Effect of Sijunzi Decoction on the Myonuclear Domain of Rat Soleus in Spleen Qi Deficiency

Objective: To study the mechanism of Sijunzi decoction treating limb weakness in spleen Qi deficiency (SQD) based on the myonuclear domain (MND) theory. Methods: 40 male Sprague-Dawley rats were randomly divided into the normal group, SQD model group (model group), SQD+ still water group (SW group) and SQD+ Sijunzi decoction group (CM group), 10 rats each group;Grip-Strength Meter was used to measure limb grip strength;transmission electron microscope was employed to observe the ultrastructural changes of the myofibers, Image Pro 6.0 was used to measure the myonuclear numbers, cross-section area (CSA) and then their ratios (the MND sizes) were calculated, immunofluorescence assay was chosen to test the expressions of paired box gene 7 (Pax7) and myogenic differentiation antigen (MyoD). Results: Compared with those in the normal group, limb grip strength was decreased, sarcomeres were abnormal, and all the myonuclear numbers, CSA and MND sizes were reduced, but the Pax7+ cell numbers were increased, significantly, in the model and SW groups;Compared with those in the model and SW groups, limb grip strength was increased, sarcomeres were basically normal, the myonuclear number and CSA were both greater, and the Pax7+ and MyoD+ cell numbers were both increased, significantly, in the CM group. Conclusion: Sijunzi decoction might increase the myonuclear number by activating the MSCs to treat limb weakness in SQD.

Molecular mechanism of fly ash affecting the performance of cemented backfill material

The great challenge of cemented tailings backfill(CTB)is difficult simultaneously maintaining its excellent mechanical properties and low cost.Fly ash(FA)can potentially address this problem and further replace cement in favor of low carbon development.However,its mechanism on CTB with low cement dosage and low Ca system remains unclear.Consequently,this study conducted uniaxial compression,Xray diffraction(XRD),and scanning electron microscopy(SEM)-energy dispersive spectrometer(EDS)tests to investigate the effect of FA dosage on the mechanical property and microstructure of CTB.A molecular model of FA-CSH was constructed to reproduce the molecular structure evolution of CTB with FA based on the test results.The influences of FA dosage and calcium/silica molar ratio(Ca/Si ratio)on the matrix strength and failure model were analyzed to reveal the mechanism of FA on calcium silicate hydrated(C-S-H).The results show that the strength of CTB increases initially and then decreases with FA dosage,and the FA supplement leads to a decrease in Ca(OH)_(2) diffraction intensity and Ca/Si ratio around the FA particles.XRD and SEM-EDS findings show that the Ca/Si ratio of C-S-H decreases with the progression of hydration.The FA-CSH model indicates that FA can reinforce the silica chain of C-S-H to increase the matrix strength.However,this enhancement is weakened by supplementing excessive FA dosage.In addition,the hydrogen bonds among water molecules deteriorate,reducing the matrix strength.A low Ca/Si ratio results in an increase in water molecules and a decrease in the ionic bonds combined with Ca^(2+).The hydrogen bonds among water molecules cannot withstand high stresses,resulting in a reduction in strength.The water absorption of the FA-CSH model is negatively correlated with the FA dosage and Ca/Si ratio.The use of optimal FA dosage and Ca/Si ratio leads to suitable water absorption,which further affects the failure mode of FA-CSH.

Harnessing therapeutic potential of induced pluripotent stem cell–derived endothelial cells for remyelination in the central nervous system

Myelin is the protective sheath surrounding nerve fibers, and its damage(demyelination) occurs in many central nervous system(CNS) diseases, including multiple sclerosis(MS), traumatic injury, neurodegenerative diseases such as Alzheimer's disease, and mental disorders such as schizophrenia(Barateiro et al., 2016). Repair of damaged myelin sheaths(remyelination) often fails in MS, leading to neuronal loss and irreversible functional deficits.

