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Background and Purpose: Dihydropyrimidine dehydrogenase (DPD) is a major determinant of 5-FU resistance in cancers. DPD catalyzes 5-FU into FBAL (α-fluoro-β-alanine) to lower intracellular 5-FU level. We aimed to investigate mechanism and clinical significance of FBAL-stimulated sphingosine 1-phosphate receptor 2 (S1PR2) in upregulation of DPD in colonic cancer. Experimental Approach: Cancer cells transfected or silenced S1PR2 were exposed to FBAL for analyzed S1PR2 and DPD levels. Luciferase reporter assay analyzed S1PR2-activated TWIST1 binding to DPYD promoter. Co-IP assay analyzed TWIST1 interaction with JMJD3-RNA Pol II complex binding to DPYD promoter. HT-29sh-S1PR2 or SW480TgS1PR2 cells xenografted nude mice were used to evaluate clinical significance of S1PR2-upregulated tumoral DPD. Key Results: Activation of S1PR2 upregulated DPD in colonic cancer cells and human fresh cancer specimens. FBAL was first time identified as an etiological stimulator of S1PR2 activation. The FBAL-stimulated S1PR2 increased TWIST1 binding to DPYD promoter and interacting with JMJD3-RNA Pol II complex, enhancing H3K27me3-enriched DPYD transcription elongation. Transfection of S1PR2 in SW480TgS1PR2 xenograft contributed 5-FU resistance by 45.14%, and silence of S1PR2 improved 5-FU sensitivity by 62.12% in HT-29sh-S1PR2 xenograft. S1PR2 inhibitor JTE013 prevented the FBAL-stimulated S1PR2’s effects in upregulating DPD. Cancer cells with high S1PR2 are more resistant to 5-FU, strongly suggesting clinical significance that combination use of S1PR2 inhibitors may be the appropriate 5-FU-based regimens of colonic cancers. Conclusions and Implications: The FBAL-stimulated S1PR2 increased TWIST1 binding to DPYD promoter and interacting with JMJD3-RNA Pol II, enhancing the H3K27me3-enriched DPYD transcription elongation.

Aberrant sphingolipid metabolism has been implicated in chemoresistance, but the underlying mechanisms are still poorly understood. Herein we revealed a previously unrecognized mechanism of 5-fluorouracil (5-FU) resistance contributed by high SphK2-upregulated dihydropyrimidine dehydrogenase (DPD) in colorectal cancer (CRC), which is evidenced from human CRC specimens, animal models, and cancer cell lines. TMA samples from randomly selected 60 CRC specimens firstly identified the clinical correlation between high SphK2 and increased DPD (p 0.001). Then the regulatory mechanism was explored in CRC models of villin-SphK2 Tg mice, SphK2

It is important to investigate the dynamic behaviors of deep rocks near explosion cavity to reveal the mechanisms of deformations and fractures. Some improvements are carried out for Grigorian model with focuses on the dilation effects and the relaxation effects of deep rocks, and the high pressure equations of states with Mie-Gruneisen form are also established. Numerical calculations of free field parameters for deep underground explosions are carried out based on the user subroutines which are compiled by means of the secondary development functions of LS-DYNA9703D software. The histories of radial stress, radial velocity and radial displacement of rock particles are obtained, and the calculation results are compared with those of U.S. Hardhat nuclear test. It is indicated that the dynamic responses of free field for deep underground explosions are well simulated based on improved Grigorian model, and the calculation results are in good agreement with the data of U.S. Hardhat nuclear test. The peak values of particle velocities are consistent with those of test, but the waveform widths and the rising times are obviously greater than those without dilation effects. The attenuation rates of particle velocities are greater than the calculation results with classic plastic model, and they are consistent with the results of Hardhat nuclear test. The attenuation behaviors and the rising times of stress waves are well shown by introducing dilation effects and relaxation effects into the calculation model. Therefore, the defects of Grigorian model are avoided. It is also indicated that the initial stress has obvious influences on the waveforms of radial stress and the radial displacements of rock particles.

