TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the KEAP1-Nrf2 Pathway

Objective Cisplatin is the first-line treatment for breast cancer,but it faces challenges of drug resistance.This study investigated new molecular mechanisms underlying cisplatin resistance in breast cancer.Methods We analyzed sequencing data from the TCGA database to identify potential associations between transmembrane emp24 protein transport domain containing 2(TMED2)and breast cancer.Western blotting,real-time PCR,CCK-8,and TUNEL assays were used to measure the effects and molecular mechanism of TMED2 on cisplatin resistance in MCF-7 and MDA-MB-231 cell lines.Results TMED2 was overexpressed in breast cancer and associated with poor prognosis.TMED2 increased cisplatin resistance in breast cancer cells in vitro via promoting ubiquitination of Kelch-like ECH-associated protein 1(KEAP1),relieving inhibition of KEAP1 on nuclear factor erythroid 2-related factor 2(Nrf2),and increasing expression of downstream drug resistance related genes,such as heme oxygenase 1(HO-1)and NAD(P)H quinone oxidoreductase 1(NQO1).Conclusion We identified a new molecular mechanism by which TMED2 affects cisplatin resistance in breast cancer.Our results provide theoretical guidance for future clinical applications.

A meta-analysis of the effects of energy intake on risk of digestive cancers

AIM:To quantitatively assess the relationship between energy intake and the incidence of digestive cancers in a meta-analysis of cohort studies.METHODS:We searched MEDLINE,EMBASE,Science Citation Index Expanded,and the bibliographies of retrieved articles.Studies were included if they reported relative risks(RRs) and corresponding 95% CIs of digestive cancers with respect to total energy intake.When RRs were not available in the published article,they were computed from the exposure distributions.Data were extracted independently by two investigators and discrepancies were resolved by discussion with a third investigator.We performed fixed-effects meta-analyses and meta-regressions to compute the summary RR for highest versus lowest category of energy intake and for per unit energy intake and digestive cancer incidence by giving each study-specific RR a weight that was proportional to its precision.RESULTS:Nineteen studies consisting of 13 independent cohorts met the inclusion criteria.The studiesincluded 995 577 participants and 5620 incident cases of digestive cancer with an average follow-up of 11.1 years.A significant inverse association was observed between energy intake and the incidence of digestive cancers.The RR of digestive cancers for the highest compared to the lowest caloric intake category was 0.90(95% CI 0.81-0.98,P < 0.05).The RR for an increment of 239 kcal/d energy intake was 0.97(95% CI 0.95-0.99,P < 0.05) in the fixed model.In subgroup analyses,we noted that energy intake was associated with a reduced risk of colorectal cancer(RR 0.90,95% CI 0.81-0.99,P < 0.05) and an increased risk of gastric cancer(RR 1.19,95% CI 1.08-1.31,P < 0.01).There appeared to be no association with esophageal(RR 0.96,95% CI 0.86-1.07,P > 0.05) or pancreatic(RR 0.79,95% CI 0.49-1.09,P > 0.05) cancer.Associations were also similar in studies from North America and Europe.The RR was 1.02(95% CI 0.79-1.25,P > 0.05) when considering the six studies conducted in North America and 0.87(95% CI 0.77-0.98,P < 0.05) for the five studies from Europe.CONCLUSION:Our findings suggest that high energy intake may reduce the total digestive cancer incidence and has a preventive effect on colorectal cancer.

Off-axis electron holography of manganite-based heterojunctions:Interface potential and charge distribution

The interfacial electrical potentials and charge distributions of two manganite-based heterojunctions, i.e.,La_(0.67)Ca_(0.33)MnO_3/SrTiO_3:0.05 wt% Nb(LCMO/STON) and La_(0.67)Ca_(0.33)MnO_3/LaMnO_3/SrTiO_3:0.05 wt% Nb(simplified as LCMO/LMO/STON), are studied by means of off-axis electron holography in a transmission electron microscope.The influences of buffer layer on the microstructure and magnetic properties of the LCMO films are explored. The results show that when a buffer layer of LaMnO_3 is introduced, the tensile strain between the STON substrate and LCMO film reduces, misfit dislocation density decreases near the interfaces of the heterojunctions, and a positive magnetoresistance is observed. For the LCMO/STON junction, positive and negative charges accumulate near the interface between the substrate and the film. For the LCMO/LMO/STON junction, a complex charge distribution takes place across the interface, where notable negative charges accumulate. The difference between the charge distributions near the interface may shed light on the observed generation of positive magnetoresistance in the junction with a buffer layer.

