Order-disorder transition during shear thickening in bidisperse dense suspensions.

Shear thickening of multimodal suspensions has proven difficult to understand because the rheology depends largely on the microscopic details of stress-induced frictional contacts at different particle size distributions (PSDs). Our discrete particle simulations below a critical volume fraction ϕc over a broad range of shear rates and PSDs elucidate the basic mechanism of order-disorder transition. Around the theoretical optimal PSD (relative content of small particles ζ1= 0.26), particles order into a layered structure in the Newtonian regime. At the onset of shear thickening, this layered structure transforms to a disordered one, accompanied by an abrupt viscosity jump. Minor increase in large-large particle contacts after the order-disorder transition causes apparent increase in radial force along the compressional axis. Bidisperse suspensions with less regular but stable layered structure at ζ1= 0.50 show good fluidity in the shear thickening regime. This work shows that in inertial flows where particle collisions dominate, order-disorder transition could play an essential role in shear thickening for bidisperse suspensions.

Characterization and Simulation of Nanoscale Catastrophic Failure of Metal/Ceramic Interfaces.

The catastrophic failure of metal/ceramic interfaces is a complex process involving the energy transfer between accumulated elastic strain energy and many types of energy dissipation. To quantify the contribution of bulk and interface cohesive energy to the interface cleavage fracture without global plastic deformation, we characterized the quasi-static fracture process of both coherent and semi-coherent fcc-metal/MgO(001) interface systems using a spring series model and molecular static simulations. Our results show that the theoretical catastrophe point and spring-back length by the spring series model are basically consistent with the simulation results of the coherent interface systems. For defect interfaces with misfit dislocations, atomistic simulations revealed an obvious interface weakening effect in terms of reduced tensile strength and work of adhesion. As the model thickness increases, the tensile failure behaviors show significant scale effects-thick models tend to catastrophic failure with abrupt stress drop and obvious spring-back phenomenon. This work provides insight into the origin of catastrophic failure at metal/ceramic interfaces, which highlights a pathway by combining the material and structure design to improve the reliability of layered metal-ceramic composites.

Nanostructure, Plastic Deformation, and Influence of Strain Rate Concerning Ni/Al2O3 Interface System Using a Molecular Dynamic Study (LAMMPS).

The plastic deformation mechanisms of Ni/Al2O3 interface systems under tensile loading at high strain rates were investigated by the classical molecular dynamics (MD) method. A Rahman-Stillinger-Lemberg potential was used for modeling the interaction between Ni and Al atoms and between Ni and O atoms at the interface. To explore the dislocation nucleation and propagation mechanisms during interface tensile failure, two kinds of interface structures corresponding to the terminating Ni layer as buckling layer (Type I) and transition layer (Type II) were established. The fracture behaviors show a strong dependence on interface structure. For Type I interface samples, the formation of Lomer-Cottrell locks in metal causes strain hardening; for Type II interface samples, the yield strength is 40% higher than that of Type I due to more stable Ni-O bonds at the interface. At strain rates higher than 1×109 s-1, the formation of L-C locks in metal is suppressed (Type I), and the formation of Shockley dislocations at the interface is delayed (Type II). The present work provides the direct observation of nucleation, motion, and reaction of dislocations associated with the complex interface dislocation structures of Ni/Al2O3 interfaces and can help researchers better understand the deformation mechanisms of this interface at extreme conditions.

Numerical homogenization of thermal conductivity of particle-filled thermal interface material by fast Fourier transform method.