A meta-analysis on the clinical efficacy of fire dragon cupping in the treatment of lumbar disc herniation

Background:The incidence of lumbar disc herniation(LDH)is notably high.Consensus among experts highlights non-surgical treatments as the primary therapeutic approach for LDH.Contemporary medicine frequently employs pharmacotherapy and epidural injections in such treatments,which are associated with numerous adverse effects.Prolonged use can severely impair the liver and kidney functions of patients.Hence,the role of safe and effective traditional Chinese medicine techniques becomes pivotal.Among various traditional Chinese medicine approaches for treating LDH,fire dragon cupping,renowned for its remarkable efficacy,cost-effectiveness,and ease of application,is extensively utilised in clinical settings for managing LDH.Nonetheless,there is a scarcity of systematic and standardised evidence from evidence-based medicine studies.Therefore,conducting a meta-analysis is imperative.Methods:A comprehensive computerised search was conducted in databases including China National Knowledge Infrastructure,WanFang Data,VIP,China Biology Medicine disc,PubMed,EMbase,The Cochrane Library,Web of Science,and CINAHL.The search aimed to gather randomised controlled trials on fire dragon cupping therapy for LDH,spanning from the inception of these databases until December 2023.Two researchers independently screened the literature according to inclusion and exclusion criteria,extracted data,and assessed the methodological quality of the studies included,utilising RevMan 5.3 software for meta-analysis.Results:The results show that the fire dragon cupping therapy group had better clinical effectiveness(relative risk=1.23,95%confidence interval(CI)(1.14,1.33),P<0.00001),less pain(standardized mean difference=–1.33,95%CI(–1.49,–1.16),P<0.00001),and some improvement in lumbar function(Japanese Orthopaedic Association scores:mean difference=3.37,95%CI(2.31,4.43),P<0.00001.Conclusion:The fire dragon cupping therapy significantly alleviates LDH,warranting its extensive application.However,considering the limitations in the number and quality of studies included,the aforementioned conclusion necessitates further validation through more high-quality research.

Uniaxial experimental study of the acoustic emission and deformation behavior of composite rock based on 3D digital image correlation(DIC)

In this paper, uniaxial compression tests were carried out on a series of composite rock specimens with different dip angles, which were made from two types of rock-like material with different strength. The acoustic emission technique was used to monitor the acoustic signal characteristics of composite rock specimens during the entire loading process. At the same time, an optical non-contact 3 D digital image correlation technique was used to study the evolution of axial strain field and the maximal strain field before and after the peak strength at different stress levels during the loading process. The effect of bedding plane inclination on the deformation and strength during uniaxial loading was analyzed. The methods of solving the elastic constants of hard and weak rock were described. The damage evolution process, deformation and failure mechanism, and failure mode during uniaxial loading were fully determined. The experimental results show that the θ = 0?–45?specimens had obvious plastic deformation during loading, and the brittleness of the θ = 60?–90?specimens gradually increased during the loading process. When the anisotropic angle θincreased from 0?to 90?, the peak strength, peak strain,and apparent elastic modulus all decreased initially and then increased. The failure mode of the composite rock specimen during uniaxial loading can be divided into three categories:tensile fracture across the discontinuities(θ = 0?–30?), slid-ing failure along the discontinuities(θ = 45?–75?), and tensile-split along the discontinuities(θ = 90?). The axial strain of the weak and hard rock layers in the composite rock specimen during the loading process was significantly different from that of the θ = 0?–45?specimens and was almost the same as that of the θ = 60?–90?specimens. As for the strain localization highlighted in the maximum principal strain field, the θ = 0?–30?specimens appeared in the rock matrix approximately parallel to the loading direction,while in the θ = 45?–90?specimens it appeared at the hard and weak rock layer interface.