The impact compression tests on HPP hybrid fibers reinforced lightweight aggregate concrete were performed with 100mm SHPB equipment. The dynamic mechanical properties and variation of HPP hybrid fibers reinforced lightweight aggregate concrete under different strain rates and loading methods were systematically studied. HPP hybrid fibers reinforced lightweight aggregate concrete is of the property of strain rate effects under impact loads as ordinary concrete. The dynamic strength and peak strain of it increased with the increase of strain rate. During multiple-impact compression tests, the specimens were able to bear multiple impacts before damage after cracks were produced. It is clear that HPP hybrid fibers reinforced lightweight aggregate concrete is an outstanding material for protective engineering to resist repetitive impacts.

Small span arch steel structures on spring-settlement support and normal support were designed as research objects. 1kg, 2kg, 3kg and 5kg TNT group charges were detonated respectively on the center surface of backfill above the structure. Numerous data was obtained during these tests. The comparisons of measured parameters were done between the structure with spring-settlement support and normal support. The results indicate that, the structure with spring-settlement support can reduce the magnitude of internal force of the structure, decrease the dynamic effects on the structure significantly, and enhance the bearing capacity.

In order to accurately estimate the anti-penetration capacity of yaw-inducing bursting layer with irregular barriers on surface impacted by projectile, the theoretical model of attack angle and angular velocity for projectile impacting on irregular barrier was achieved according to the macroscopic relation of contact force versus contact time, in which the main factors such as the relative geometrical characteristics of projectile and irregular barrier, material property and impact velocity of projectile influencing on yaw-inducing effectiveness were considered. On the basis of considering synthetically the influences of attack angle, impact velocity, impact angle of projectile and uncontrolled free surface of target, the theoretical formulation of penetration depth for bursting layer with irregular barriers on surface impacted by projectile was presented by expressing the stress of an optional point on the nose of projectile according to the relation of stress versus velocity. The theoretical results indicate that in the case of oblique impact embodying effect of attack angle, the penetration depth is reduced with the increase of impact angle, attack angle or angular velocity, and penetration trajectory is also deflected obviously. The effectiveness of angular velocity influencing on penetration depth is increased with impact velocity increasing. The theoretical results are in good agreement with test data for low impact velocity.

The bearing capacities of one-way reinforced concrete beams with elastic supports are investigated in this paper. According to the nonlinear characteristics of the beams, the basic equations based on plastic theory of concrete are derived by considering the in-plane force effects that aroused by the constraints of supports when the beams deforming. It is indicated that the calculation results are in good agreement with experimental datum, and the influences of different supports on the bearing capacities of the beams are quantitatively given for the first time.

In order to study the mechanism of the zonal disintegration phenomenon (ZDP), both experimental and theoretical investigations were carried out. Firstly, based on the similarity law, gypsum was chosen as equivalent material to simulate the deep rock mass, the excavation of deep tunnel was modeled by drilling a hole in the gypsum models, two circular cracked zones were measured in the model, and ZDP in the enclosing rock mass around deep tunnel was simulated in 3D gypsum model tests. Secondly, based on the elasto-plastic analysis of the stressed-strained state of the surrounding rock mass with the improved Hoek-Brown strength criterion and the bilinear constitutive model, the maximum stress zone occurred in vicinity of the elastic-plastic interface due to the excavation of the deep tunnel, rock material in maximum stress zone is in the approximate uniaxial loading state owing to the larger tangential force and smaller radial force, the mechanism of ZDP was explained, which lay in the creep instability failure of rock mass due to the development of plastic zone and transfer of the maximum stress zone within the rock mass. Thirdly, the analytical critical depth for the occurrence of ZDP was obtained, which depended on the mechanical indices and stress concentration coefficient of rock mass.

Zonal disintegration is a typical static phenomenon of deep rock masses. It has been defined as alternating regions of fractured and relatively intact rock mass that appear around or in front of the working stope during excavation of a deep tunnel. Zonal disintegration phenomenon was successfully demonstrated in the laboratory with 3D tests on analogous gypsum models, two circular cracked zones were observed in the test. The linear Mohr-Coulomb yield criterion was used with a constitutive model that showed linear softening and ideal residual plastic to analyze the elasto-plastic field of the enclosing rock mass around a deep tunnel. The results show that tunneling causes a maximum stress zone to appear between an elastic and plastic zone in the surrounding rock. The zonal disintegration phenomenon is analyzed by considering the stress-strain state of the rock mass in the vicinity of the maximum stress zone. Creep instability failure of the rock due to the development of the plastic zone, and transfer of the maximum stress zone into the rock mass, are the cause of zonal disintegration. An analytical criterion for the critical depth at which zonal disintegration can occur is derived. This depth depends mainly on the character and stress concentration coefficient of the rock mass.

