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The VEGF/SphK1/S1P pathway is closely related to angiogenesis in rheumatoid arthritis (RA), but the precise underlying mechanisms are unclear at present. Here, we explored the involvement of the VEGF/SphK1/S1P cascade in RA models and determined the effects of GE intervention. Our results showed abnormal expression of proteins related to this pathway in RA synovial tissue. Treatment with GE effectively regulated the signal axis, inhibited angiogenesis, and alleviated RA symptoms. In vitro, TNF-ɑ enhanced the VEGF/SphK1/S1P pathway in a co-culture model of fibroblast-like synoviocytes (FLS) and vascular endothelial cells (VEC). GE induced downregulation of VEGF in FLS, restored the dynamic balance of pro-/antiangiogenic factors, and suppressed SphK1/S1P signaling in VEC, resulting in lower proliferation activity, migration ability, tube formation ability, and S1P secretion ability of VEC cells. Additionally, SphK1-specific small interfering RNA (siRNA) blocked the VEGF/SphK1/S1P cascade, which can effectively alleviate the stimulatory effect of FLS on VEC and further enhanced the therapeutic effect of GE. Taken together, our results demonstrate that GE suppresses the VEGF/SphK1/S1P pathway and alleviates the stimulation of VEC by FLS, thereby preventing angiogenesis and promoting therapeutic effects against RA.

Imbalance of macrophage polarization plays a critical role in the progression of rheumatoid arthritis (RA). Geniposide (GE) has been shown to exert anti-inflammatory effects. However, the effect of GE on macrophage polarization remains unclear. Here, we investigated the regulation of GE on the imbalance of macrophage polarization in RA and how it functions. We established a mouse model of collagen-induced arthritis (CIA) and isolated bone marrow-derived macrophages (BMDMs). The results confirmed that pro-inflammatory M1 macrophages were dominant in CIA mice, but the polarization imbalance of macrophages was restored to a certain extent after GE treatment. Furthermore, the membrane targeting of sphingosine kinase 1 (SphK1) was increased in BMDMs of CIA mice, as manifested by increased membrane and cytoplasmic expression of p-SphK1 and high secretion level of sphingosine-1-phosphate (S1P). RAW264.7 cells were stimulated with lipopolysaccharide (LPS)-interferon (IFN)-γ or interleukin (IL)-4 to induce M1 or M2 phenotype, respectively, to revalidate the results obtained in BMDMs. The results again observed SphK1 membrane targeting in LPS-IFN-γ-stimulated RAW264.7 cells. Selective inhibition of SphK1 by PF543 or inhibition of the S1P receptors by FTY720 both restored the proportion of M1 and M2 macrophages in LPS-IFN-γ-stimulated RAW264.7 cells, confirming that SphK1 membrane targeting mediated a proportional imbalance in M1 and M2 macrophage polarization. In addition, GE inhibited SphK1 membrane targeting and kinase activity. Taken together, results confirmed that the inhibition of SphK1 membrane targeting by GE was responsible for restoring the polarization balance of macrophages in CIA mice.

The activated Gα protein subunit (Gαs) and the inhibitory Gα protein subunit (Gαi) are involved in the signal transduction of G protein coupled receptors (GPCRs). Moreover, the conversion of Gαi/Gαs can couple with sphingosine-1-phosphate receptors (S1PRs) and have a critical role in rheumatoid arthritis (RA). Through binding to S1PRs, sphingosine-1-phosphate (S1P) leads to activation of the pro-inflammatory signaling in rheumatoid arthritis synovial fibroblasts (RASFs). Geniposide (GE) can alleviate RASFs dysfunctions to against RA. However, its underlying mechanism of action in RA has not been elucidated so far. This study aimed to investigate whether GE could regulate the biological functions of MH7A cells by inhibiting S1PR1/3 coupling Gαi/Gαs conversion. We use RASFs cell line, namely MH7A cells, which were obtained from the patient with RA and considered to be the main effector cells in RA. The cells were stimulated with S1P (5 μmol/L) and then were treated with or without different inhibitors: Gαi inhibitor pertussis toxin (0.1 μg/mL), S1PR1/3 inhibitor VPC 23019 (5 μmol/L), Gαs activator cholera toxin (1 μg/mL) and GE (25, 50, and 100 μmol/L) for 24 h. The results showed that GE may inhibit the abnormal proliferation, migration and invasion by inhibiting the S1P-S1PR1/3 signaling pathway and activating Gαs or inhibiting Gαi protein in MH7A cells. Additionally, GE could inhibit the release of inflammatory factors and suppress the expression of cAMP, which is the key factor of the conversion of Gαi and Gαs. GE could also restore the dynamic balance of Gαi and Gαs by suppressing S1PR1/3 and inhibiting Gαi/Gαs conversion, in a manner, we demonstrated that GE inhibited the activation of Gα downstream ERK protein as well. Taken together, our results indicated that down-regulation of S1PR1/3-Gαi/Gαs conversion may play a critical role in the effects of GE on RA and GE could be an effective therapeutic agent for RA.