Thermal interface material (TIM) is pivotal for the heat dissipation between layers of high-density electronic packaging. The most widely used TIMs are particle-filled composite materials, in which highly conductive particulate fillers are added into the polymer matrix to promote heat conduction. The numerical simulation of heat transfer in the composites is essential for the design of TIMs; however, the widely used finite element method (FEM) requires large memory and presents limited computational time for the composites with dense particles. In this work, a numerical homogenization algorithm based on fast Fourier transform was adopted to estimate the thermal conductivity of composites with randomly dispersed particles in 3D space. The unit cell problem is solved by means of a polarization-based iterative scheme, which can accelerate the convergence procedure regardless of the contrast between various components. The algorithm shows good precision and requires dramatically reduced computation time and cost compared with FEM. Moreover, the effect of the particle volume fraction, interface thermal resistance between particles (R-PP), interface thermal resistance between particle and matrix (R-PM), and particle size have been estimated. It turns out that the effective conductivity of the particulate composites increases sharply at a critical filler volume fraction, after which it is sensitive to the variation of filler loading. We can observe that the effective thermal conductivity of the composites with low filler volume fraction is sensitive to R-PM, whereas the it is governed by R-PP for the composites with high filler content. The algorithm presents excellent efficiency and accuracy, showing potential for the future design of highly thermally conductive TIMs.

[Knockdown of AKT1 gene enhances the sensitivity of gastric cancer xenografts of nude mice to doxorubicin].

Objective To investigate the effect of lentivirus-mediated shRNA targeting AKT1 gene on the sensitivity of gastric cancer xenografts to doxorubicin. Methods To establish the lentiviral vector of AKT1 RNA interference (RNAi), the vector of pGCSIL-shAKT1-GFP was infected into HEK293T cells, and meanwhile, the empty vector pGCSIL-shCON-GFP was assigned as a blank group, and then the viruses were harvested. BGC-823 gastric cancer cells were infected with the viruses. The protein expression of AKT1 was detected by Western blotting. The gastric cancer xenografts in nude mice were constructed using BGC-823 cells infected with the viruses, followed by the administration of doxorubicin. The size of tumor was evaluated and the growth curve of the tumor was drawn; HE staining was used to observe the pathological conditions of the xenografts; and the apoptosis of xenografts was examined by TUNEL assay. Results The recombinant plasmid of LV-shAKT1 was successfully constructed, and then transfected into HEK293T cells to produce high-titer lentivirus with a titer of 5×108 TU/mL. The expression of AKT1 protein in gastric cancer BGC-823 cells was significantly down-regulated after successfully infected with the LV-shAKT1. Nude mice xenografts experiment showed that AKT1 gene silencing inhibited the growth of tumor xenografts, and also enhanced the inhibitory effect of doxorubicin on the growth of tumor xenografts. TUNEL staining showed that AKT1 gene silencing promoted the apoptosis of tumor xenograft cells, and the effect was more obvious when combined with doxorubicin. Conclusion AKT1 gene silencing can enhance the sensitivity of gastric cancer xenografts to doxorubicin through promoting cell apoptosis.

PAK4 confers cisplatin resistance in gastric cancer cells via PI3K/Akt- and MEK/ERK-dependent pathways.

CDDP [cisplatin or cis-diamminedichloroplatinum(II)] and CDDP-based combination chemotherapy have been confirmed effective against gastric cancer. However, CDDP efficiency is limited because of development of drug resistance. In this study, we found that PAK4 (p21-activated kinase 4) expression and activity were elevated in gastric cancer cells with acquired CDDP resistance (AGS/CDDP and MKN-45/CDDP) compared with their parental cells. Inhibition of PAK4 or knockdown of PAK4 expression by specific siRNA (small interfering RNA)-sensitized CDDP-resistant cells to CDDP and overcome CDDP resistance. Combination treatment of LY294002 [the inhibitor of PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B or PKB) pathway] or PD98509 {the inhibitor of MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] pathway} with PF-3758309 (the PAK4 inhibitor) resulted in increased CDDP efficacy compared with LY294002 or PD98509 alone. However, after the concomitant treatment of LY294002 and PD98509, PF-3758309 administration exerted no additional enhancement of CDDP cytotoxicity in CDDP-resistant cells. Inhibition of PAK4 by PF-3758309 could significantly suppress MEK/ERK and PI3K/Akt signalling in CDDP-resistant cells. Furthermore, inhibition of PI3K/Akt pathway while not MEK/ERK pathway could inhibit PAK4 activity in these cells. The in vivo results were similar with those of in vitro In conclusion, these results indicate that PAK4 confers CDDP resistance via the activation of MEK/ERK and PI3K/Akt pathways. PAK4 and PI3K/Akt pathways can reciprocally activate each other. Therefore, PAK4 may be a potential target for overcoming CDDP resistance in gastric cancer.

