Targeted mechanical forces enhance the effects of tumor immunotherapy by regulating immune cells in the tumor microenvironment

Mechanical forces in the tumor microenvironment(TME)are associated with tumor growth,proliferation,and drug resistance.Strong mechanical forces in tumors alter the metabolism and behavior of cancer cells,thus promoting tumor progression and metastasis.Mechanical signals are transformed into biochemical signals,which activate tumorigenic signaling pathways through mechanical transduction.Cancer immunotherapy has recently made exciting progress,ushering in a new era of“chemo-free”treatments.However,immunotherapy has not achieved satisfactory results in a variety of tumors,because of the complex tumor microenvironment.Herein,we discuss the effects of mechanical forces on the tumor immune microenvironment and highlight emerging therapeutic strategies for targeting mechanical forces in immunotherapy.

Computational Simulation of Aptamer-target Binding Mechanisms

Aptamers are a type of single-chain oligonucleotide that can combine with a specific target.Due to their simple preparation,easy modification,stable structure and reusability,aptamers have been widely applied as biochemical sensors for medicine,food safety and environmental monitoring.However,there is little research on aptamer-target binding mechanisms,which limits their application and development.Computational simulation has gained much attention for revealing aptamer-target binding mechanisms at the atomic level.This work summarizes the main simulation methods used in the mechanistic analysis of aptamer-target complexes,the characteristics of binding between aptamers and different targets(metal ions,small organic molecules,biomacromolecules,cells,bacteria and viruses),the types of aptamer-target interactions and the factors influencing their strength.It provides a reference for further use of simulations in understanding aptamer-target binding mechanisms.

The deterministic condition for the ground reaction force acting point on the combined knee valgus and tibial internal rotation moments in early phase of cutting maneuvers in female athletes

Background:Combined knee valgus and tibial internal rotation(VL+IR)moments have been shown to stress the anterior cruciate ligament(ACL)in several in vitro cadaveric studies.To utilize this knowledge for non-contact ACL injury prevention in sports,it is necessary to elucidate how the ground reaction force(GRF)acting point(center of pressure(CoP))in the stance foot produces combined knee VL+IR moments in risky maneuvers,such as cuttings.However,the effects of the GRF acting point on the development of the combined knee VL+IR moment in cutting are still unknown.Methods:We first established the deterministic mechanical condition that the CoP position relative to the tibial rotational axis differentiates the GRF vector’s directional probability for developing the combined knee VL+IR moment,and theoretically predicted that when the CoP is posterior to the tibial rotational axis,the GRF vector is more likely to produce the combined knee VL+IR moment than when the CoP is anterior to the tibial rotational axis.Then,we tested a stochastic aspect of our theory in a lab-controlled in vivo experiment.Fourteen females performed 60˚cutting under forefoot/rearfoot strike conditions(10 trials each).The positions of lower limb markers and GRF data were measured,and the knee moment due to GRF vector was calculated.The trials were divided into anterior-and posterior-CoP groups depending on the CoP position relative to the tibial rotational axis at each 10 ms interval from 0 to 100 ms after foot strike,and the occurrence rate of the combined knee VL+IR moment was compared between trial groups.Results:The posterior-CoP group showed significantly higher occurrence rates of the combined knee VL+IR moment(maximum of 82.8%)at every time point than those of the anterior-CoP trials,as theoretically predicted by the deterministic mechanical condition.Conclusion:The rearfoot strikes inducing the posterior CoP should be avoided to reduce the risk of non-contact ACL injury associated with the combined knee VL+IR stress.

Performances of a Stinger PDC cutter breaking granite: Cutting force and mechanical specific energy in single cutter tests