The catalytic enantioselective diorganozinc additions to cyclic diketones including pyrazolin-4,5-diones and isatins have been developed. In the presence of morpholine-containing chiral amino alcohol ligand, the corresponding chiral cyclic tertiary alcohols were produced in good to excellent yields (up to 97 %) and enantioselectivities (up to 95 % ee). The notable feature of this protocol includes its mild reaction conditions, Lewis acid additives free and broad functional group tolerance.

Sphingosine 1-phosphate (S1P) exerts its various physiological and pathological effects by interacting with G protein-coupled receptors. In addition, S1P can induce biological dysfunction in fibroblast-like synoviocytes (FLSs) in the development of rheumatoid arthritis (RA). However, the mechanism underlying this S1P-induced dysfunction remains unclear. An imbalance between Gαi and Gαs can affect the level of cAMP, an important regulator of numerous cell functions. Therefore, we studied the effects of S1P receptor (S1PR) 1-, 2-, and 3-associated Gαi/Gαs imbalance on the biological function of rheumatoid arthritis fibroblast-like synoviocyte (MH7A cells). The results showed that blocking S1PR1/3 and Gαi, and activating Gαs, inhibited the proliferation, migration, invasion, and proinflammatory cytokine release of MH7A cells in a S1P-induced inflammation model, whereas suppressing S1PR2 only affected the invasion and the release of proinflammatory cytokines of these cells. Analysis of the expression of S1PR1/2/3 and Gαi/Gαs further showed that S1PR1/2/3 could regulate the Gαi/Gαs balance. Furthermore, our data suggested that the level of cAMP was also affected. Combined, our results showed that impaired S1PR1/2/3 signalling can affect MH7A cells biological function via Gαi/Gαs-cAMP signalling, which can provide a new idea for the treatment of RA.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age. Insulin resistance/hyperinsulinemia is a prevalent finding in women with PCOS, which indicates that insulin resistance/hyperinsulinemia may be an important player in the pathogenesis of the PCOS. However, the underlying mechanism of insulin resistance/hyperinsulinemia on the pathogenesis of the PCOS remains elusive. In this study, we found an increased high-mobility group box 1 (HMGB1) in the serum from women with PCOS having insulin resistance/hyperinsulinemia. Furthermore, we discovered that high concentration of insulin, which mimics insulin resistance model, promoted apoptosis in primary cultured rat ovarian granulosa cells (GCs) via its effect on the increase in extracellular HMGB1. Our data presented the first evidence that increased HMGB1 induced by insulin resistance/hyperinsulinemia promoted apoptosis of ovarian GCs, which provided new molecular basis for the PCOS pathogenesis.

An approach is presented to investigate the nonlinear vibration of stiffened plates. A stiffened plate is divided into one plate and some stiffeners, with the plate considered to be geometrically nonlinear, and the stiffeners taken as geometrically nonlinear Euler beams. Lagrange equation and modal superposition method are used to derive the dynamic equilibrium equations of the stiffened plate according to the energy of the system. Besides, the effect caused by boundary movement is transformed into equivalent excitations. The primary parametric resonance–primary resonance of the stiffened plate is studied by using homotopy analysis method. Numerical examples for stiffened plates with different thicknesses of the plates are presented to discuss the amplitude–frequency and amplitude–excitation relationship of the primary parametric resonance–primary resonance. In addition, the analysis on how the damping coefficients and the transverse excitations influence amplitude–frequency curves is also carried out. Some nonlinear vibration characteristics of stiffened plates are obtained, which are useful for engineering design.