Aberrant expression of SIRT3 is conversely correlated with the progression and prognosis of human gastric cancer.

SIRT3 is a NAD(+)-dependent histone deacetylaseand and plays a critical role in various human carcinomas. However, its precise role in the pathogenesis of gastric cancer (GC) is still unclear. Western blot and Real-Time PCR were used to detect the protein and mRNA level of SIRT3 in freshly collected samples from GC patients. Immunohistochemistry staining was adopted to determine the expression of SIRT3 in 65 formalin-fixed, paraffin-embedded samples from GC patients. In addition, western blot was used to detect the protein levels of SIRT3 and HIF-1α in gastric cancer cells MGC-803 transfected with SIRT3 or control siRNA. Western blot analysis of 25 samples from GC patients showed that 64% (16/25) of patients exhibited decreased expression of SIRT3, whereas 4.0% (1/25) of patients displayed complete loss. In addition, Real-Time PCR analysis showed that GC patients had decreased expression of SIRT3 mRNA. Furthermore, immunohistochemistry analysis of 65 formalin-fixed, paraffin-embedded samples from GC patients showed that 67.7% (44/65) had decreased SIRT3 staining in the cancer tissues. Notably, the expression level of SIRT3 was inversely correlated with clinicopathological variable, including tumor infiltration, tumor differentiation and tumor stage and 5-year survival of these patients. In vitro experiment showed that knockdown of SIRT3 in MGC-803 gastric cancer cells significantly increased the expression of HIF-1α. Our results provide the first evidence showing that an aberrantly decreased expression of SIRT3 occurred in GC patients, suggesting that SIRT3 might function as a mitochondrial tumor suppressor in GC. Furthermore, the possible mechanism by which SIRT3 affect the progress of GC is its direct control of HIF-1α.

RNAi knockdown of the Akt1 gene increases the chemosensitivity of gastric cancer cells to cisplatin both in vitro and in vivo.

AIM: To examine the in vitro and in vivo effects of a combined treatment of cis-d iamminedichloroplatinum(II) (cisplatin) with downregulation of Akt1 expression in gastric cancer cells. MATERIALS AND METHODS: Lentivirus-mediated RNA interference (RNAi) was used to silence the Akt1 gene. pGCSIL-Akt1 small hairpin RNA (shRNA) was stably transfected into gastric cancer cells (SGC7901 and BGC823). Next, the effects of Akt1 downregulation on the growth and apoptosis of SGC7901 (BGC823) cells in the presence or absence of cisplatin were investigated by real-time polymerase chain reaction (RT-PCR), Western blot analysis, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-d-iphenyltetrazolium bromide) assay, Hoechst assay, flow cytometric analysis of annexin V-FITC/PI staining, and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). Finally, the effects of downregulation of Akt1 expression on the sensitivity of SGC7901 cells in a tumor xenograft model of cisplatin were also determined. RESULT: Akt1 silencing reduced gastric cancer proliferation and increased cell apoptosis both in vitro and in vivo. The chemosensitivity of SGC7901 (BGC823) cells to cisplatin increased significantly following the downregulation of Akt1 expression, which might be associated with the inactivation of the PI3K/Akt1 signaling pathway, followed by the induced expression of the pro-apoptotic protein Bax and a concomitant decrease of Bcl-2 expression. CONCLUSION: This study confirmed that downregulation of Akt1 reduced chemotherapy tolerance of gastric cancer cells to cisplatin treatment. Thus, Akt1 silencing and cisplatin appear to be an effective combination treatment strategy for gastric cancer.