The Stinger PDC cutter has high rock-breaking efficiency and excellent impact and wear resistance, which can significantly increase the rate of penetration (ROP) and extend PDC bit life for drilling hard and abrasive formation. The knowledge of force response and mechanical specific energy (MSE) for the Stinger PDC cutter is of great importance for improving the cutter's performance and optimizing the hybrid PDC bit design. In this paper, 87 single cutter tests were conducted on the granite. A new method for precisely obtaining the rock broken volume was proposed. The influences of cutting depth, cutting angle, and cutting speed on cutting force and MSE were analyzed. Besides, a phenomenological cutting force model of the Stinger PDC cutter was established by regression of experimental data. Moreover, the surface topography and fracture morphology of the cutting groove and large size cuttings were measured by a 3D profilometer and a scanning electron microscope (SEM). Finally, the rock-breaking mechanism of the Stinger PDC cutter was illustrated. The results indicated that the cutting depth has the greatest influence on the cutting force and MSE, while the cutting speed has no obvious effects, especially at low cutting speeds. As the increase of cutting depth, the cutting force increases linearly, and MSE reduces with a quadratic polynomial relationship. When the cutting angle raises from 10° to 30°, the cutting force increases linearly, and the MSE firstly decreases and then increases. The optimal cutting angle for breaking rock is approximately 20°. The Stinger PDC cutter breaks granite mainly by high concentrated point loading and tensile failure, which can observably improve the rock breaking efficiency. The key findings of this work will help to reveal the rock-breaking mechanisms and optimize the cutter arrangement for the Stinger PDC cutter.

FORCE ANALYSIS CONSIDERING MANUFACTURE ERROR OF PIN-HOLE-OUTPUT MECHANISM IN CYCLOID DRIVE

Based on the analysis of the pin-hole-output mechanism in the cycloid drive,a more accurate force analysis method is provided, in which the manufacture error is considered, bywhich the contact force between pin and pin-hole can be calculated more accurately in the wholedriving process.

Limit analysis of roof collapse in tunnels under seepage forces condition with three-dimensional failure mechanism

The state of roof collapse in tunnels is actually three-dimensional, so constructing a three-dimensional failure collapse mechanism is crucial so as to reflect the realistic collapsing scopes more reasonably. According to Hoek-Brown failure criterion and the upper bound theorem of limit analysis, the solution for describing the shape of roof collapse in circular or rectangular tunnels subjected to seepage forces is derived by virtue of variational calculation. The seepage forces calculated from the gradient of excess pore pressure distribution are taken as external loading in the limit analysis, and it is of great convenience to compute the pore pressure with pore pressure coefficient. Consequently, the effect of seepage forces is taken as a work rate of external force and incorporated into the upper bound limit analysis. The numerical results of collapse dimensions with different rock parameters show great validity and agreement by comparing with the results of that with two-dimensional failure mechanism.

A force transfer mechanism for triggering landslides during rainfall infiltration

Shallow slope failures induced by rainfall infiltration occur frequently, and the relevant triggering mechanisms have been widely studied.Rainfall-induced landslides are widely recognized to be caused by increases in soil weight, seepage force and pore water pressure or decreases in soil mechanical properties. However, even when all these factors are considered, some landslides still cannot be explained well. The increased pore water pressure in a slope reduces the effective stress of the soil and may trigger slope failure. Similarly, the pore gas pressure in a slope also reduces the effective stress of the soil but has been neglected in previous studies. As the viscosity of air is nearly negligible when compared with that of water, the pore gas pressure spreads faster, and its influence is wider, which is harmful for the stability of the slope. In this paper, the effects of pore gas pressure are considered in a shallow slope stability analysis, and a self-designed experiment is conducted to validate the force transfer mechanism.Numerical simulation results show that the pore gas pressure in the slope increases sharply at different locations under heavy rainfall conditions and that the pore gas pressure causes a rapid decrease in the slope safety factor. Laboratory experimental results show that the pore gas pressure throughout the whole unsaturated zone has the same value, which indicates that the gas pressure could spread quickly to the whole sample.

A method to calculate and counterbalance the inertia force of slider-crank mechanisms in high-speed presses

A new method to calculate and counterbalance the inertia force of slider-crank mechanisms in high-speed mechanical presses was put forward. By analyzing the kinematic characteristics of a center-located slider-crank mechanism whose crank rotates at a constant angular velocity,the kinematic parameters of the slide,connecting rod and crank were formulated approximately. On the basis of the results above,three inertia forces and the input moment in the mechanism during its idle running were investigated and formulated by dynamic analysis. A verification experiment was performed on a slider-crank mechanism at a high-speed press machine. The forces derived from the established formulas were compared respectively with those obtained by the ADAMS software and the classical method of connecting rod mass substitution. It was experimentally found that the proposed formulas have an improved performance over related earlier techniques. By use of these results,a 1 000 kN 1 250 rpm four-point high-speed press machine was designed and manufactured. The slide of this press is driven by four sets of slider-crank mechanisms with symmetrical layout and opposite rotation directions to counterbalance the horizontal inertia forces. Four eccentric counterbalance blocks were designed to counterbalance the vertical force after their mass and equivalent eccentric radius were formulated. The high-speed press machine designed by the proposed counterbalance method has worked with satisfactory performance and good dynamic balance for more than four years in practical production.