Evolution of electrical and magnetotransport properties with lattice strain in La0.7Sr0.3MnO3 film

In this paper,we investigate the effects of lattice strain on the electrical and magnetotransport properties of La0.7Sr0.3MnO3(LSMO)films by changing film thickness and substrate.For electrical properties,a resistivity upturn emerges in LSMO films,i.e.,LSMO/STO and LSMO/LSAT with small lattice strain at a low temperature,which originates from the weak localization effect.Increasing film thickness weakens the weak localization effect,resulting in the disappearance of resistivity upturn.While in LSMO films with a large lattice strain(i.e.,LSMO/LAO),an unexpected semiconductor behavior is observed due to the linear defects.For magnetotransport properties,an anomalous in-plane magnetoresistance peak(pMR)occurs at low temperatures in LSMO films with small lattice strain,which is caused by two-dimensional electron gas(2DEG).Increasing film thickness suppresses the 2DEG,which weakens the pMR.Besides,it is found that the film orientation has no influence on the formation of 2DEG.While in LSMO/LAO films,the 2DEG cannot form due to the existence of linear defects.This work can provide an efficient way to regulate the film transport properties.

Investigation on the vortical structures by the Liutex method in turbulent channels at Re_(τ)=180 with scalloped and triangular riblet control

Riblets are a series of small protrusions formed along the flow direction,which have been extensively studied as a passive turbulent drag reduction technique.Experiments and numerical simulations have shown that well-designed riblets can significantly reduce drag in turbulent flows,making them highly promising and valuable for various applications.In this study,we focus on a scalloped riblet,which is designed by smoothly connecting two third-order polynomials,and thus the sharpness of the tip and the curvature of the valley can be well defined.We conduct direct numerical simulations of turbulent channel with smooth plate,scalloped riblet-mounted and triangular riblet-mounted walls.Width in wall units of W^(+)=20 and height-width ratio ofγ=0.5 are selected for both riblet cases.Compared with the smooth plate case,the scalloped riblet case achieves an 8.68%drag reduction,while the triangular riblet case achieves a 4.79%drag reduction.The obtained drag reduction rate of the triangular riblet is consistent with previous experiments and simulations,and the results indicate that the scalloped riblet is more effective in reducing drag and deserves further investigation.We compare turbulent statistics of the scalloped riblet case with those of the triangular riblet case.The mean velocity profiles of riblets are similar,but both the Reynolds shear stress and second-order statistics of velocity fluctuations and Liutex are significantly reduced in the scalloped riblets controlled turbulent channel,indicating that the scalloped riblet can more effectively suppress the spanwise and wall-normal turbulent intensity near the wall.We also compare the pre-multiplied spectra of streamwise velocity and streamwise Liutex component for the three cases to investigate the energy distribution and characteristics of Liutex distribution.The Liutex vortex identification method is also utilized to analyze the instantaneous flow field,which provides insights into the flow field and could be beneficial for the further optimization of riblet.

Identification of vortex boundaries in two-dimensional incompressible flows based on the Liutex-shear interaction

