Simultaneously expressed miR-424 and miR-381 synergistically suppress the proliferation and survival of renal cancer cells---Cdc2 activity is up-regulated by targeting WEE1

OBJECTIVES: MiRNAs are intrinsic RNAs that interfere with protein translation. Few studies on the synergistic effects of miRNAs have been reported. Both miR-424 and miR-381 have been individually reported to be involved in carcinogenesis. They share a common putative target, WEE1, which is described as an inhibitor of G2/M progression. Here, we studied the synergistic effects of miR-424 and miR-381 on renal cancer cells. METHODS: The viability of 786-O cells was analyzed after transfection with either a combination of miR-424 and miR-381 or each miRNA alone. We investigated cell cycle progression and apoptosis with flow cytometry. To confirm apoptosis and the abrogation of G2/M arrest, we determined the level of pHH3, which is an indicator of mitosis, and caspase-3/7 activity. The expression levels of WEE1, Cdc25, γH2AX, and Cdc2 were manipulated to investigate the roles of these proteins in the miRNA-induced anti-tumor effects. To verify that WEE1 was a direct target of both miR-424 and miR-381, we performed a dual luciferase reporter assay. RESULTS: We showed that the combination of these miRNAs synergistically inhibited proliferation, abrogated G2/M arrest, and induced apoptosis. This combination led to Cdc2 activation through WEE1 inhibition. This regulation was more effective when cells were treated with both miRNAs than with either miRNA alone, indicating synergy between these miRNAs. WEE1 was verified to be a direct target of each miRNA according to the luciferase reporter assay. CONCLUSIONS: These data clearly demonstrate that these two miRNAs might synergistically act as novel modulators of tumorigenesis by down-regulating WEE1 expression in renal cell cancer cells

Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection

Invasive Aspergillus fumigatus infection poses a serious threat to global human health, especially to immunocompromised individuals. Currently, triazole drugs are the most commonly used antifungals for aspergillosis. However, owing to the emergence of drug-resistant strains, the effect of triazole drugs is greatly restricted, resulting in a mortality rate as high as 80%. Succinylation, a novel post-translational modification, is attracting increasing interest, although its biological function in triazole resistance remains unclear. In this study, we initiated the screening of lysine succinylation in A. fumigatus. We discovered that some of the succinylation sites differed significantly among strains with unequal itraconazole (ITR) resistance. Bioinformatics analysis showed that the succinylated proteins are involved in a broad range of cellular functions with diverse subcellular localizations, the most notable of which is cell metabolism. Further antifungal sensitivity tests confirmed the synergistic fungicidal effects of dessuccinylase inhibitor nicotinamide (NAM) on ITR-resistant A. fumigatus. In vivo experiments revealed that treatment with NAM alone or in combination with ITR significantly increased the survival of neutropenic mice infected with A. fumigatus. In vitro experiments showed that NAM enhanced the killing effect of THP-1 macrophages on A. fumigatus conidia. Our results suggest that lysine succinylation plays an indispensable role in ITR resistance of A. fumigatus. Dessuccinylase inhibitor NAM alone or in combination with ITR exerted good effects against A. fumigatus infection in terms of synergistic fungicidal effect and enhancing macrophage killing effect. These results provide mechanistic insights that will aid in the treatment of ITR-resistant fungal infections

Experimental Study on Shear Behavior and Acoustic Emission Characteristics of Nonpersistent Joints

The shear behavior of rock discontinuities controls the stability of rock masses to a great extent. In this paper, laboratory shear tests were performed on rock-like materials with different cracks to study the effect of nonpersistent joints on the shear behavior of rock masses. The results show that the variation trends of the shear stress-displacement curves of specimens with different cracks are generally similar and have the same stage characteristics. When the crack length is relatively short, the elastic stage is prolonged, the peak shear strength decreases, and the shear displacement corresponding to the peak shear strength and the residual shear strength increases with the increase of the crack length. When the crack length is relatively long, the elastic stage is shortened, the peak shear strength decreases, and the shear displacement corresponding to the peak shear strength increases with the increase of the crack length. The peak shear stress gradually decreases with the increase of the crack length. The shear strength of the specimens with unilateral cracks is much higher than that of the specimens with bilateral cracks. The shear strength of the specimens is affected not only by the crack length but also by the crack distribution. The acoustic emission (AE) count peak occurs when the shear stress drops sharply and has an inverse "S"-type variation trend with the increase of the crack length. The inclination angle of the fracture decreases, the roughness of the fracture surface decreases, and the proportion of the wear area on the fracture surface increases gradually with the increase of the crack length. The AE source decreases with the increase of the crack length, and their locations are obviously asymmetric. This work can greatly contribute to the insight into the shear failure mechanism of rock discontinuities with nonpersistent joints

Advances in understanding of dendritic cell in the pathogenesis of acute kidney injury

Acute kidney injury (AKI) is characterized by a rapid decline in renal function and is associated with a high morbidity and mortality rate. At present, the underlying mechanisms of AKI remain incompletely understood. Immune disorder is a prominent feature of AKI, and dendritic cells (DCs) play a pivotal role in orchestrating both innate and adaptive immune responses, including the induction of protective proinflammatory and tolerogenic immune reactions. Emerging evidence suggests that DCs play a critical role in the initiation and development of AKI. This paper aimed to conduct a comprehensive review and analysis of the role of DCs in the progression of AKI and elucidate the underlying molecular mechanism. The ultimate objective was to offer valuable insights and guidance for the treatment of AKI