The mechanism of unconventional hydrocarbon formation: Hydrocarbon self-sealing and intermolecular forces

The successful development of unconventional hydrocarbons has significantly increased global hydrocarbon resources, promoted the growth of global hydrocarbon production and made a great breakthrough in classical oil and gas geology. The core mechanism of conventional hydrocarbon accumulation is the preservation of hydrocarbons by trap enrichment and buoyancy, while unconventional hydrocarbons are characterized by continuous accumulation and non-buoyancy accumulation. It is revealed that the key of formation mechanism of the unconventional reservoirs is the self-sealing of hydrocarbons driven by intermolecular forces. Based on the behavior of intermolecular forces and the corresponding self-sealing, the formation mechanisms of unconventional oil and gas can be classified into three categories:(1) thick oil and bitumen, which are dominated by large molecular viscous force and condensation force;(2) tight oil and gas, shale oil and gas and coal-bed methane, which are dominated by capillary forces and molecular adsorption;and(3) gas hydrate, which is dominated by intermolecular clathration. This study discusses in detail the characteristics, boundary conditions and geological examples of self-sealing of the five types of unconventional resources, and the basic principles and mathematical characterization of intermolecular forces. This research will deepen the understanding of formation mechanisms of unconventional hydrocarbons, improve the ability to predict and evaluate unconventional oil and gas resources, and promote the development and production techniques and potential production capacity of unconventional oil and gas.

A Numerical Study on the Mechanisms Producing Forces on Cylinders Interacting with Stratified Shear Environments

A three dimensional(3D)numerical wave flume is used to investigate carefully the ISWs(Internal solitary wave)forces acting on cylinders interacting with a stratified shear environment.Using the Large-Eddy Simulation(LES)approach and analyzing the distribution of shear stress and pressure along the surface of the cylinder,the differential pressure resistance and the viscous force are obtained.The method of multiple linear regression analysis is adopted and a comprehensive influence coefficient is determined accordingly to account for the dimensionless forces acting on the cylinder.Results show that the differential pressure resistance on a square cylinder is 1.5 times higher than that on a circular cylinder in the upper layer,while the differential pressure resistance on a square cylinder is 3.5 times larger than that on a circular cylinder in the lower layer.The viscous force is 1–2 orders of magnitude smaller than the differential pressure resistance,which means that the viscous force could be ignored.The comprehensive influence coefficient shows positive correlation with the relative wave height and negative correlation with upper and lower water depth ratio.

Nanoscale domain switching mechanism of Bi_(3.15)Eu_(0.85)Ti_3O_(12) thin film under the different mechanical forces

The switching process of ferroelectric thin films in electronic devices is one of the most important requirements for their application. Especially for the different external fields acting on the film surface, the mechanism of domain switching is more complicated. Here we observe the nanoscale domain switchings of Bi3.15Eu0.85Ti3O12 thin film under different mechanical forces at a fast scan rate. As the force increases from initial state to 247.5 n N, the original bright or grey contrasts within the selected grains are all changed into dark contrasts corresponding to the polarization vectors reversed from the up state to the down state, except for the clusters. As the mechanical force increases to 495 n N, the color contrasts in all of the selected grains further turn into grey contrasts and some are even changed into grey contrasts completely showing the typical 90° domain switching. When another stronger loading force 742.5 n N is applied, the phase image becomes unclear and it indicates that the piezoelectric signal can be suppressed under a sufficiently high force, which is coincident with previous experimental results. Furthermore, we adopt the domain switching criterion from the perspective of equilibrium state free energy of ferroelectric nanodomain to explain the mechanisms of force-generated domain switchings.

Confirmation of the Ball-Screw Force for the Differential Cushion System of Space Docking Mechanism

Based on the analysis of the differential cushion damping system kinematic relation and using principle of virtual work, a new kinematic function expression is established which is between six ball-screws and cushion components. At last the relationship between ball-screw force and attitude is intreduced.

