Metabolic reprogramming greatly contributes to the regulation of macrophage activation. However, the mechanism of lipid accumulation and the corresponding function in tumor-associated macrophages ...(TAMs) remain unclear. With primary investigation in colon cancer and confirmation in other cancer models, here we determine that deficiency of monoacylglycerol lipase (MGLL) results in lipid overload in TAMs. Functionally, macrophage MGLL inhibits CB2 cannabinoid receptor-dependent tumor progression in inoculated and genetic cancer models. Mechanistically, MGLL deficiency promotes CB2/TLR4-dependent macrophage activation, which further suppresses the function of tumor-associated CD8+ T cells. Treatment with CB2 antagonists delays tumor progression in inoculated and genetic cancer models. Finally, we verify that expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients. Taken together, our findings identify MGLL as a switch for CB2/TLR4-dependent macrophage activation and provide potential targets for cancer therapy.
To study the influence of freeze-thaw weathering on dynamic tensile properties and damage mechanism of rock material, the porosity and T2 spectrum distribution of rock samples underwent different ...freeze-thaw cycles were obtained by nuclear magnetic resonance (NMR), and the variation of micropores and macropore that caused by freeze-thaw cycles were calculated by T2 spectrum and then analyzed. In addition, the dynamic splitting tensile test was carried out on rock samples by using split Hopkins pressure bar (SHPB), and dynamic tensile peak strength, Young's modulus and peak strain were gained and analyzed. Dynamic tensile strength degradation prediction model was established to predict the damage of rock caused by freeze-thaw weathering. Results show that the porosity of the rock sample increases with freeze-thaw cycles increase, the freeze-thaw damage on rock microstructure is mainly caused by the expansion of micropores into macropores, while the initiation of micropores is the secondary reason. With freeze-thaw cycles increasing, the peak strain increases, the dynamic Young's modulus decreases. In addition, the effect of freeze-thaw weathering deteriorates the rock's anti-deformation ability and durability.
•Dynamic mechanical property of freeze-thaw weathering treated Granite was test on SHPB system.•Microstructure of Granite sample under different freeze-thaw cycles was test by NMR and then analyzed.•Dynamic tensile strength decay model was then established to predict the damage of rock caused by freeze-thaw weathering.•When freeze-thaw cycle reaches 204, the mechanical parameters will decay to half of the initial value.
The experiment of rock-like material plays an important role in the simulation of engineering fractured rock mass. To further understand the influence of raw materials on rock-like materials, this ...paper carried out the indoor mechanical properties test and the micro-pore structure detection combining NMR and SEM. The effects of micron-silica fume (SF) on microporous structure parameters and macroscopic mechanical properties under different conditions of water-cement ratio (WCR) and sand-cement ratio (SCR) were discussed. The intrinsic relationship between parameters of different scales was analyzed. The experimental results showed that the porosity parameters of different radii gradually decreased with the increase in SF. The reduction rate of macroporous porosity was the greatest, and the decreasing rate of microporous porosity was the smallest. With the increase in SF, the microscopic characteristics of the internal surface changed from more pores, complex morphological distribution, rough surface to fewer pores, regular morphological distribution and flat and uniform surface. The box fractal dimension also showed a decreasing trend. Micro-pore structure makes a valuable contribution to the influence of SF on mechanical properties. The compressive strength and tensile strength increased with the increase in SF. The box fractal dimension and porosity of different radii were negatively correlated with mechanical strength. Different porosity parameters conformed to a good exponential relationship with mechanical properties. The research results can provide reference value and research space for subsequent rock-like material research.
Phosphate-activated mitochondrial glutaminase (GLS2) is suggested to be linked with elevated glutamine metabolism. It plays an important role in catalyzing the hydrolysis of glutamine to glutamate. ...The present study was to investigate the potent effect of GLS2 on radioresistance of cervical carcinoma. GLS2 was examined in 144 cases of human cervical cancer specimens (58 radioresistant specimens, 86 radiosensitive specimens) and 15 adjacent normal cervical specimens with immunohistochemistry. HeLa cells were treated with a cumulative dose of 50Gy X-rays, over 6months, yielding the resistant sub-line HeLaR. The expressions of GLS2 were measured by Western blot. Radioresistance was tested by colony survival assay. Apoptosis was determined by flow cytometry. The levels of glutathione (GSH), reactive oxygen species (ROS), NAD+/NADH ratio and NADP+/NADPH ratio were detected by quantization assay kit. Xenografts were used to confirm the effect of GLS2 on radioresistance in vivo. The expressions of GLS2 were significantly enhanced in tumor tissues of radioresistant patients compared with that in radiosensitive patients. In vitro, the radioresistant cell line HeLaR exhibited significantly increased GLS2 levels than its parental cell line HeLa. GLS2 silenced radioresistant cell HeLaR shows substantially enhanced radiosensitivity with lower colony survival and higher apoptosis in response to radiation. In vivo, xenografts with GLS2 silenced HeLaR were more sensitive to radiation. At the molecular level, knock-down of GLS2 increased the intracellular ROS levels of HeLaR exposed to irradiation by decreasing the productions of antioxidant GSH, NADH and NADPH. GLS2 may have an important role in radioresistance in cervical cancer patients.