Influence of voxel size on forest canopy height estimates using full-waveform airborne LiDAR data

Background: Forest canopy height is a key forest structure parameter. Precisely estimating forest canopy height is vital to improve forest management and ecological modelling. Compared with discrete-return LiDAR(Light Detection and Ranging), small-footprint full-waveform airborne LiDAR(FWL) techniques have the capability to acquire precise forest structural information. This research mainly focused on the influence of voxel size on forest canopy height estimates.Methods: A range of voxel sizes(from 10.0 m to 40.0 m interval of 2 m) were tested to obtain estimation accuracies of forest canopy height with different voxel sizes. In this study, all the waveforms within a voxel size were aggregated into a voxel-based LiDAR waveform, and a range of waveform metrics were calculated using the voxelbased LiDAR waveforms. Then, we established estimation model of forest canopy height using the voxel-based waveform metrics through Random Forest(RF) regression method.Results and conclusions: The results showed the voxel-based method could reliably estimate forest canopy height using FWL data. In addition, the voxel sizes had an important influence on the estimation accuracies(R2 ranged from 0.625 to 0.832) of forest canopy height. However, the R2 values did not monotonically increase or decrease with the increase of voxel size in this study. The best estimation accuracy produced when the voxel size was 18 m(R2= 0.832, RMSE = 2.57 m, RMSE% = 20.6%). Compared with the lowest estimation accuracy, the R2 value had a significant improvement(33.1%) when using the optimal voxel size. Finally, through the optimal voxel size, we produced the forest canopy height distribution map for this study area using RF regression model. Our findings demonstrate that the optimal voxel size need to be determined for improving estimation accuracy of forest parameter using small-footprint FWL data.

Will high-frequency trading practices transform the financial markets in the Asia Pacific Region?

High-frequency trading(HFT)practices in the global financial markets involve the use of information and communication technologies(ICT),especially the capabilities of high-speed networks,rapid computation,and algorithmic detection of changing information and prices that create opportunities for computers to effect low-latency trades that can be accomplished in milliseconds.HFT practices exist because a variety of new technologies have made them possible,and because financial market infrastructure capabilities have also been changing so rapidly.The U.S.markets,such as the National Association for Securities Dealers Automated Quote(NASDAQ)market and the New York Stock Exchange(NYSE),have maintained relevance and centrality in financial intermediation in financial markets settings that have changed so much in the past 20 years that they are hardly recognizable.In this article,we explore the technological,institutional and market developments in leading financial markets around the world that have embraced HFT trading.From these examples,we will distill a number of common characteristics that seem to be in operation,and then assess the extent to which HFT practices have begun to be observed in Asian regional financial markets,and what will be their likely impacts.We also discuss a number of theoretical and empirical research directions of interest.

A Numerical Gas Fracturing Model of Coupled Thermal,Flowing and Mechanical Effects

Gas fracturing,which overcomes the limitation of hydraulic fracturing,is a potential alternative technology for the development of unconventional gas and oil resources.However,the mechanical principle of gas fracturing has not been learned comprehensively when the fluid is injected into the borehole.In this paper,a damage-based model of coupled thermal-flowing-mechanical effects was adopted to illustrate the mechanical principle of gas fracturing.Numerical simulation tools Comsol Multiphysics and Matlab were integrated to simulate the coupled process during the gas fracturing.Besides,the damage evolution of drilling areas under several conditions was fully analyzed.Simulation results indicate that the maximum tensile stress,which occurs in the upper and lower of the injection hole,decreases with the increase of the tectonic stress coefficient(TSC).As the TSC increases,shear fractures increase,a crushed area is gradually formed and the seepage area increases rapidly.The influence of TSC on fracture expansion is concluded as follows:with the decrease of TSC,the relative width of fractures decreases whilst the depth increases.It indicates that thermal stress and pore pressure promote the expansion of tensile fractures but restrain the expansion of shear fractures.Therefore,a relatively lower injection gas pressure is required to obtain the same degree of fracturing with a coupled thermal gradient.

Conformational change-modulated spin transport at single-molecule level in carbon systems

Controlling the spin transport at the single-molecule level,especially without the use of ferromagnetic contacts,becomes a focus of research in spintronics.Inspired by the progress on atomic-level molecular synthesis,through firstprinciples calculations,we investigate the spin-dependent electronic transport of graphene nanoflakes with side-bonded functional groups,contacted by atomic carbon chain electrodes.It is found that,by rotating the functional group,the spin polarization of the transmission at the Fermi level could be switched between completely polarized and unpolarized states.Moreover,the transition between spin-up and spin-down polarized states can also be achieved,operating as a dual-spin filter.Further analysis shows that,it is the spin-dependent shift of density of states,caused by the rotation,that triggers the shift of transmission peaks,and then results in the variation of spin polarization.Such a feature is found to be robust to the length of the nanoflake and the electrode material,showing great application potential.Those findings may throw light on the development of spintronic devices.