Substantially enhanced plasticity of bulk metallic glasses by densifying local atomic packing

Common wisdom to improve ductility of bulk metallic glasses (BMGs) is to introduce local loose packing regions at the expense of strength. Here the authors enhance structural fluctuations of BMGs by introducing dense local packing regions, resulting in simultaneous increase of ductility and strength

A New Conjugate Gradient Projection Method for Convex Constrained Nonlinear Equations

The conjugate gradient projection method is one of the most effective methods for solving large-scale monotone nonlinear equations with convex constraints. In this paper, a new conjugate parameter is designed to generate the search direction, and an adaptive line search strategy is improved to yield the step size, and then, a new conjugate gradient projection method is proposed for large-scale monotone nonlinear equations with convex constraints. Under mild conditions, the proposed method is proved to be globally convergent. A large number of numerical experiments for the presented method and its comparisons are executed, which indicates that the presented method is very promising. Finally, the proposed method is applied to deal with the recovery of sparse signals

Application of the Coordination Control Strategy of pH and SO2 Concentration in the Desulphurization Slurry Supply

The desulphurization slurry flow of the coal-fired unit is usually regulated by a single PID loop that controls the pH value of the gypsum slurry. And the desulphurization system is characterized with large inertia and serious hysteresis, which often results in SO2 concentration of the outlet exceeding the standard, and leads the operators to turn the regulating valve to manual mode. The SO2 concentration of the outlet was taken into consideration into the optimized control strategy of desulphurization slurry supply introduced in this paper, and it is with the gypsum slurry pH value for cooperative control of the slurry regulating valve. Finally, the experiment proved that after the optimization of the control strategy, the desulfurization loop could be automatically put into operation for a long time, and the SO2 concentration of the outlet keeps stable, and the comprehensive utilization rate of limestone and the automation level of auxiliary equipment are significantly improved

Application of the Coordination Control Strategy of pH and SO

The desulphurization slurry flow of the coal-fired unit is usually regulated by a single PID loop that controls the pH value of the gypsum slurry. And the desulphurization system is characterized with large inertia and serious hysteresis, which often results in SO2 concentration of the outlet exceeding the standard, and leads the operators to turn the regulating valve to manual mode. The SO2 concentration of the outlet was taken into consideration into the optimized control strategy of desulphurization slurry supply introduced in this paper, and it is with the gypsum slurry pH value for cooperative control of the slurry regulating valve. Finally, the experiment proved that after the optimization of the control strategy, the desulfurization loop could be automatically put into operation for a long time, and the SO2 concentration of the outlet keeps stable, and the comprehensive utilization rate of limestone and the automation level of auxiliary equipment are significantly improved

Reducing Power Spectrum Regrowth for Concurrent Dual-Band OFDM Signals

Concurrent multi-band or dual-band transmitters and receivers are the key components for future wireless communication. However, the nonlinearity and memory effects caused by power amplifiers will degrade the performance of transmitters and receivers and produce undesired interference to other channels. In this article, the out-of-band intermodulation is discussed, and a method of two-dimensional digital (2D-DPD) is applied to linearize the spectrum for dual-band OFDM signals based on an inverse auto-regression moving-average (IM-ARMA) model

Experimental Investigation on the Law of Grout Diffusion in Fractured Porous Rock Mass and Its Application

Because of the limitation of mining techniques and economic conditions, large amounts of residual coal resources have been left in underground coal mines around the world. Currently, with mining technology gradually developing, residual coal can possibly be remined. However, when residual coal is remined, caving areas might form, which can seriously affect the safety of coal mining. Hence, grouting technology is put forward as one of the most effective technologies to solve this problem. To study the grouting diffusion in fractured rock mass, this paper developed a visualization platform of grouting diffusion and a three-dimensional grouting experimental system that can monitor the grout diffusion range, diffusion time and grout pressure; then, a grouting experiment is conducted based on this system. After that, the pattern of the grouting pressure variation, grout flow and grout diffusion surface are analyzed. The relationship among some factors, such as the grouting diffusion radius, compressive strength of the grouted gravel, porosity, water-cement ratio, grouting pressure, grouting time, permeability coefficient and level of grout, is quantitatively analyzed by using MATLAB. The study results show that the flow pattern of the grout in fractured porous rock mass has a parabolic shape from the grouting hole to the bottom. The lower the level is, the larger the diffusion range of the grout is. The grouting pressure has the greatest influence on the grouting diffusion radius, followed by the grouting horizon and water-cement ratio. The grouting permeability coefficient has the least influence on the grouting diffusion radius. The grout water-cement ratio has the greatest influence on the strength of the grouted gravel, followed by the grouting permeability. The grouting pressure coefficient has the least amount of influence on the grouting diffusion radius. According to the results, the grouting parameters are designed, and a layered progressive grouting method is proposed. Finally, borehole observation and a core mechanical property test are conducted to verify the application effect. This grouting technology can contribute to the redevelopment and efficient utilization of wasted underground coal resources