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.

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.

Dynamics of perinuclear actin ring regulating nuclear morphology

Cells are capable of sensing and responding to the extracellular mechanical microenvironment via the actin skeleton.In vivo,tissues are frequently subject to mechanical forces,such as the rapid and significant shear flow encountered by vascular endothelial cells.However,the investigations about the transient response of intracellular actin networks under these intense external mechanical forces,their intrinsic mechanisms,and potential implications are very limited.Here,we observe that when cells are subject to the shear flow,an actin ring structure could be rapidly assembled at the periphery of the nucleus.To gain insights into the mechanism underlying this perinuclear actin ring assembly,we develop a computational model of actin dynamics.We demonstrate that this perinuclear actin ring assembly is triggered by the depolymerization of cortical actin,Arp2/3-dependent actin filament polymerization,and myosin-mediated actin network contraction.Furthermore,we discover that the compressive stress generated by the perinuclear actin ring could lead to a reduction in the nuclear spreading area,an increase in the nuclear height,and a decrease in the nuclear volume.The present model thus explains the mechanism of the perinuclear actin ring assembly under external mechanical forces and suggests that the spontaneous contraction of this actin structure can significantly impact nuclear morphology.

Targeting micromotion for mimicking natural bone healing by using NIPAM/Nb_(2)C hydrogel

Natural fracture healing is most efficient when the fine-tuned mechanical force and proper micromotion are applied.To mimick this micromotion at the fracture gap,a near-infrared-II(NIR–II)–activated hydrogel was fabricated by integrating two-dimensional(2D)monolayer Nb2C nanosheets into a thermally responsive poly(Nisopropylacrylamide)(NIPAM)hydrogel system.NIR–II–triggered deformation of the NIPAM/Nb2C hydrogel was designed to generate precise micromotion for co-culturing cells.It was validated that micromotion at 1/300 Hz,triggering a 2.37-fold change in the cell length/diameter ratio,is the most favorable condition for the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs).Moreover,mRNA sequencing and verification revealed that micromotion-induced augmentation was mediated by Piezo1 activation.Suppression of Piezo1 interrupts the mechano-sensitivity and abrogates osteogenic differentiation.Calvarial and femoral shaft defect models were established to explore the biocompatibility and osteoinductivity of the Micromotion Biomaterial.A series of research methods,including radiography,micro-CT scanning,and immunohistochemical staining have been performed to evaluate biosafety and osteogenic efficacy.The in vivo results revealed that tunable micromotion strengthens the natural fracture healing process through the sequential activation of endochondral ossification,promotion of neovascularization,initiation of mineral deposition,and combinatory acceleration of full-thickness osseous regeneration.This study demonstrated that Micromotion Biomaterials with controllable mechanophysical characteristics could promote the osteogenic differentiation of BMSCs and facilitate full osseous regeneration.The design of NIPAM/Nb2C hydrogel with highly efficient photothermal conversion,specific features of precisely controlled micromotion,and bionic-mimicking bone-repair capabilities could spark a new era in the field of regenerative medicine.

A Simplified Method for the Stress Analysis of Underground Transfer Structures Crossing Multiple Subway Tunnels

According to the design specifications,the construction of extended piles involves traversing the tunnel’s upper region and extending to the underlying rock layer.To address this challenge,a subterranean transfer structure spanning multiple subway tunnels was proposed.Deliberating on the function of piles in the transfer structure as springs with axial and bending stiffness,and taking into account the force balance and deformation coordination conditions of beams and plates within the transfer structure,we established a simplified mechanical model that incorporates soil stratification by combining it with the Winkler elastic foundation beam model.The resolved established simplifiedmechanicalmodel employed finite difference technology and the Newton-Simpsonmethod,elucidating the mechanical mechanism of the transfer structure.The research findings suggest that the load carried by the upper structural columns can be transferred to the pile foundation beneath the beams through the transfer structure,subsequently reaching the deep soil layer and ensuring minimal impact on adjacent tunnels.The established simplified analysis method can be used for stress analysis of the transfer structure,concurrently considering soil stratification,pile foundation behavior,and plate action.The pile length,pile section size,and beam section size within the transfer structure should account for the characteristics of the upper load,ensuring an even distribution of the beam bending moment.