Correction to: Uniaxial experimental study of the acoustic emission and deformation behavior of composite rock based on 3D digital image correlation (DIC)

In the original publication of this article,Table 2 is incorrectly published due to the negligence of the author's proofreading.The correct version of Table 2 is provided below.

Three-Dimensional Nonlinear Dynamic Model and Macro Control of Real Estate

In this paper, according to economics of real estate and macro-control theory, combine with the characteristics of the real estate market, macro-control of the real estate market is studied. After giving the dynamic model of three-dimensional nonlinear differential equations based on the total number of houses on the real estate business, the government’s averages housing investment funds and the standard price, systematically established the stability conditions of equilibrium point for this model. What’s more, through the use of extreme value analysis model, government funds have been invested in real estate business building devotion principles and the construction base of the real estate businessmen has also been estimated successfully. This provides the corresponding theoretical basis for government macro control policy-making.

Mechanical and hydraulic properties of fault rocks under multi‑stage cyclic loading and unloading

The rock mass in fault zones is frequently subjected to cyclic loading and unloading during deep resource exploitation and tunnel excavation.Research on the mechanical and hydraulic characteristics of fault rock during the cyclic loading and unloading is of great signifcance for revealing the formation mechanism of water-conducting pathways in fault and preventing water inrush disasters.In this study,the mechanical and seepage tests of fault rock under the multi-stage cyclic loading and unloading of axial compression were carried out by using the fuid–solid coupling triaxial experimental device.The hysteresis loop of the stress–strain curve,peak strain rate,secant Young's modulus,and permeability of fault rock were obtained,and the evolution law of the dissipated energy of fault rock with the cyclic number of load and unloading was discussed.The experimental results show that with an increase in the cyclic number of loading and unloading,several changes occur.The hysteresis loop of the stress–strain curve of the fault rock shifts towards higher levels of strain.Additionally,both the peak strain rate and the secant Young's modulus of the fault rock increase,resulting in an increase in the secant Young's modulus of the fault rock mass.However,the growth rate of the secant Young's modulus gradually slows down with the increase of cyclic number of loading and unloading.The permeability evolution of fault rock under the multi-stage cyclic loading and unloading of axial compression can be divided into three stages:steady increase stage,cyclic decrease stage,and rapid increase stage.Besides,the calculation model of dissipated energy of fault rock considering the efective stress was established.The calculation results show that the relationship between the dissipated energy of fault rock and the cyclic number of loading and unloading conforms to an exponential function.

Association of NOD1 and NOD2 genes polymorphisms with Helicobacter pylori related gastric cancer in a Chinese population

AIM:To investigate the association between the tag single nucleotide polymorphisms(TagSNPs) of NOD1 and NOD2 and the risk of developing gastric cancer.METHODS:We conducted a hospital-based case-control study including 296 incident gastric cancer patients and 160 gastritis controls.Eight TagSNPs in the NOD1 and NOD2 genes were selected from the Hapmap database using the haploview software and genotyped by the Sequenom MassArray system.The serum levels of anti-Helicobacter pylori(H.pylori) IgG were measured by enzyme-linked immunosorbent assay to indicate H.pylori infection.The odds ratios(OR) and 95% confidence intervals(CI) were calculated by unconditional logistic regression,including sex and age as confounding factors.RESULTS:The NOD1 rs2907749 GG genotype showed a decreased risk for gastric cancer(OR 0.50,95% CI:0.26-0.95,P = 0.04) while the rs7789045 TT genotype showed an increased risk(OR 2.14,95% CI:1.20-3.82,P = 0.01).An elevated susceptibility to gastric cancer was observed in the subjects with H.pylori infection and the NaOD1 rs7789045 TT genotype(OR 2.05,95% CI:1.07-3.94,P = 0.03) or the NOD2 rs7205423 GC genotype(OR 2.52,95% CI:1.05-6.04,P = 0.04).Haplotype analysis suggested that the distribution of AGT(rs2907749,rs2075820 and rs7789045) in NOD1 between the cases and control groups was significantly different(P corrected:0.04),and the diplotype AGT/AGT was associated with an elevated gastric cancer risk(OR 1.98,95% CI:1.04-3.79,P = 0.04).The association of the NOD1 rs7789045 TT genotype and the diplotype AGT/AGT was significant with H.pylori-related diffuse-type gastric cancer(OR 3.00,95% CI:1.38-6.53,P = 0.01;OR 4.02,95% CI:1.61-10.05,P < 0.01,respectively).CONCLUSION:Genetic polymorphisms in NOD1 and NOD2 may interact with H.pylori infection and may play important roles in promoting the development of gastric cancer in the Chinese population.