According to the Liutex-shear decomposition,vorticity can be decomposed into a rotational part,i.e.,the Liutex vector,and a residual shear part.With this decomposition,the vorticity transport equation can be used to formulate a governing equation for Liutex easily for two-dimensional incompressible flows with a source term depending on the residual shear.The dynamics of Liutex-identified structures is then studied in a Taylor-Green vortex flow and a flow past a cylinder at Reynolds number of 200.It is revealed that such boundaries exist outside which the shear has trivial impact on the evolution of Liutex and inside which enhancing and weakening effects of shear on Liutex can be observed.In addition,there is a strong dissipation effect upon Liutex on these boundaries.Based on the interaction mechanism between Liutex and shear,we argue that the vortex boundaries can be identified by these highly dissipative boundaries.In contrast,traditional methods use iso-surfaces of arbitrarily selected thresholds to represent vortex boundaries.The current method of identifying vortex boundaries based on the Liutex-shear interaction has a clearer theoretical base and avoids the arbitrary selection of thresholds.Extensions to three-dimensional incompressible flows can be made in future following the same procedure but with a slightly more complex vorticity transport equation which includes the velocity gradient induced stretching or tilting term.

Third generation of vortex identification methods:Omega and Liutex/Rortex based systems

A vortex is intuitively recognized as the rotational/swirling motion of fluids,but a rigorous and universally-accepted definition is still not available.Vorticity tube/filament has been regarded equivalent to a vortex since Helmholtz proposed the concepts of vorticity tube/filament in 1858 and the vorticity-based methods can be categorized as the first generation of vortex identification methods.During the last three decades,a lot of vortex identification methods,including 0,A,and Aci criteria,have been proposed to overcome the problems associated with the vorticity-based methods.Most of these criteria are based on the Cauchy-Stokes decomposition and/or eigenvalues of the velocity gradient tensor and can be considered as the second generation of vortex identification methods.Starting from 2014,the Vortex and Turbulence Research Team at the University of Texas at Arlington(the UTA team)focus on the development of a new generation of vortex identification methods.The first fruit of this effort,a new Omega(/2)vortex identification method,which defined a vortex as a connected region where the vorticity overtakes the deformation,was published in 2016.In 2017 and 2018,a Liutex(previously called Rortex)vector was proposed to provide a mathematical definition of the local rigid rotation part of the fluid motion,including both the local rotational axis and the rotational strength.Liutex/Rortex is a new physical quantity with scalar,vector and tensor forms exactly representing the local rigid rotation of fluids.Meanwhile,a decomposition of the vorticity to a rotational part namely Liutex/Rortex and an anti-symmetric shear part(RS decomposition)was introduced in 2018,and a universal decomposition of the velocity gradient tensor to a rotation part(7?)and a non-rotation part(NR、was also given in 2018 as a counterpart of the traditional Cauchy-Stokes decomposition.Later in early 2019,a Liutex/Rortex based Omega method called Omega-Liutex,which combines the respective advantages of both Liutex/Rortex and Omega methods,was developed.And a latest objective Omega method,which is still under development,is also briefly introduced.These advances are classified as the third generation of vortex identification methods in the current paper.To elaborate the advantages of the third-generation methods,six core issues for vortex definition and identification have been raised,including:(1)the absolute strength,(2)the relative strength,(3)the rotational axis,(4)the vortex core center location,(5)the vortex core size,(6)the vortex boundary.The new third generation of vortex identification methods can provide reasonable answers to these questions,while other vortex identification methods fail to answer all questions except for the approximation of vortex boundaries.The purpose of the current paper is to summarize the main ideas and methods of the third generation of vortex identification methods rather than to conduct a comprehensive review on the historical development of vortex identification methods.

Explicit formula for the Liutex vector and physical meaning of vorticity based on the Liutex-Shear decomposition

In the present study, the physical meaning of vorticity is revisited based on the Liutex-Shear (RS) decomposition proposed by Liu et al. in the framework of Liutex (previously called Rortex), a vortex vector field with information of both rotation axis and swirling strength (Liu et al. 2018). It is demonstrated that the vorticity in the direction of rotational axis is twice the spatial mean angular velocity in the small neighborhood around the considered point while the imaginary part of the complex eigenvalue (2c.) of the velocity gradient tensor (if exist) is the pseudo-time average angular velocity of a trajectory moving circularly or spirally around the axis. In addition, an explicit expression of the Liutex vector in terms of the eigenvalues and eigenvectors of velocity gradient is obtained for the first time from above understanding, which can further, though mildly, accelerate the calculation and give more physical comprehension of the Liutex vector.

