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Osteosarcoma is the most common primary malignant tumor of bone, the long-term survival of which has stagnated in the past several decades. Celastrol, a triterpene from traditional Chinese medicine, has been proved to possess potent anti-tumor effect on various cancers. However, the effect of celastrol on human osteosarcoma and the underlying mechanisms remains to be elucidated. We reported here that celastrol could inhibit cell proliferation by causing G2/M phase arrest. Exposure to celastrol resulted in the activation of caspase-3, -8, and -9, indicating that celastrol induced apoptosis through both extrinsic and intrinsic pathways. Autophagy occurred in celastrol-treated cells as evidenced by formation of autophagosome and accumulation of LC3B-II. The celastrol-induced cell death was remarkably restored by the combination of autophagy and apoptosis inhibitors. Furthermore, inhibition of apoptosis enhanced autophagy while suppression of autophagy diminished apoptosis. Celastrol also induced JNK activation and ROS generation. The JNK inhibitor significantly attenuated celastrol-triggered apoptosis and autophagy while ROS scavenger could completely reverse them. The ROS scavenger also prevented G2/M phase arrest and phosphorylation of JNK. Importantly, we found that celastrol had the similar effects on primary osteosarcoma cells. Finally, in vivo , celastrol suppressed tumor growth in the mouse xenograft model. Taken together, our results revealed that celastrol caused G2/M phase arrest, induced apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells. Celastrol is therefore a promising candidate for development of antitumor drugs targeting osteosarcoma.

Aims/hypothesis To investigate racial/ethnic disparities in diabetes risk after gestational diabetes mellitus (GDM). Methods This is a retrospective cohort study of women enrolled in the Kaiser Permanente Southern California health plan from 1995 to 2009. GDM status was identified on the basis of plasma glucose levels during pregnancy. The incidence of diabetes after the first delivery complicated by GDM before 31 December 2009 ( n  = 12,998) was compared with the experience for women without GDM ( n  = 64,668) matched on maternal age at delivery, race/ethnicity and year of delivery (1:5 ratio). Matched Cox regression was used to compare the RRs of diabetes associated with GDM within and across racial/ethnic groups. Results Compared with the women without GDM, the HRs (95% CI) of diabetes for women after GDM were 6.5 (5.2, 8.0) in non-Hispanic white, 7.7 (6.8, 8.7) in Hispanic, 9.9 (7.5, 13.1) in black and 6.3 (5.0, 7.9) in Asian/Pacific Islanders after adjustment for parity, maternal education, comorbidity and number of outpatient visits before the index pregnancy. The HR of diabetes for black women was significantly higher than that for non-Hispanic white women ( p  = 0.032). Further adjustment for prepregnancy BMI reduced the diabetes risk association with GDM for each racial/ethnic group, but did not explain the risk differences across groups. Conclusions/interpretations Racial/ethnic disparities exist in risk of diabetes after GDM. Black women with GDM had the highest risk of developing diabetes. This highlights the importance of developing an effective diabetes screening and prevention programme in women with GDM, particularly black women with GDM.

The friction and wear behaviors of a Fe-19Cr-15Mn-0.66N high nitrogen austenitic stainless steel (HNSS) were investigated. Tribological investigations were carried out under different applied loads of 5 N, 10 N, 15 N, and 20 N. Scanning electron microscope (SEM) and laser scanning confocal microscope (LSCM) were used to understand the wear mechanisms under different loads and the reasons for the improved wear resistance. The lower friction coefficient and improved wear resistance were observed with the increase in applied loads. Under a higher load, the friction enhanced the work hardening ability of HNSS, which in turn improved its surface hardness and thus the increased wear resistance of HNSS.

To address the measurement instability of reflective ultrasonic anemometers in complex wind fields, this study systematically investigates the mechanisms by which shadow effects caused by transducers and reflector support pillars affect measurement accuracy under varying wind speeds and directions. By integrating particle image velocimetry (PIV) experiments with computational fluid dynamics (CFD) simulations, 1:1 and 1:2 scale models are employed to reveal the flow field characteristics and error mechanisms. The results indicate that at a wind direction of 0°, wall-following vortices and turbulent wakes generated by transducer structures cause systematic wind speed deviations along the measurement paths. At a 45° wind direction, flow disturbances around the support pillars become the dominant source of shadow effects. The 1:1 scale model exhibits insufficient decay of large-scale, low-frequency turbulent energy, resulting in the accumulation of turbulent kinetic energy and significant wind speed errors at 0°. In contrast, the 1:2 scale model enables efficient energy transfer through high-frequency, small-scale vortices, enhances vortex intensity uniformity, and achieves improved spatial homogeneity in cross-wind measurement errors. These findings provide an important theoretical foundation for improving the high-precision measurement performance of reflective ultrasonic anemometers in complex wind environments.