A state‑of‑the‑art review on rock seepage mechanism of water inrush disaster in coal mines

Water inrush is one of the most dangerous disasters in coal mining.Due to the large-scale mining and complicated hydrogeological conditions,thousands of deaths and huge economic losses have been caused by water inrush disasters in China.There are two main factors determining the occurrence of water inrush:water source and water-conducting pathway.Research on the formation mechanism of the water-conducting pathway is the main direction to prevent and control the water inrush,and the seepage mechanism of rock mass during the formation of the water-conducting pathway is the key for the research on the water inrush mechanism.This paper provides a state-of-the-art review of seepage mechanisms during water inrush from three aspects,i.e.,mechanisms of stress-seepage coupling,fow regime transformation and rock erosion.Through numerical methods and experimental analysis,the evolution law of stress and seepage felds in the process of water inrush is fully studied;the fuid movement characteristics under diferent fow regimes are clearly summarized;the law of particle initiation and migration in the process of water inrush is explored,and the efect of rock erosion on hydraulic and mechanical properties of the rock media is also studied.Finally,some limitations of current research are analyzed,and the suggestions for future research on water inrush are proposed in this review.

Experimental study on expansion and cracking properties of static cracking agents in different assembly states

Rolled static cracking agent(RSCA)can solve the intractable problem of traditional bulk static cracking agent(BSCA)in engineering applications.This paper innovatively studies the rational water-cement ratio of BSCA and the immersion soaking time of RSCA under the condition of controlling temperature.Through the expansion and cracking performance experiments,the development characteristics of expansion pressure,the cracking effect of the single-hole specimen and the performance of hole spraying prevention under the action of BSCA and RSCA were compared and analyzed.The results show that:(1)The volume growth rate of static cracking agent decreases with the increase of water-cement ratio,and the fluidity increases with the increase of water-cement ratio.The rational water-cement ratio for BSCA application is 0.3,and the rational immersion time of RSCA is 2-2.5 min;(2)Under the bore diameters of 30,35,40 and 45 mm,the expansion pressure of BSCA with a water-cement ratio of 0.3 is 38.2,52.3,61.5 and 68 MPa,and the expansion pressure of RSCA immersed in water for 2.5 min is 43.5,58.8,69.5 and 75.1 MPa,respectively.Among them,the development speed of expansion pressure of BSCA is higher than that of RSCA,and the arrival time of the peak expansion pressure of RSCA is 1.7 times that of BSCA;(3)The crack initiation speed of single-hole specimen under the action of RSCA is 10.3%lower than that under the action of BSCA,but the cracking speed of the former is 72.6%higher than that of the latter;(4)The hole spraying occurs in BSCA under the bore diameter of 50,55 and 60 mm,while the hole spraying occurs in RSCA under the bore diameter of 60 mm.In terms of bore diameter,the hole spraying prevention of the RSCA is better than that of BSCA.The research results enrich the static blasting technology and provide data support and theoretical reference for field application.