Ultrasound-assisted isolation:A new method to isolate stromal vascular fraction

Background:The stromal vascular fraction(SVF),a cluster of stem and progenitor cells isolated from adipose tissue,holds significant promise for application in regenerative medicine.However,the existing methods for SVF isolation are time-consuming and expensive.Thus,in this study,we explored a new method of SVF extrac-tion-ultrasound-assisted SVF isolation(USASI)-and compared the viability and characteristics of SVF isolated using different methods.Methods:SVF extraction methods using different combinations of ultrasound power,ultrasound time,collagenase dosage,and collagenase digestion time were compared with those of the control group(collagenase digestion method).The cell yield and vitality of the SVF were evaluated via cell counting and trypan blue staining.The cell components and immunophenotypes of freshly isolated SVF were analyzed using flow cytometry.The prolifer-ative capacity and differentiation potential of the SVF were also identified.Results:Ultrasonication at 95 W-20 kHz for 30 s followed by digestion with 0.15%collagenase for 30 min was identified as the most suitable parameter for the USASI method in isolating SVF,as recommended based on the evaluation of various tested conditions.The USASI method significantly reduced the collagenase dosage and shortened the digestion time.Compared to the collagenase digestion method,the USASI method had a higher cell yield and cell viability,with no adverse effects on cell components,proliferative capacity,or multipotential differentiation capacity.Conclusion:With reduced processing time,lower collagenase dosage,and increased cell yield without impairing the viability and characteristics of SVF,USASI holds the potential to emerge as a time-saving and cost-effective method for future clinical applications.

Mass Transfer and Reaction Kinetics in the Carbonization of Magnesium Oxide from Light Calcined Magnesia with Mechanical Force Enhancement

The carbonization of magnesium oxide particles by CO2 was investigated using a stirring mill reactor. The effects of the system temperature, stirring rotation speed, influx rate of CO2 and initial diameter of the magnesium oxide particles on the carbonization process were determined, The results show that the system temperature and the stirring rotation speed are the most significant influencing factors on the carbonization rate. The determi-nation of critical decomposition temperature (CDT) gives the maximum carbonization rate with other conditions fixed. A theoretical model involving mass transfer and reaction kinetics was presented for the carbonization process. The apparent activation energy was calculated to be 32.8kJ·mol-1. The carbonization process is co-controlled by diffusive mass transfer and chemical reaction. The model fits well with the experimental results.

Role of the mechanical microenvironment in cancer development and progression

Cross-talk between tumor cells and mechanical stress in the tumor microenvironment has been shown to be involved in carcinogenesis.High mechanical stress in tumors can alter the metabolism and behaviors of cancer cells and cause cancer cells to attain cancer stem-like cell properties,thus driving tumor progression and promoting metastasis.The mechanical signal is converted into a biochemical signal that activates tumorigenic signaling pathways through mechanotransduction.Herein,we describe the physical changes occurring during reprogramming of cancer cell metabolism,which regulate cancer stem cell functions and promote tumor progression and aggression.Furthermore,we highlight emerging therapeutic strategies targeting mechanotransduction signaling pathways.

CHARACTERISTCS OF FLUID FILM IN OPTIMIZED SPIRAL GROOVE MECHANICAL SEAL

In order to investigate the sealing performance variation resulted from the thermal deformation of the end faces, the equations to calculate the fluid film pressure distribution, the bearing force and the leakage rate are derived, for the fluid film both in parallel gap and in wedgy gap. The geometrical parameters of the sealing members are optimized by means of heat transfer analysis and complex method. The analysis results indicate that the shallow spiral grooves can generate hydrodynamic pressure while the rotating ring rotates and the bearing force of the fluid film in spiral groove end faces is much larger than that in the flat end faces. The deformation increases the bearing force of the fluid film in flat end faces, but it decreases the hydrodynamic pressure of the fluid film in spiral groove end faces. The gap dimensions which determine the characteristics of the fluid film is obtained by coupling analysis of the frictional heat and the thermal deformation in consideration of the equilibrium condition of the bearing force and the closing force. For different gap dimensions, the relation- ship between the closing force and the leakage rate is also investigated, based on which the leakage rate can be controlled by adjusting the closing force.

Mechanical force enhanced bony formation in defect implanted with calcium sulphate cement

To improve the osteogenic property of bone repairing materials and to accelerate bone healing are major tasks in bone biomaterials research. The objective of this study was to investigate if the mechanical force could be used to accelerate bone formation in a bony defect in vivo. The calcium sulfate cement was implanted into the left distal femoral epiphyses surgically in 16 rats. The half of rats were subjected to external mechanical force via treadmill exercise, the exercise started at day 7 postoperatively for 30 consecutive days and at a constant speed 8 m·min-1 for 45 min·day-1, while the rest served as a control. The rats were scanned four times longitudinally after surgery using microcomputed tomography and newly formed bone was evaluated. After sacrificing, the femurs had biomechanical test of three-point bending and histological analysis. The results showed that bone healing under mechanical force were better than the control with residual defect areas of 0.64±0.19 mm2 and 1.78±0.39 mm2（P〈0.001）, and the ultimate loads to failure under mechanical force were 69.56±4.74 N, stronger than the control with ultimate loads to failure of 59.17±7.48 N（P=0.039）. This suggests that the mechanical force might be used to improve new bone formation and potentially offer a clinical strategy to accelerate bone healing.