Instability Mechanism of a Rotating Disc Subjected to Various Transverse Interactive Forces

In the past three decades, numerous papers have bee n publishedon the dynamics of rotating discs. most of them have focused on the ma thematical modeling and solution for a specific interactive force, such as a n elastic force produced by a stationary spring or a damping force from a statio nary viscous damper. Few of them have looked into the instability mechanisms. This study has established a generalized approach to investigate the instability mechanisms that are involved in the interaction between a rotating and an arbit rary interactive force. An energy flux equation has been developed, which leads to the following conclusions: (1) The possibility of the occurrence of instability due to any interactive forc es may be identified based on the energy flux analysis, even without solving equ ations. (2) Instabilities will occur if the interactive forces are in phase with the vel ocity measured at the interactive point from the coordinates rotating with the d isc. (3) Instability cannot occur when a rotating disc is subjected to a stationary c onstant lateral force, but a stationary harmonic lateral force, a moving constan t lateral force or a moving harmonic lateral force may cause instability. (4) Conservative forces may only cause coupling instability associated with two modes, and non-conservative forces usually cause terminal instability where onl y one mode is involved.

Forced bursting and transition mechanism in CO oxidation with three time scales

The mathematical model of CO oxidation with three time scales on platinum group metals is investigated, in which order gaps between the time scales related to external perturbation and the rates associated with different chemical reaction steps exist. Forced bursters, such as point–point type forced bursting and point–cycle type forced bursting, are presented. The bifurcation mechanism of forced bursting is novel, and the phenomenon where two different kinds of spiking states coexist in point–cycle type forced bursting has not been reported in previous work. A double-parameter bifurcation set of the fast subsystem is explored to reveal the transition mechanisms of different forced bursters with parameter variation.

Coercive Force and Antimagnetizing Mechanism Relating to Size of Ferromagnetic Microcrystal--A Consummating to Result of Stoner-Wohlforth Theory

The expression of critical size of ferromagnetic microcrystal in an external magnetic field with an intensity of H is derived by means of comparing energies of domain structure states.The ferromagnetic microcrystal here means an ferromagnetic single crystal with the size which is smaller than L0, and L0 is the critical value of the size of single-domain particles at the external magnetic field intensity H =0.Also, the coercive strength H(Ls) relating to the size of microcrystal Ls is given and quantitatively evaluated with the material SmCo5 as an instance.It is thus concluded that if L0 ＞ Ls ＞ LC, the antimagnetization of microcrystal will be subjected to a multi-domain process just like the particles of a size greater than L0, only if Ls ＜ LC, the anti-magnetizaton will be carried on in accordance with the Stoner-Wohlforth mechanism( LC is the maximum size of microcrystal with MHcth ).It is suggested that the material RECo5 is available to make an advanced magnet with MHC = 2 K/Mc.

Atomic Force Microscopy Measurement in the Lignosulfonate/Inorganic Silica System:From Dispersion Mechanism Study to Product Design

Designing and preparing high-performance lignin-based dispersants are crucial steps in realizing the value-added utilization of lignin on an industrial scale.Such process depends heavily on an understanding of the dispersion mechanism of lignin-based dispersants.Here,atomic force microscopy(AFM)is employed to quantitatively investigate the dispersion mechanism of a lignosulfonate/silica(LS/SiO_(2))system under different pH conditions.The results show that the repulsive force between SiO_(2)particles in LS solution is stronger than it is in water,resulting in better dispersion stability.The Derjaguin–Landau–Verwey–Overbeek(DLVO)formula as well as the DLVO formula combined with steric repulsion is utilized for the fitting of the AFM force/distance(F/D)curves between the SiO_(2)probe and substrate in water and in LS solution.Based on these fitting results,electrostatic and steric repulsive forces are respectively calculated,yielding further evidence that LS provides strong steric repulsion between SiO_(2)particles.Further studies indicate that the adsorbance of LS on SiO_(2)(Q),the normalized interaction constant(A),and the characteristic length(L)are the three critical factors affecting steric repulsion in the LS/SiO_(2)system.Based on the above conclusions,a novel quaternized grafted-sulfonation lignin(QAGSL)dispersant is designed and prepared.The QAGSL dispersant exhibits good dispersing performance for SiO_(2)and real cement particles.This work provides a fundamental and quantitative understanding of the dispersion mechanism in the LS/inorganic particle system and provides important guidance for the development of high-performance lignin-based dispersants.