The dorsal motor nucleus of vagus (DMV) plays an important role in the regulation of gastrointestinal function. Dopamine (DA) exerts potent neuromodulatory effects on the motoneurons in the DMV via dopamine receptors (DRs). However, the distribution of DRs and their neurochemical phenotypes in the DMV are unclear. In the present study, the distribution of DRs D1- and D2-immunoreactive (IR) neurons and their neurochemical phenotypes in the DMV of rats were investigated using a double-labeling immunofluorescence technique combined with confocal microscopy. The results indicated that a considerable quantity of D1 and D2 was expressed throughout the DMV. A large amount of choline acetyltransferase (ChAT)-IR and a few tyrosine hydroxylase (TH)-IR neurons were observed in the DMV. Nearly all of the neurons were also D1-IR and D2-IR. In conclusion, the present study demonstrates the wide distribution of D1 and D2 in the cholinergic and catecholaminergic neurons in the DMV of rats. The DRs might play an important role in the regulation of DA on the activity of cholinergic and catecholaminergic neurons in the DMV.

AIM: To establish an easily-handled method to isolate mesenchymal stem cells (MSCs) from coagulated human bone marrow samples. METHODS: Thrombin was added to aliquots of seven heparinized human bone marrow samples to mimic marrow coagulation. The clots were untreated, treated with urokinase or mechanically cut into pieces before culture for MSCs. The un-coagulated samples and the clots were also stored at 4 °C for 8 or 16 h before the treatment. The numbers of colony-forming unit-fibroblast (CFU-F) in the different samples were determined. The adherent cells from different groups were passaged and their surface profile was analyzed with flow cytometry. Their capacities of in vitro osteogenesis and adipogenesis were observed after the cells were exposed to specific inductive agents. RESULTS: The average CFU-F number of urokinase-treated samples (16.85 ± 11.77/106) was comparable to that of un-coagulated control samples (20.22 ± 10.65/106, P = 0.293), which was significantly higher than those of mechanically-cut clots (6.5 ± 5.32/106, P < 0.01) and untreated clots (1.95 ± 1.86/106, P < 0.01). The CFU-F numbers decreased after samples were stored, but those of control and urokinase-treated clots remained higher than the other two groups. Consistently, the numbers of the attached cells at passage 0 were higher in control and urokinase-treated clots than those of mechanically-cut clots and untreated clots. The attached cells were fibroblast-like in morphology and homogenously positive for CD44, CD73 and CD90, and negative for CD31 and CD45. Also, they could be induced to differentiate into osteoblasts and adipocytes in vitro. CONCLUSION: Urokinase pretreatment is an optimal strategy to isolate MSCs from human bone marrow samples that are poorly aspirated and clotted.

Once a RC structure is laterally restrained, both the static and dynamic load resistances will be enhanced due to the membrane action. Despite this known advantage, the apparent lack of systemic and efficient methods of analysis poses a drawback in the design and assessment of blast-resistant RC structures. First, a simplified membrane action theory was presented by modifying the maximum membrane force design method (MMFM) for predicting the total static resistance-deflection curves of restrained beam-slab RC structures. Second, a series of constrained beams were tested to validate the new theory, for which better agreement was observed between the test data, the results predicted by the proposed theory and those by MMFM. The results show that the static load carrying capacity and membrane force increase with increasing restraint stiffness, and the smaller the reinforcement ratio is, the larger the load carrying capacity increases. Third, based on the improved compressive static membrane action theory, a new analytical method was developed to investigate the dynamic responses of restrained RC structures subjected to blast loads, using an equivalent single degree of freedom system that combines the three-parameter elasto-viscoplastic rate-sensitive material model with the proposed static theory. Good agreement is observed between the test data and the analytical results. Finally, it is demonstrated that the dynamic resistance capacity increases with increasing load rate and restraint stiffness and with decreasing tensile reinforcement ratio, but the larger the dynamic resistance is, the larger the plastic deformation of the structure.