Mechanical force and cytoplasmic Ca^(2+) activate mechanosensitive BK channel in parallel

BK channels are widely expressed in both excitable and non-excitable cells and known to be involved in many physiological processes,such as vascular smooth tone regulation,neuronal firing and endocrine cell secretion[1].Recently, the BK channels have

REGULARITY OF VIBRATION RESPONSE OF MECHANICAL SYSTEM UNDER AFFECT OF VARI-FREQUENCY EXCITING FORCE

The vibration response formulas of the mechanical system under the affect of thevari-frequency exciting force are deduced. It is proved by the theoretical analysis and experimentalresults that the vibration response amplitude of the mechanical system under the affect of thevari-frequency exciting force is far smaller than that under the affect of the constant frequency exciting force on condition that the exciting force amplitudes are just the same;while the vari-fre-quency rate a increases to 5 Hz per second the vibration amplitude will decrease to 10% only as lowas that under the affect of the constant frequency exciting force. All these conclusions will be of significance for revealing the mechanism of suppressing chatter in van-speed cutting and analyzing theexperimental results of sine-wave scanning exciting test.

Understanding cell-extracellular matrix interactions for topology-guided tissue regeneration

Tissues are made up of cells and the extracellular matrix(ECM)which surrounds them.These cells and tissues are actively adaptable to enduring significant stress that occurs in daily life.This astonishing mechanical stress develops due to the interaction between the live cells and the non-living ECM.Cells in the matrix microenvironment can sense the signals and forces produced and initiate a signaling cascade that plays a crucial role in the body’s normal functioning and influences various properties of the native cells,including growth,proliferation,and differentiation.However,the matrix’s characteristic features also impact the repair and regeneration of the damaged tissues.The current study reviewed how the cell-ECM interaction regulates cellular behavior and physicochemical properties.Herein,we have described the response of cells to mechanical stresses,the importance of substrate stiffness and geometry in tissue regeneration,and the development of scaffolds to mimic the nature of native ECM in 3D for tissue engineering applications has also been discussed.Finally,the study summarizes the conclusions and promising prospects based on the cell-ECM interplay.

Vibration of a Two-Layer“Metal+PZT”Plate Contacting with Viscous Fluid

The present work investigates the mechanically forced vibration of the hydro-elasto-piezoelectric system consisting of a two-layer plate“elastic+PZT”,a compressible viscous fluid,and a rigid wall.It is assumed that the PZT(piezoelectric)layer of the plate is in contact with the fluid and time-harmonic linear forces act on the free surface of the elastic-metallic layer.This study is valuable because it considers for the first time the mechanical vibration of the metal+piezoelectric bilayer plate in contact with a fluid.It is also the first time that the influence of the volumetric concentration of the constituents on the vibration of the hydro-elasto-piezoelectric system is studied.Another value of the present work is the use of the exact equations and relations of elasto-electrodynamics for elastic and piezoelectric materials to describe the motion of the plate layers within the framework of the piecewise homogeneous body model and the use of the linearized Navier-Stokes equations to describe the flow of the compressible viscous fluid.The plane-strain state in the plate and the plane flow in the fluid take place.For the solution of the corresponding boundary-value problem,the Fourier transform is used with respect to the spatial coordinate on the axis along the laying direction of the plate.The analytical expressions of the Fourier transform of all the sought values of each component of the system are determined.The origins of the searched values are determined numerically,after which numerical results on the stress on the fluid and plate interface planes are presented and discussed.These results are obtained for the case where PZT-2 is chosen as the piezoelectric material,steel and aluminum as the elastic metal materials,and Glycerin as the fluid.Analysis of these results allows conclusions to be drawn about the character of the problem parameters on the frequency response of the interfacial stress.In particular,it was found that after a certain value of the vibration frequency,the presence of the metal layer in the two-layer plate led to an increase in the absolute values of the above interfacial stress.