This study aims to explore dynamic behaviours of fracturing and damage evolution of rock materials at the grain scale. A grain-based discrete element method (GB-DEM) is proposed to reveal microscale characterisation and mineral grain compositions of rock materials realistically. Micro-parameters of GB-DEM are obtained by calibrating quasi-static strengths, elastic modulus, stress–strain curves, and fracture characteristics of igneous rocks. Comprehensive numerical simulations are conducted to compare with dynamic experimental results obtained by the split Hopkinson pressure bar (SHPB). The reasonability of using the GB-DEM is presented to validate fundamental pre-requisites of the SHPB technique. Combined with crack strain and acoustic emissions, the rate dependency of crack initiation stress threshold and crack damage stress threshold is investigated. The dynamic damage evolution in the form of Weibull distribution is distinctively different from that in static tests and the shape/scale parameters are presented as functions of strain rate. Moreover, microcharacteristics of crack fracturing transition and fracturing patterns formation are discussed in detail. It is found that there exist two classes of mechanical behaviour (i.e., Class I and Class II) observed from stress–strain responses of dynamic tests. Main fracturing surfaces induced by intergranular fractures split the specimen along the direction of stress wave propagation in the type of Class I behaviour. Branching cracks derive the cracks’ nucleation and in turn increases the fragment degree. A shearing band formed near the fracture surface is caused by grain pulverisations, which eventually enhances the sustainability of rocks under dynamic loading. At last, we propose a generalised equation of dynamic increase factor in the range from 10− 5 to 500/s, and also discuss the characteristic strain rate.

Inflammatory storm is an important pathological mechanism of multiple organ dysfunction, and it is associated with most deaths in septic patients, deserving to be studied. Recent findings have confirmed that the Medullary Visceral Zone (MVZ) regulates inflammation and immunity through the cholinergic anti-inflammatory pathway (CAP), but how sepsis affects the MVZ and leads to uncontrolled inflammation remain unclear. The current study reported that sepsis induced MVZ to inhibit CAP which underlies the inflammation storm. Our studies have shown that the rat models of sepsis prepared by cecal ligation and puncture had a higher inflammatory level, higher mortality, and higher Murine Sepsis Score. In septic rats, some indicators of heart rate variability (HRV) such as SDNN, HF band, RMSSD, SD1, and SD2 significantly reduced. In MVZ of septic rats, many cholinergic and catecholaminergic neurons showed apoptotic, with low expressions of tyrosine hydroxylase and choline acetyltransferase. The α7nAChR agonist GTS-21 can improve these pathologies, while the α7nAChR antagonist MLA is the opposite. Our study demonstrates for the first time that cholinergic and catecholaminergic neurons in MVZ went through significant apoptosis and inactiveness in sepsis, which contributes to the inhibition of CAP and acceleration of the inflammation storm in early sepsis. Intervening with CAP has a significant effect on the activity and apoptosis of MVZ neurons while altering systemic inflammation and immunity; in addition, for the first time, we confirmed that some indicators of HRV such as SDNN, HF band, RMSSD, SD1, and SD2 can reflect the activity of CAP, but the CAP interference had little effect on these indicators.

Vascular smooth muscle cell (VSMC) foam cell formation is an important hallmark, especially in advanced atherosclerosis lesions. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) promotes foam cell formation by promoting intracellular cholesteryl ester synthesis. The present study tests the hypothesis that oxidized low-density lipoprotein (oxLDL) increases the ACAT1 expression by activating the Toll-like receptor 4 (TLR4)-mediated inflammation, and ultimately promotes VSMC foam cell formation. Wild-type, ApoE −/− , TLR4 −/− and ACAT1 −/− mice on a C57BL/6J background were used. Increased TLR4, proinflammatory cytokines and ACAT1 were observed in high-fat (HF) diet-induced atherosclerotic plaque formation and in oxLDL-stimulated VSMCs. ACAT1 deficiency impeded the HF diet-induced atherosclerotic plaque formation and impaired the TLR4-manipulated VSMC foam cell formation in response to oxLDL. TLR4 deficiency inhibited the upregulation of myeloid-differentiating factor 88 (MyD88), nuclear factor- κ B (NF- κ B), proinflammatory cytokines and ACAT1, and eventually attenuated the HF diet-induced atherosclerotic plaque formation and suppressed the oxLDL-induced VSMC foam cell formation. Knockdown of MyD88 and NF- κ B, respectively, impaired the TLR4-manipulated VSMC foam cell formation in response to oxLDL. Rosiglitazone (RSG) attenuated HF diet-induced atherosclerotic plaque formation in ApoE −/− mice, accompanied by reduced expression of TLR4, proinflammatory cytokines and ACAT1 accordingly. Activation of peroxisome proliferator-activated receptor γ (PPAR γ ) suppressed oxLDL-induced VSMC foam cell formation and inhibited the expression of TLR4, MyD88, NF- κ B, proinflammatory cytokines and ACAT1, whereas inhibition of PPAR γ exerted the opposite effect. TLR4 −/− mice and VSMCs showed impaired atherosclerotic plaque formation and foam cell formation, and displayed no response to PPAR γ manipulation. In conclusion, our data showed that oxLDL stimulation can activate the TLR4/MyD88/NF- κ B inflammatory signaling pathway in VSMCs, which in turn upregulates the ACAT1 expression and finally promotes VSMC foam cell formation.

