruses still represent a major health issue, for both humans and animals. One of the main viral proteins of interest to target is the NS1 protein, which counters the host immune response and promotes viral replication. NS1 is a homodimer composed of a dimeric RNA-binding domain (RBD), which is structurally stable and conserved in sequence, and two effector domains that are tethered to the RBD by linker regions. This linker flexibility leads to NS1 polymorphism and can therefore exhibit different forms. Previously, we identified a putative drug-binding site, located in the RBD interface in a crystal structure of NS1. This pocket could be targeted to block RNA binding and inhibit NS1 activities. The objective of the present study is to confirm the presence of this druggable site, whatever the sequence variants, in order to develop a universal therapeutic compound that is insensitive to sequence variations and structural flexibility. Using a set of four NS1 full-length structures, we combined different bioinformatics approaches such as pocket tracking along molecular dynamics simulations, druggability prediction and classification. This protocol successfully confirmed a frequent large binding-site that is highly druggable and shared by different NS1 forms, which is promising for developing a robust NS1-targeted therapy. Full article

The effect of cylinder liners on engine performance is substantial. Typically, the cylinder surfaces were plateau honed. However, recently additional dimples or grooves were created on them. This work discusses the tribological impacts of textured cylinder liner surfaces based on a review of the literature. The results of the experimental research obtained using test rigs and fired engines were critically reviewed. In addition, the results of the modeling are shown. Circular oil pockets and grooves perpendicular to the sliding direction of piston rings of small depths were typically used. Surface texturing of the cylinder liners governs lubrication between the cylinder liner and the piston ring by an increase in oil film thickness near the reversal points leading to reductions in friction force and wear and in the fired engine to a decrease in fuel consumption and to an increase in power or torque. The correct texturing pattern ensures a decrease in the oil consumption, blow-by, and emissions of the internal combustion engine compared to plateau-honed surfaces. Considerations of future challenges are also addressed. The volume of lubricant reservoir in surface topography, called oil capacity, should be a substantial parameter characterizing textured surfaces. Full article