Liutex theoretical system and six core elements of vortex identification

The third-generation vortex identification method of Liutex(previously called Rortex)was introduced by the team led by Prof.Chaoqun Liu from University of Texas at Arlington to mathematically extract the rigid rotation part from the fluid motion,and thus to define and visualize vortices.Unlike the vorticity-based first generation and the scalar-valued second generation,Q,λ2,Δandλci methods for example,the Liutex vector provides a unique,mathematical and systematic way to define vortices and visualize vortical structures from multiple perspectives without ambiguity.In this article,we summarize the recent developments of the Liutex framework and discuss the Liutex theoretical system including its existence,uniqueness,stability,Galilean invariance,locality and globality,decomposition in tensor and vector forms,Liutex similarity in turbulence,and multiple Liutex-based vortex visualization methods including Liutex lines,Liutex magnitude iso-surfaces,Liutex-Ωmethod,and Liutex core line method,etc..Thereafter,the six core elements of vortex identification,including(1)absolute strength,(2)relative strength,(3)local rotational axis,(4)vortex rotation axes,(5)vortex core size,(6)vortex boundary,are used as touchstones against which the Liutex vortex identification system is examined.It is demonstrated with illustrative examples that the Liutex system is able to give complete and precise information of all six core elements in contrast to the failure and inaccuracy of the first and second-generation methods.The important concept that vorticity cannot represent vortex and the superiority of the Liutex system over previous methods are reiterated and stated in appropriate places throughout the paper.Finally,the article concludes with future perspectives,especially the application of the Liutex system in studying turbulence mechanisms encouraged by the discovery of Liutex similarity law.As a newly defined physical quantity,Liutex may open a door for quantified vortex and turbulence research including Liutex(vortex)dynamics and lead the community out of the shadow of turbulence research which traditionally relies on observations,graphics,assumptions,hypotheses,and other qualitative analyses.An optimistic projection is that the Liutex system could be critical to investigation of the vortex dynamics in applications from hydrodynamics,aerodynamics,oceanography,meteorology,etc.and to research of the generation,sustenance,modelling and controlling of turbulence.

Liutex similarity in turbulent boundary layer

Kolmogorov's 1941 theory(K41)of similarity hypotheses and the-5/3 law for energy spectrum are considered as the most important theoretical achievement in turbulence research and the success of the modem turbulence theory.The assumptions of sufficient high Reynolds number and isotropy of turbulence that K41 based upon,however,cannot generally be met in practice,and thus discrepancy is often observed between the f law and direct numerical simulation(DNS)results of boundary layers in wall bounded turbulence,especially for moderate to low Reynolds number flows.Liutex vector is a recently defined new physical quantity which is extracted from turbulent flow to represent the rigid rotation part of fluid motion.Actually,Liutex is free from viscous dissipation and thus independent of Reynolds number,relaxing the very high Reynold number assumption of K41.Liutex similarity has been solidly demonstrated by DNS for a moderate Reynolds number turbulent boundary layer(Reθ≈1000),both the frequency and wavenumber spectrum of Liutex accurately matches the-5/3 law,which is obviously much better than the turbulence energy spectrum,while vorticity and other popular vortex identification methods,Q criterion for example,do not possess such a distinguished feature due to stretching and shearing contamination.

Liutex-based vortex dynamics:A preliminary study

Vortex dynamics,with the possibility of efficient flow control,is explored in this study based on the new introduced vortex definition and identification system of Liutex.With the six core elements of vortex identification,including(1)absolute strength,(2)relative strength,(3)local rotational axis,(4)global rotational axis,(5)vortex core size and(6)vortex boundary,provided by the Liutex system,it is possible to numerically devise strategies,primarily by introducing additional source terms in Navier-Stokes equations,which we call Liutex force field model here,to control the vortex regions.Two methodologies of centripetal force model and counter-rotation force model are preliminarily investigated in a cavitating flow around two-dimensional Clark-Y hydrofoil.It is found that Liutex based models are capable of illustrating the vortex dynamics and possibly strengthening or weakening the vortices.

