Mesenchymal stem cells (MSC) which have self-renewal and multiple differentiation potential in vitro play important roles in regenerative medicine and tissue engineering. However, long-term culture in vitro leads to senescence which results in the growth arrest and reduction of differentiation. In this study, MSC derived from human bone-marrow (BM-MSC) and umbilical cord (UC-MSC) were cultured in vitro lasted to senescence. Senescence and apoptosis detection showed that the senescent cells increased significantly but the increase of apoptosis was not significant in the long term culture. Senescence related genes p16, p21 and p53 increased gradually in BM-MSC. However, p16 and p53 reduced and then increased but with the gradual increase of p21 in UC-MSC. Adipogenic differentiation decreased whereas the propensity for osteogenic differentiation increased in senescent MSC. Real time RT-PCR demonstrated that both C/EBPα and PPARγ decreased in senescent BM-MSC. However, in UC-MSC, PPARγ decreased but C/EBPα increased in late phase compared to early phase. The study demonstrated p21 was important in the senescence of BM-MSC and UC-MSC. C/EBPα and PPARγ could regulate the balance of adipogenic differentiation in BM-MSC but only PPARγ not C/EBPα was involved in the adipogenic differentiation in UC-MSC.

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The calibration of discrete element method (DEM) simulations is typically accomplished in a trial-and-error manner. It generally lacks objectivity and is filled with uncertainties. To deal with these issues, the sequential quasi-Monte Carlo (SQMC) filter is employed as a novel approach to calibrating the DEM models of granular materials. Within the sequential Bayesian framework, the posterior probability density functions (PDFs) of micromechanical parameters, conditioned to the experimentally obtained stress-strain behavior of granular soils, are approximated by independent model trajectories. In this work, two different contact laws are employed in DEM simulations and a granular soil specimen is modeled as polydisperse packing using various numbers of spherical grains. Knowing the evolution of physical states of the material, the proposed probabilistic calibration method can recursively update the posterior PDFs in a five-dimensional parameter space based on the Bayes' rule. Both the identified parameters and posterior PDFs are analyzed to understand the effect of grain configuration and loading conditions. Numerical predictions using parameter sets with the highest posterior probabilities agree well with the experimental results. The advantage of the SQMC filter lies in the estimation of posterior PDFs, from which the robustness of the selected contact laws, the uncertainties of the micromechanical parameters and their interactions are all analyzed. The micro-macro correlations, which are byproducts of the probabilistic calibration, are extracted to provide insights into the multiscale mechanics of dense granular materials.

Arsenic trioxide (ATO) as an anti-tumor drug could induce differentiation and apoptosis in tumor cells. Mesenchymal stem cells (MSCs) play important roles in the hematogenesis of bone marrow. Many reports have shown that the disorder of MSC adipogenic and osteogenic differentiation occurs in some diseases. However, reports about the effects of ATO on MSCs are limited. In this study, we found that 1 mM ATO promoted MSC senescence mainly through p21, although it had no effect on apoptosis at this dose. Furthermore, ATO promoted adipogenic differentiation, but inhibited osteogenic differentiation in MSCs. Our study also showed that CCAAT/ enhancer-binding protein alpha C/EBPa and peroxisome proliferator-activated receptor gamma PPARg might be involved in the regulation of adipogenic and osteogenic differentiation induced by ATO. Our results indicated that ATO may exert an anti-tumor effect by influencing bone marrow micro-environment. Moreover, it may regulate the adipogenic and osteogenic differentiation of MSCs.

A series of high-pressure compression tests with various stress paths under monotonic and cyclic loadings were performed to examine the compression and particle crushing characteristics of silica sand in a dense state. Different stress paths were particularly designated to individually investigate the influences of mean and shear stress on particle crushing. Test results show that the degree of particle crushing increases with the stress level and is pronouncedly affected by the stress paths. For each compression test following a designated stress path, an increase in the cyclic loading number also enhances the degree of particle crushing.Particle morphology is affected by the accompanying occurrence and evolution of grain damage. Notably, the relative breakage expresses a liner relationship with the maximum volumetric strain during monotonic and repeated compression loadings. A good correlation between the relative breakage and plastic work per unit volume is obtained for silica sand at various mean stresses regardless of the stress history. However, this correlation is affected by cyclic loading number because of different crushing mechanisms. During the entire cyclic compression process, the increasing rate of relative breakage is lower than the plastic work increment for dense silica sand as the cyclic loading progresses.

Osteosarcoma (OS) is among the most frequently occurring bone tumors, particularly in children. Clinical treatment of OS is limited due to several factors including resistance to chemotherapy drugs and metastasis, and the underlying molecular mechanisms remain unclear. In the present study, tripartite motif containing 37 (TRIM37) expression levels were upregulated in tumor samples and associated with the development of drug resistance in OS. Furthermore, chemotherapy drug treatment (doxorubicin, cisplatin and methotrexate) induced TRIM37 expression in OS cells in vitro. TRIM37 mRNA and protein were upregulated in 41 pediatric osteosarcoma clinical specimens. To further elucidate the effect of TRIM37, gain and loss-of-function analysis was performed. Overexpression of TRIM37 induced cell proliferation and drug resistance ability of OS cells, whilst TRIM37 knockdown suppressed cell growth rate and restored chemosensitivity. TRIM37-regulated genes were subsequently analyzed by expression microarray and gene set enrichment analysis. Using the Wnt/β-catenin inhibitor XAV-939, the present study demonstrated that TRIM37-induced chemoresistance is partially dependent on the activation of the Wnt/β-catenin signaling pathway. Collectively, the results of the present study suggest that TRIM37 may have a key role in the development of OS and in the ability for the cells to acquire drug resistance, thus it may be a novel target for the treatment of OS.

Elastic wave propagation provides a noninvasive way to probe granular materials. The discrete element method using particle configuration as input, allows a micromechanical interpretation on the acoustic response of a given granular system. This paper compares static and dynamic numerical probing methods, from which wave velocities are either deduced from elastic moduli or extracted from the time/frequency-domain signals. The dependence of wave velocities on key characteristics, i.e., perturbation magnitude and direction for static probing, and maximum travel distance and inserted signals for dynamic probing, is investigated. It is found that processing the frequency-domain signals obtained from dynamic probing leads to reproducible wave velocities at all wavenumbers, irrespective of the perturbation characteristics, whereas the maximum travel distance and input signals for the time domain analysis have to be carefully chosen, so as to obtain the same long-wavelength limits as from the frequency domain. Static and dynamic probes are applied to calibrated representative volumes of glass beads, subjected to cyclic oedometric compression.Although the perturbation magnitudes are selected to reveal only the elastic moduli, the deduced wave velocities are consistently lower than the long-wavelength limits at various stress states, and thus sensitive to sample size. While the static probes investigate the influence of stress history on modulus degradation, dynamic probing offers insights about how dispersion relations evolve during cyclic compression. Interestingly, immediately after each load reversal the incremental behavior is reversibly elastoplastic, until it becomes truly elastic with further unload/reload. With repeating unload/reload, the P-or S-wave dispersion relations become increasingly scalable with respect to their long-wavelength limits.