Electromagnetic Self-Force Mechanisms and Origin of <i>R</i>^-1Term

An accelerating charged particle exerts a force upon itself. If we model the particle as a spherical shell of radius R, and calculate the force of one piece of this shell on another and eventually integrate over the whole particle, there will be a net force on the particle due to the breakdown of Newton’s third law. This symmetry breaking mechanism relies on the finite size of the particle;thus, as Feynman has stated, conceptually this mechanism doesn’t make good sense for point particles. Nonetheless, in the point particle limit, two terms survive in the self-force series: R0 and R-1 terms. The R0 term can alternatively be attributed to the well-known radiation reaction but the origin of R-1 term is not clear. In this study, we will show that this new term can be accounted for by an inductive mechanism in which the changing magnetic field induces an inductive force on the particle. Using this inductive mechanism, we derive R-1 term in an extremely easy way.

Influence of layer orientation and interlayer bonding force on the mechanical behavior of shale under Brazilian test conditions

The mechanical behavior of inherently anisotropic shale rocks under Brazilian test conditions are investigated in this study based on experimental studies and numerical simulations. The effects of the weak lamination planes and interlayer bonding force of these layers on the failure strength and fracture patterns are studied systematically. Numerical simulations using particle flow code in two dimensions based on the discrete element method showed a good agreement with the experimental results in the failure strength and fracture patterns. The shale revealed strong anisotropic behavior with the failure strength perpendicular to the lamination plane greater than failure strength parallel to lamination plane. The failure strength of the different interlayer bonding force against the layer orientations changed significantly. Four types of fracture patterns were observed: curved fracture, broken-linear fracture, layeractivated fracture, and central-linear fracture. The observed fracture patterns are either or a combination of tensile and/or shear fractures. Increase in interlayer bonding strength decreased the quantity of micro cracks and this directly led to reduction in the anisotropic behavior. Overall the layer orientation and interlayer bonding force of the shale thus play a very important role in the anisotropic behavior of the shale.

Holocene Dune Mobility and Forcing Mechanisms at the Northern Margin of the East Asian Monsoon

Dune fields at the northern margin of the East Asian monsoon （EAM）, are mosaics of mobile and vegetation-stabilized aeolian dunes. These sand dunes are highly sensitive to environmental change, thus the distribution and the timing of their development may provide important clues to past environmental dynamics. Due to the strong wind erosion and dune migration, long and continuous stratigraphic records are seldom preserved. Synthesizing a large body of events, ultimately producing a relatively complete and high-resolution record, may be a proper method to investigate the dune development history and climate change. In this study, we synthesized a large body of luminescence ages for aeolian deposits from the Mu Us, Otindag, Horqin dune fields at the northern margin of the EAM. The results show that these dune fields, as a whole experienced a most extensive mobility during the early Holocene, followed by a widespread shift toward limited mobility and soil development in the mid-Holocene, and widespread reactivation occurred during late Holocene. The dune developments are directly linked to the effective moisture change controlled by the EAM changes, which respond to the low latitude summer insolation variation. The increased subsidence at the margin contrary to the core EAM, the delay from the feedback of the soil-vegetation-air coupled system, the increased evaporation due to the high temperature all play partial role in the lag of the margin EAM effective moisture change to the low latitude summer insolation. The asynchronous end of the wetter mid-Holocene mainly responds to the southeastwardly shift of the precipitation belt, while the regional sensitivity, response speed and internal feedback also contributed. The correspondence between dune records and North Atlantic drift-ice records of the rapid climate changes implies a close relationship between North Atlantic climate and the frequent dune activity at the northern margin of EAM.

Mechanical Nature of Gravity and Tectonic Forces

There are two models of ultrahigh pressure metamorphism (UHPM) zone in Dabie: the model of under thrusting returning which even arrives at the mantle and the superimposed model of tectonics in the crust. There are two points of view in the argument about formation depth of ultrahigh pressure metamorphism: (1) the depth can be calculated by hydrostatic equation; (2) the high pressure was composed of gravity, tectonic and other forces instead of merely gravity force. Some misunderstandings of mechanical conceptions presented in the paper showing the hydrostatic viewpoints should be open to question. The main conceptions are: (1) the confining pressure was only formed by gravity, and the differential stress was only formed by tectonic force; (2) the differential stress is not big enough to lead to form ultrahigh pressure metamorphism; (3) once tectonic overpressure goes beyond the limited strength of rocks the tectonic force would disappear and the rocks would be broken or rheomorphied at the same time. A short discussion in basic mechanics is made in this paper for a perfect process for discussing the argument.