Liutex-based vortex control with implications for cavitation suppression

Viewed as sinews and muscles of fluid motion,coherent vortical structures with their interactions are key to understanding the flow dynamics.Based upon this observation,we explore the possibility of efficient flow control by directly manipulating vortices numerically inside the flow field based on the vortex definition and identification system of Liutex.The objective is twofold:(1)to study the vortex dynamics,for example,by observing the response of the flow to strengthening or weakening of certain vortices,and(2)to obtain efficient vortex-based control strategies which might lead us to practical applications.In the present numerical study,the manipulating of vortices is achieved by introducing additional source(force)terms to the Navier-Stokes equations,which hereafter will be collectively called Liutex force field model.Methodologies including controlling the rotation strength and centripetal force of particular vortices are detailed in a flow past a cylinder with different control purposes at Reynolds number of 200.Further examples are provided with a cavitating flow around two-dimensional Clark-Y hydrofoil,with particular interests on cavitation suppression.It is illustrated particular vortex with cavitation encircled could be effectively suppressed.

Galilean invariance of Omega vortex identification method

In the new vortex identification method(Liu et al.2016)to represent the rotation level and capture and visualize the vortices,proposed in our previous study,the independence of the reference frame and the Galilean invariant were not proved.In the present study,the Galilean invariance of the omega vortex identification method is proved and several examples are presented to verify the conclusion.

Parametric study of Liutex-based force field models

The motion of fluid consists of different scales of coherent vortical structures.These vortical structures determine the characteristics of fluid motion and are key to understand fluid dynamics.In this paper,we study the fine control method of vortical structures based on the Liutex force field model.This is achieved by constructing a source term using Liutex and directly add it to the Navier-Stokes equations.To investigate the influence of the constructed Liutex force model on vortical structures,a flow past a cylinder at Reynolds number of 100 is numerically studied with different source term magnitude and region.The drag and lift forces on the cylinder,as well as the flow field near and behind the cylinder are compared and analyzed.Results show that Liutex force model can effectively strengthen or weaken the vortical structures based on different purpose.

Vortex tuning of a submarine by Liutex force field model

Vortical structures of a submarine with appendages are fully turbulent and complex.Thus,flow control and vortex manipulation are of great importance for the hydrodynamic performance and acoustic characteristics.Take the generic submarine model DARPA Suboff as the test case,a vortex tuning method based on the Liutex force field is proposed to manipulate the vorticity field.Viscous flow past the submarine model in straight-line motion at a Reynolds number of 1.2×107 is achieved by solving the Reynolds averaged Navier-Stokes(RANS)equations.Multi-block structured mesh topology is used to discretize the computational domain,and the shear stress transport(SST)k-ωturbulence model is implemented to close the equations.The control of vortex is achieved by introducing additional source terms based on Liutex vortex definition and identification system to the RANS equations.The resistance acting on the submarine,flow field as well as the vortical structures are compared and analyzed.Results show that Liutex force model can effectively reduce the resistance by 9.31%and change the vortical structures apparently.

A Liutex-based subgrid stress model for large-eddy simulation

The concept of vortex is crucial in both understanding and modeling of turbulence.For large eddy simulation(LES),the effect of small-scale eddies onto the large scales or the resolved flow field is modeled by subgrid stress models.Even though the rotating motions of fluids,i.e.,vortices or eddies are central in developing turbulent models,vortex identification methods are seldom used in these models.In this study,we develop a new subgrid model based on the Liutex vector,a new quantity introduced to decompose fluid motions into rigid rotation,pure shear and stretching,and thus identify vortices.The new model is then applied in a decaying homogeneous isotropic turbulence(DHIT)and a turbulent channel flow at Reynolds number Reτ=180.It is shown that the new model can predict accurate energy spectra compared with experiments in DHIT and give a well-matched velocity profile in turbulent channel flow without changing the form of the model.Future directions include improvement of the Liutex based model,for example developing anisotropic subgrid models,and its applications in various turbulent flows.