5 radial heat exchange wells were designed, and the different angle drilling, drilling pipe, and grouting backfill construction technology was studied. In addition, the heat transfer performance of the buried radial heat exchange wells was tested. The results show that, design of pipe equipment is feasible, construction is convenient, and the ratio of backfill material is reasonable; the heat transfer performance of 90 °buried tube is the best. The smaller the angle with the ground heat exchanger, the greater the heat exchange performance is affected by the surface temperature.

To improve the axial compression mechanical properties of the EPS particle-EPS board composite insulation wallboard, added fiber web at different levels of it, got the best arrangement to improve the performance of axial compression through the test.

The problem of form-finding for the suspended cable is actually the problem of determining all key points coordinates on main cable, which are by equilibrium relation on the horizontal force, main cable sagitta and lifting point force under the precondition of determining the endpoints boundary conditions of cable segment. According from the static equilibrium relationship of cable element, based on the analysis of its analytical solution process, in this paper, the cable elements are divided into two types in accordance withthe vertical distribution load along the arc length and along the string length , the corresponding shape curve of cable element is the parabola and the catenary, and with parabolic results as its initial value for the iteration of nonlinear solution, then cable element eventually converge for the catenary. And based on the exact coordinates results ,the calculation method of the length without stress is presented,and compiled corresponding computational procedures. By comparing the results of form-finding and the cable-length in non-stress according to program compiled and the results from the finite element software and the measured value of Aizhai suspension bridge, compared with the nonlinear finite element method,it confirmed the method requireing smaller dividing element density, the convergence speed is quicker and the results can ensure the precision.

In this paper, by establishing the finite element model to study the dynamic characteristics of rigid frame single-rib arch bridge. By respectively changing structural parameters of the span ratios, and the compressive stiffness of arch, and the bending stiffness of arch, and the bending stiffness of bridge girder, and the layout of boom to find out the regularity of the structure on lateral stiffness, and vertical stiffness, and torsional stiffness as well as dynamic properties, it come out the results of that lateral stiffness of the structure is weaker, and increasing the span ratios and the compressive strength of arch are conducive to the improvement of the overall stiffness, and improving the bending strength of arch and layout of boom are less effect on the overall stiffness and mode shape.

An approach is presented to study the nonlinear forced vibration of a stiffened plate. The stiffened plate is divided into one plate and some stiffeners, with the plate considered to be geometrically nonlinear, and the stiffeners taken as geometrically nonlinear Euler beams. Assuming the displacement of the stiffened plate, Lagrange equation and modal superposition method are used to derive the dynamic equilibrium equations of the stiffened plate according to energy of the system. A stiffened plate with four clamped edges subjected to harmonic excitation is studied by means of the method of multiple scales; the first approximation solutions of the double-modal motion of the system are obtained. Numerical examples for different stiffened plates are presented to discuss the steady response of the primary resonance and the amplitude–frequency relationship; and some nonlinear forced vibration characteristics of the stiffened plate are obtained, which are useful for engineering design.

Magnetic separation is an emerging and promising technology in biological sample preparation. In this paper, a high-intensity and high-gradient magnetic separation system was developed to separate magnetic nanobeads from aqueous solution. This system mainly consisted of a magnetic separator, a micropump and an electronic timer. The magnetic separator was designed by placing two columns of permanent magnets in an aluminum holder. Two magnets in each column were laid out in repelling mode and a hole between the two columns was used to accommodate a 1.5 ml tube. Working with the electronic timer, the micropump was employed to remove waste solution at a certain rate after magnetic nanobeads captured onto the sides of the tube wall. The experiments for separation of magnetic nanobeads with diameters of 150 nm and 50 nm using the developed magnetic separation system were conducted to optimize the key parameters of the system including nanobeads concentration, separation time and flow rate. The separation efficiencies of magnetic nanobeads increased as the nanobeads concentration and the separation time increased, whereas decreased when the flow rate was increased. Experimental results proved that the proposed magnetic separation system was able to separate magnetic nanobeads (diameters of 150 nm and 50 nm) with separation efficiencies of 99% and 90% in 30 min and 150 min respectively.

：On the basis of preliminary exploration, complement exploration is executed to obtain excavation seepage analysis detail parameters. According to the three-dimension finite difference method and regulating calculation method, the excavation seepage analysis of anchorage circular foundation at Huangpu bridge south and the influence of different depth rock-socketed on foundation seepage are discussed. With the experience in similar projects at home and abroad, the depth of diaphragm wall embedded in weak weathered rock is not less than 3 meters, grouting curtain wall consists of 10 meters, and the waterproof curtain outside the foundation is canceled from preliminary design. The stress, strain and water level are monitored during the excavation process, and the deformation of the supporting structure is within the control. The structure is under reasonable force and the sealing effect is obvious when the foundation is excavated. Construction practice shows that the excavation seepage analysis of anchorage circular foundation at Huangpu bridge south are consistent with engineering practice.