The blood-brain barrier models to study apolipoprotein E genotypes in Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative disease that is characterized by an age-dependent progressive decline of memory,impairment of cognitive functions and changes in personality and behavior.Despite the improvement in understanding of the mechanisms underlying the disease,AD remains an incurable complex disorder with multifaceted pathophysiology to date.Apolipoprotein E(ApoE)is the main cholesterol carrier in the brain that supports lipid transport between brain cells.The individuals carrying the APOE4 allele are known to be at increased risk of developing AD compared with those carrying the more common APOE3 allele.

Development and future perspectives of natural orifice specimen extraction surgery for gastric cancer

In recent years,natural orifice specimen extraction surgery(NOSES),a novel minimally invasive surgical technique,has become a focus in the surgical field,and has been initially applied in gastric surgery in many national medical centers worldwide.In addition,this new surgical technique was launched in major hospitals in China.With an increasing number of patients who have accepted this new surgical technique,NOSES has provided new prospects for the treatment of gastric cancer(GC),which may achieve a better outcome for both patients and surgeons.More and more experts and scholars from different countries and regions are currently paying close attention to NOSES for the treatment of GC.However,there are only a few reports of its use in GC.This review focuses on the research progress in NOSES for radical gastrectomy in recent years.We also discuss the challenges and prospects of NOSES in clinical practice.

Mitophagy in the Skeletal Muscle Is Suppressed in Spleen Qi Deficiency

Objective: Mitochondrial impairment in the skeletal muscle contributes to useless of limbs in spleen qi deficiency;however the genesis of such impairment is not clear. Herein, PTEN-induced putative kinase 1 (PINK1)-Parkin pathway and mitophagy were studied to explore the machinery of mitochondrial impairment. Methods: 16 male SD rats were randomly divided in the control group and spleen qi deficiency group (model group);transmission electron microscope was used to observe mitochondrial morphology;mitochondrial oxidative phosphorylation was assessed by testing mitochondrial membrane potential (MMP) and levels of ATP and ROS;western blot was used to analyze expressions of PINK1, Parkin, microtubule-associated protein 1 light chain 3-II (LC3-II) and p62. Results: Compared with those in the control group, mitochondria became small, less and scattered, MMP and the ATP level were reduced, the ROS level was elevated, PINK1 expression was decreased, p62 expression was increased, but Parkin and LC3-II expressions were not altered, in the model group. Conclusions: Suppression of mitophagy might be related to the mitochondrial damage in the skeletal muscle when spleen qi deficiency develops.

Circle formation control for multi-agent systems with a leader

In this paper, we focus on circle formation control of multi-agent systems （MAS） with a leader. The circle formation is achieved based on the lead-following and the artificial potential field method. A distributed control law is given to make a group of agents form a circle and consequently achieve an expected angle. Finally, simulation results show that the proposed circle formation strategies are effective.

Effect of Histone Deacetylase Inhibition on the Expression of Multidrug Resistance-associated Protein 2 in a Human Placental Trophoblast Cell Line

Background： Placental multidrug resistance-associated protein 2 （MRP2）, encoded by ABCC2 gene in human, plays a significant role in regulating drugs＇ transplacental transfer rates. Studies o11 placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases （HDACs） inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC 1/2/3 are preliminarily involved in this process. Methods： The human choriocarcinoma-derived trophoblast cell line （Bewo cells） was treated with the HDAC inhibitors-trichostatin A （TSA） at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 μmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA （siRNA） specific for HDACI/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC 1/2/3/ABCC2 messenger RNA （mRNA） and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively. Results： TSA could inhibit total HDAC activity and HDAC 1/2/3 expression in company with increase ofM RP2 expression in Bewo cells. Reduction of HDAC 1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 μmol/L （vs. vehicle group, all P 〈 0.001 ）, accompanied with dose-dependent induction of MRP2 expression （P = 0.045 for 1.0 μmol/L, P = 0.001 for 3.0 μmol/L, and P 〈 0.001 for 5.0 μmol/L）, whereas no significant diferences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells weir week, and no significant differences were noticed among these three groups （all P 〉 0.05）. However, MRP2 expression was remarkably elevated in H DAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells （P 〈 0.001 ）. Conclusions： HDACs inhibition could up-regulate placental MRP2 expression in ritzy, and HDAC 1 was probably to be involved in this process.