Liutex-based centripetal force field model for improving the resistance and wake performances of JBC ship sailing in calm water

For complex aerodynamic and hydrodynamic problems,the analysis of vortex is very important.The Liutex method is an eigenvalue-based method which is local,accurate,and unique,which can give an accurate definition of vortex,so the control of vortex can be implemented and effectively guaranteed.Based on Liutex method,two methodologies of centripetal force model and counter-rotation force model were proposed to illustrate the vortex dynamics and possibly strengthen or weaken the vortices.In this paper,the Liutex-based centripetal force model is applied by adding a source term to the Navier-Stokes equations.In order to investigate the influence of the constructed Liutex force model on the 3-dimensional flow around a slow-fat ship,the calm-water drag calculation result of JBC ship is regarded as the initial flow field,and the new resistance and wake performances of the ship are obtained after applying the centripetal force model to the flow field with different strengths.Several views of the comparisons of the new steady flow fields are shown,and the parametric study results indicate that the Liutex-based centripetal force model can effectively change the resistance and wake performances of the JBC ship,which provides a new idea and theoretical basis for the comprehensive hydrodynamic performance optimization of the ship hull.

Applications of Liutex-based force field models for cavitation simulation

When studying the flow dynamics and the characteristics of fluid motion,vortex structure with their interactions is the key issue.In the present work,a vortex control method is investigated based on the vortex identification system of Liutex.The numerical study is carried out in OpenFOAM by directly adding a source term to the Navier-Stokes equations,which is called the centripetal force model in Liutex method.A 2-D test case is examined to justify the proposed method in cavitating flow around Clark-Y hydrofoil,the simulation results show that the improved Liutex solver is feasible.Methodologies of controlling the rotation strength of vortices are able to change the flow field and suppress the cavitation.The applicability of vortex-based control method in 3-D flow field is also studied.The results show that cavitation surrounded by particular vortex can be effectively influenced.

Vortex structures of dynamic pure yaw test using DDES approach and vortex identification method

Considered as the building blocks,vortex structures with variety of sizes and intensity are widely recognized in the viscous flow field around ship.In this paper,the computational fluid dynamics(CFD)solver,naoe-FOAM-SJTU,coupled with delayed detached-eddy simulation(DDES)is adopted to analyze the vortex structures around the benchmark model Yupeng Ship in dynamic pure yaw tests,which are captured by third generation of vortex identification method.The good agreement of the predicted force/moment by DDES method with the experimental data indicates that the present numerical schemes are reliable and robust.Three vortex identification methods,Q-criteria,Ω_(R) and Liutex,are used to capture the vortex structures around the hull.The large separated flow is able to be investigated by these three methods,in which more vortex structures are captured byΩ_(R) approach and Liutex method with scalar,vector and tensor form seems to be more suitable for analyzing the flow mechanism around the hull in dynamic pure yaw test.In general,each vortex structure corresponds to a dominant positive/negative axial Liutex and a bound vortex pair.The streamlines are spiral in the large separated flow,indicating that the flow in corresponding region is rotational.But the rotation of the flow is not directly related to the intensity of Liutex.

Liutex force field model applied to three-dimensional flows around a circular cylinder at Re=3900

Recently,the Liutex-based force field models are proposed and applied to some two-dimensional flows to explore the possibility of direct vortex control strategies.In this paper,we applied the Liutex-based centripetal force model to three-dimensional flow around a circular cylinder at Re=3900.The turbulent flows around the three-dimensional cylinder are modeled by the delayed detached-eddy simulations based on the two-equation k-ω shear stress transport(SST)model.The cylinder flow without adding the force field model is simulated in the first place.The statistical flow quantities are compared with experimental data to validate the accuracy of the current numerical models.Then the force field model is applied to the momentum equation in a specific control region near the cylinder to study the change of flow field and hydrodynamic performance.The effect of different control region locations with the same force field strength is discussed to find out the most influenced locations on the drag and lift.Based on the screened control region,the influence source term strength is further studied.Variations on the global statistical flow quantities,local instantaneous three-dimensional flow structures are analyzed and discussed.It is concluded that the Liutex-based force field model can effectively change the hydrodynamic behavior of flow past a cylinder and may provide a new direction for performance improvement and optimization.