A few rice (Oryza sativa L.) varieties or rice straw produce and release allelochemicals into soil in which interfere with the growth of neighboring or successive plants. Allelopathic rice PI312777 and Huagan-1 at their early growth stages released momilactone B, 3-isopropyl-5-acetoxycyclohexene-2-one-1, and 5,7,4'-trihydroxy-3',5'-dimethoxyflavone into soil at phytotoxic levels, but non-allelopathic rice Huajingxian did not. Both allelopathic and non-allelopathic rice residues released momilactone B and lignin-related phenolic acids (p-hydroxybenzoic, p-coumaric, ferulic, syringic and vanillic acids) into the soil during residue decomposition to inhibit successive plants. The results indicated that allelochemicals involved in rice allelopathy from living and dead plants are substantially different. Interestingly, the concentrations of the allelochemicals released from the allelopathic rice seedlings in soil increased dramatically when they were surrounded with Echinochloa crus-galli. The concentrations of the allelochemicals were over 3-fold higher in the presence of E. crus-galli than in the absence of E. crus-galli. However, the same case did not occur in non-allelopathic Huajingxian seedlings surrounded with E. crus-galli. In addition to allelochemical exudation being promoted by the presence of E. crus-galli, allelopathic rice seedlings also increased allelochemical exudation in response to exudates of germinated E. crus-galli seeds or lepidimoide, an uronic acid derivative exuded from E. crus-galli seeds. These results imply that allelopathic rice seedlings can sense certain allelochemicals released by E. crus-galli into the soil, and respond by increased production of allelochemicals inhibitory to E. crus-galli. This study suggests that rice residues of both allelopathic and non-allelopathic varieties release similar concentrations and types of allelochemicals to inhibit successive plants. In contrast, living rice plants of certain allelopathic varieties appear to be able to detect the presence of interspecific neighbors and respond by increased allelochemicals.

Study design: An animal model of transected spinal cord injury (SCI) was used to test the hypothesis that cografted neural stem cells (NSCs) and NT-3-SCs promote morphologic and functional recoveries of injured spinal cord. Objective: To explore whether cotransplant of NSCs and NT-3-SCs could promote the injured spinal cord repair. Setting: Zhongshan Medical College, Sun Yat-sen University, PR China. Methods: Female Sprague–Dawley (SD) rats weighing on 200–220 g were used to prepare SCI models. The spinal cord was transected between T 9 and T 10 , then NSCs, SCs+NSCs, LacZ-SCs+NSCs, or NT-3-SCs+NSCs were grafted into the transected site. Results: (1) Part of NSCs could differentiate to neuron-like cells in the transected site and the percentage of differentiation was NT-3-SCs+NSCs group>SCs+NSCs group>NSCs group. (2) In the grafted groups, there were 5-HT, CGRP, and SP positive nerve fibres within the transected site. Some fluorogold (FG)-labeled cells were found in the spinal cord rostral to the transected site, the red nuclei and the inner pyramidal layer of sensorimotor cortex. (3) The cells grafted could enhance the injured neurons survival in inner pyramidal layer of sensorimotor cortex, red nuclei of midbrain, and Clark's nuclei of spinal cord's L1 segment, could decrease the latency and increase the amplitude of cortical somatosensory evoked potential (CSEP) and cortical motor evoked potential (CMEP), and could promote partly structural and functional recovery of the SCI rats. Conclusion: These results demonstrate that cografted NT-3-SCs and NSCs is a potential therapy for SCI. Sponsorship: This research was supported by Chinese National Key Project for Basic Research (G1999054009), Chinese National Natural Science Foundation (30270700) and Social Developmental Foundation of Guangdong Province (2003C33808) to YS Zeng; Natural Science Foundation of Guangdong Province (04300468) and Medical Science Research Grant of Guangdong Province (A2004081) to JS Guo.

A series of dynamic tests were carried out to investigate the effect of joint roughness on the wave energy attenuation in rock masses and estimate the relation between joint roughness and seismic quality factor of rock masses. The modified split Hopkinson pressure bar (SHPB) apparatus was adopted in this study, where the loading, input and output bars were made of gypsum. The propagation coefficient of the gypsum bars was measured from trial tests. According to the propagation coefficient of the gypsum bars, the strain, stress and particle velocity on the contact surfaces between the specimen and input/output bars were obtained from the test data recorded by the strain gauges. The specimens were prepared by a three-dimensional printer with plaster and binder. Each specimen modeled a rock mass with one joint with different roughness. The seismic quality factor of specimen is also estimated from the proposed approach of wave energy dissipation. The effects of joint roughness on the seismic quality factor of rock mass and the wave energy attenuation across the rock mass are analyzed from test results.