Effects of connection types and elevated temperature on the impact behaviour of restrained beam in portal steel frame

Based on the background of structural protection and Disaster Reduction Engineering, the dynamic behaviour and failure mechanism of restrained beams in portal steel frames in localised fire are investigated via experimental measurement and numerical simulation techniques. Comprehensive parametric studies are carried out to discuss the influence of end connection types, temperature, impact velocity,impact mass and span-to-depth ratio(SDR) on the dynamic response of the beams. The characteristics of deformation, internal force and energy distribution about the restrained beams and its joints are investigated. A temperature dependent criterion for evaluating the frame joint performance is proposed to measure the degree of performance degradation and impact resistance of the joint. The dynamic displacement amplification factor in different temperature environments are proposed for the different beam end constraint types and SDRs. Results of the experimental and numerical analysis show that the welded connection(WC) of three typical joint types is the strongest, and the extended endplate connection(EEC) is the weakest in terms of the impact resistance performance. With regard to the failure mode of the joint, the failure positions of the WC and the welded-bolted connection are located in the inner web of the column. Meanwhile, the EEC is located in the connection position between the beam and the endplate. Three different internal force stages and two obvious critical temperature boundaries of the restrained beams emerge with the increase in temperature, and they have significant characteristics in terms of deformation trend, internal force transfer and energy distribution. During the impact, a phenomenon known as “compression arch action” develops into “catenary action” with the increase in deflection in the frame beam mechanism.

Hemodialysis bilayer bionic blood vessels developed by the mechanical stimulation of hepatitis B viral X(HBX)genetransfected hepatic stellate cells

Artificial vascular graft(AVG)fistula is widely used for hemodialysis treatment in patients with renal failure.However,it has poor elasticity and compliance,leading to stenosis and thrombosis.The ideal artificial blood vessel for dialysis should replicate the structure and components of a real artery,which is primarily maintained by collagen in the extracellular matrix(ECM)of arterial cells.Studies have revealed that in hepatitis B virus(HBV)-induced liver fibrosis,hepatic stellate cells(HSCs)become hyperactive and produce excessive ECM fibers.Furthermore,mechanical stimulation can encourage ECM secretion and remodeling of a fiber structure.Based on the above factors,we transfected HSCs with the hepatitis B viral X(HBX)gene for simulating the process of HBV infection.Subsequently,these HBX-HSCs were implanted into a polycaprolactonepolyurethane(PCL-PU)bilayer scaffold in which the inner layer is dense and the outer layer consists of pores,which was mechanically stimulated to promote the secretion of collagen nanofiber from the HBX-HSCs and to facilitate crosslinking with the scaffold.We obtained an ECM-PCL-PU composite bionic blood vessel that could act as access for dialysis after decellularization.Then,the vessel scaffold was implanted into a rabbit’s neck arteriovenous fistula model.It exhibited strong tensile strength and smooth blood flow and formed autologous blood vessels in the rabbit’s body.Our study demonstrates the use of human cells to create biomimetic dialysis blood vessels,providing a novel approach for creating clinical vascular access for dialysis.

Unveiling the morphogenetic code:A new path at the intersection of physical energies and chemical signaling

In this editorial,we discuss the remarkable role of physical energies in the control of cell signaling networks and in the specification of the architectural plan of both somatic and stem cells.In particular,we focus on the biological relevance of bioelectricity in the pattern control that orchestrates both developmental and regenerative pathways.To this end,the narrative starts from the dawn of the first studies on animal electricity,reconsidering the pioneer work of Harold Saxton Burr in the light of the current achievements.We finally discuss the most recent evidence showing that bioelectric signaling is an essential component of the informational processes that control pattern specification during embryogenesis,regeneration,or even malignant transformation.We conclude that there is now mounting evidence for the existence of a Morphogenetic Code,and that deciphering this code may lead to unprecedented opportunities for the development of novel paradigms of cure in regenerative and precision medicine.

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.

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.

Method for Six-Legged Robot Stepping on Obstacles by Indirect Force Estimation

Adaptive gaits for legged robots often requires force sensors installed on foot-tips,however impact,temperature or humidity can affect or even damage those sensors.Efforts have been made to realize indirect force estimation on the legged robots using leg structures based on planar mechanisms.Robot Octopus III is a six-legged robot using spatial parallel mechanism（UP-2UPS） legs.This paper proposed a novel method to realize indirect force estimation on walking robot based on a spatial parallel mechanism.The direct kinematics model and the inverse kinematics model are established.The force Jacobian matrix is derived based on the kinematics model.Thus,the indirect force estimation model is established.Then,the relation between the output torques of the three motors installed on one leg to the external force exerted on the foot tip is described.Furthermore,an adaptive tripod static gait is designed.The robot alters its leg trajectory to step on obstacles by using the proposed adaptive gait.Both the indirect force estimation model and the adaptive gait are implemented and optimized in a real time control system.An experiment is carried out to validate the indirect force estimation model.The adaptive gait is tested in another experiment.Experiment results show that the robot can successfully step on a 0.2 m-high obstacle.This paper proposes a novel method to overcome obstacles for the six-legged robot using spatial parallel mechanism legs and to avoid installing the electric force sensors in harsh environment of the robot＇s foot tips.