Based on plane strain theory, the formula for calculating the tensile stress on the interface between the steel tube and concrete under the axial pressure was derived, and the stress distribution coefficient K was analyzed. Practical formula for calculating the interfacial tensile stress of CFST members under low stress condition was fitted. Using the fitted formula the interfacial stress calculation process can be greatly simplified, and the results have enough assurance. This formula can be easily applied to CFST members’ interfacial stress calculation.

Based on tension-compression and bending equivalences, an equivalent single material plate is formed to substitute bridge deck of composite girder with steel fiber reinforced concrete (SFRC) and steel. Thickness and elastic modulus of the equivalent plate are then formulated. After three dimensional finite-element analyses of the bridge deck, in terms of shell element membrane effect and girder flexion-torsion theory, combined with compatibility of deformation, single material shell element stress is restored to stresses on SFRC plate and steel plate separately; shear force distribution on shear keys between SFRC and steel is analyzed.

Two 1:2 reduced-scale model tests with different types of shear connectors are conducted to study the mechanical properties of shear connectors for a composite beam un- der complex stress conditions. The strain of the shear connector and relative slipping on the steel-concrete interface of the rigid shear connector model and flexible shear connector model under the same boundary conditions is measured. Responses of two types of shear con- nectors under three different load cases are compared. The test results show that the ultimate bearing capacity of concrete is the key factor of relative slipping on the steel-concrete inter- face, and differences between rigid and flexible shear connectors are large.

Making use the prior knowledge that higher order cumulant and wavlet transformation methods are combined, which is used in the multi-dim-small target detection with the Gaussian noise and natural background. In this paper, a method of magnifying image based on two dimension discrete wavelet is introduced. Comparing with traditional interpolation methods, it not only enhanced resolution of the aero-image, but maintained the detail character of the image. Experiment results have shown that it is good method for enhancing aero-image. The same aerial image is magnified with above-mentioned wavelet-based algorithms, conventional bilinear interpolation and tri-spline sampling interpolation algorithm separately. The values of mean gradient on three graphs are calculated using three approach, they are 6.31, 7.43 and 8.45. In accordance with the result, the value of the magnified image by this method is largest.

This paper introduces a saving-energy controlling method of water-circling pump. It is a method that traditional PID control combined temperature fuzzy-PID and PWM. The enactment in advance include that turn frequency, turn delay and the value of floor and upper limit difference in temperature pulse. The pump's running-frequency is adjusted by saving-energy controlling tank through PID arithmetic bases on difference temperature between input pipe and output pipe. When it is the moment that the running-frequency under the turn-frequency and it is turn-delay, the method of PWM is adopted. When it is the moment that the running-frequency up the turn-frequency, it will be into the method of fuzzy-PID adjusting. It will be truth that heating temperature will be controlled through out-temperature because the application of PWM technology. This method will save energy of pump above 30 percent, as the user's requirement is met.

The problem about energy consumed by central air-condition is paid attention by people. There are great non-linearity, lag and variety of parameter in this system. Traditional PID control arithmetic has some difficulty. The merit of fussy-control is that there is better dynamic response characteristic. The mathematic model is not needed in this arithmetic. There is better adaptability, faster rise time and better robust characteristic. But there is error in fussy-control by limited grade. So we use AT89C58 as control kernel and use fussy-PID arithmetic in this system. It ensures that there is faster, more stability and smaller error. This control system has been proved stable by some experiment, the anti-interference ability is strong. It can satisfy completely the need of variable-flux equip.

A novel two-dimensional (2-D) adaptive filtering algorithm to enhance 2-D signals of small spatial extent embedded in white Gaussian noise and a variety of outstanding modern digital signal processing methods are combined in background segmentation. The coefficients of the adaptive filter converge to a special 2-D slice of the fourth-order cumulant function of the input signal. The proposed algorithm is called the 2-D cumulant adaptive enhancer (2DCAE). And the methods in background segmentation is combining the wavelet energy transformation, data integration and threshold segmentation.