LY294002 potentiates the anti-cancer effect of oxaliplatin for gastric cancer via death receptor pathway.

AIM: To examine the effects of combined treatment of oxaliplatin and phosphatidylinositol 3'-kinase inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) for gastric cancer. METHODS: Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptotic cells were detected by flow cytometric analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Western blotting and immuno-precipitation were used to examine protein expression and recruitment, respectively. Nuclear factor κB (NFκB) binding activities were investigated using electrophoretic mobility shift assay. Nude mice were used to investigate tumor growth. RESULTS: Treatment with combined oxaliplatin and LY294002 resulted in increased cell growth inhibition and cell apoptosis in vitro, and increased tumor growth inhibition and cell death in the tumor mass in vivo. In MKN45 and AGS cells, oxaliplatin treatment promoted both protein kinase B (Akt) and NFκB activation, while pretreatment with LY294002 significantly attenuated oxaliplatin-induced Akt activity and NFκB binding. LY294002 promoted oxaliplatin-induced Fas ligand (FasL) expression, Fas-associated death domain protein recruitment, caspase-8, Bid, and caspase-3 activation, and the short form of cellular caspase-8/FLICE-inhibitory protein (c-FLIP(S)) inhibition. In vivo, LY294002 inhibited oxaliplatin-induced activation of Akt and NFκB, and increased oxaliplatin-induced expression of FasL, inhibition of c-FLIP(S), and activation of caspase-8, Bid, and caspase-3. CONCLUSION: Combination of oxaliplatin and LY294002 was therapeutically promising for gastric cancer treatment. The enhanced sensitivity of the combined treatment was associated with the activation of the death receptor pathway.

[The expression and role of PTEN in doxorubicin induced gastric cancer cell apoptosis].

OBJECTIVE: To study the expression of PTEN and its significance in doxorubicin-treated gastric cancer cells. METHODS: (1) Gastric cancer BGC-823 cells were treated with doxorubicin. Cell proliferation and apoptosis were evaluated by MTT and flow cytometry. The expression of PTEN at the mRNA and protein level were determined by RT-PCT and Western blot, respectively. (2) The gastric cancer xenografts model was constructed. The apoptosis of gastric cancer xenografts cells was determined by TUNEL. The expression of PTEN at the mRNA and protein level were detected using RT-PCR and Western blot, respectively. (3)BGC-823 cells were transfected with PTEN siRNA before addition of doxorubicin. The proliferation and apoptosis of these cells as well as the expression level of PTEN protein were determined. RESULTS: (1) After administration of doxorubicin, the proliferation of BGC-823 cells was inhibited in a time-dependent manner. (2) Doxorubicin significantly induced apoptosis of BGC-823 cells. (3) Doxorubicin treated BGC-823 cells showed a significant increase in the expression of PTEN at the mRNA and protein level in a time-dependent manner. TUNEL assay also showed a significant increase of apoptosis rate in gastric cancer xenografts treated with doxorubicin compared with control group [(28.11 ± 1.05)% vs (2.78 ± 1.63)%]. The expression of PTEN at the mRNA and protein level in the gastric cancer xenografts were significantly increased after administration of doxorubicin (0.5667 ± 0.0043 vs 0.2217 ± 0.0063, 0.14 ± 0.26 vs 0.04 ± 0.15, P < 0.05). (4) After treated with doxorubicin, the expression of PTEN in siRNA-transfected BGC-823 cells was significantly higher than that in non-transfected BGC-823 cells (P < 0.0001). The apoptosis of PTEN siRNA-transfected BGC-823 cells was significantly decreased compared with non-transfected BGC-823 cells [(10.35 ± 1.04)% vs (31.37 ± 3.58)%, P < 0.05]. CONCLUSION: Doxorubicin can effectively inhibit the growth and induce the apoptosis of BGC-823 gastric cancer cells. Increasing PTEN protein may be one of the main mechanism involved in this effect.