•GLS2 plays an important role in regulating radiosensitivity of cervical carcinomas.•GLS2 knockdown decreases cellular GSH and NADH and eventually increases ROS levels.•GLS2 should be a potential target to improve radiosensitivity in cervical cancer.
•α-Fe2O3@graphene nanocomposites were developed by one-step facile hydrothermal method.•α-Fe2O3@graphene nanocomposites exhibit good gas-sensing performance to ethanol in comparison with pure ...α-Fe2O3.•The gas sensing mechanism of as-prepared nanocomposites to ethanol is investigated.
A simple and straightforward strategy was developed for anchoring α-Fe2O3 nanoparticles on graphene as gas sensor material. The XRD and TEM results indicate that graphene sheets are decorated with α-Fe2O3 nanoparticles with various diameters and shapes. To demonstrate the potential applications, we have fabricated gas sensors using the as-synthesized α-Fe2O3@graphene and investigated sensor activity for ethanol detection. The results show that an appropriate content of graphene dopant could effectively enhance the gas-sensing properties of α-Fe2O3 operated at different temperatures. Especially, the α-Fe2O3@graphene (contained 2wt% of graphene) sensor exhibits better sensor performances in comparison with pure α-Fe2O3 counterpart, indicating the potential applications as sensor material toward ethanol detection.
In this paper, an improved AC-link voltage matching control (IVM) strategy is proposed for the multiport modular multilevel DC transformer (M3DCT), which comprises a single-phase modular multilevel ...converter (MMC) and a series of cascaded H-bridge units. The objective of the proposed IVM strategy is to address the AC-link voltage mismatch phenomenon. Distinct from existing control methods, such as various phase-shifting control methods and the conventional AC-link voltage matching control strategy, the proposed IVM strategy orchestrates the operation of the M3DCT in an innovative fashion. It allows the sum of inserted submodule (SM) numbers in the upper and lower arms to be flexible, no longer confined to a specific SM number per arm. Consequently, the AC-link voltage of the M3DCT is maintained proximate to the matched operating condition, regardless of the degree of mismatch in the DC side voltage of the M3DCT. This enables the enhancement of the M3DCT’s overall operational performance, particularly under conditions of light loads within medium-voltage DC (MVDC) distribution systems. The correctness and effectiveness of the proposed control strategy and the corresponding analysis are substantiated through simulation results.
Voltage source converter (VSC)-based DC distribution networks (DCDNs) can automatically adjust the control strategy of overloaded VSCs to adapt to the variation in renewable energy power, but it ...brings difficulties to the steady-state performance analysis of DCDNs. This paper presents a piecewise linear power flow (PLPF) algorithm to estimate the joint effect of power disturbance and VSC control strategy adjustment on steady-state performance. Firstly, according to the VSC power balance, the critical point of the VSC hitting the capacity limit is directly determined, and the power variations in each node before VSC control strategy adjustment are obtained. Then, the linear power flow is revised considering the VSC control strategy adjustment. Inversion of the block Jacobian matrix is used to improve the calculation speed of linear power flow revision. Finally, linear power flow calculation is performed in each stage, and the steady-state performance is obtained by using the superposition method. Simulation results show that the proposed PLPF model can estimate the steady-state performance faster and more simply.
In order to study the energy characteristics of seismic waves on the liquid CO2 blasting system, the blasting seismic wave signal of liquid CO2 blasting was obtained by on-site microseismic ...monitoring tests. The adaptive optimal kernel time-frequency analysis method was used to study the basic time-frequency properties of the seismic wave signal. Combining wavelet packet transform decomposition and reconstruction and adaptive optimal kernel time-frequency analysis method, the liquid CO2 energy distribution of the seismic wave signal was further analyzed. And the energy regression model of seismic wave source of liquid CO2 blasting system was discussed. The results show that the vibration velocity is at a low level, and the main frequency range is between 30 and 70 Hz, and the duration is about 20-30 ms. The energy is mainly distributed in 0-125 Hz, which is composed of two main regions. The power function model can be used to describe the attenuation law of the seismic wave energy. The energy conversion coefficient and characteristic coefficient of the source of liquid CO2 blasting system were defined and analyzed. Combined with the empirical formula of the Sadovsky vibration velocity, the energy regression model of the seismic wave source of liquid CO2 blasting system was obtained.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Significance Alternative splicing of RNA allows a limited number of coding regions in the human genome to produce proteins with diverse functionality. Alternative splicing has also been implicated as ...an oncogenic process. Identifying aspects of cancer cells that differentiate them from noncancer cells remains an ongoing challenge, and our research suggests that alternatively spliced mRNA and subsequent protein isoforms will provide new anticancer targets. We determined that the key oncoprotein of Ewing sarcoma (ES), EWS-FLI1, regulates alternative splicing in multiple cell line models. These experiments establish oncogenic aspects of splicing that are specific to cancer cells and thereby illuminate potentially oncogenic splicing shifts as well as provide a useful stratification mechanism for ES patients.
The synthesis and processing of mRNA, from transcription to translation initiation, often requires splicing of intragenic material. The final mRNA composition varies based on proteins that modulate splice site selection. EWS-FLI1 is an Ewing sarcoma (ES) oncoprotein with an interactome that we demonstrate to have multiple partners in spliceosomal complexes. We evaluate the effect of EWS-FLI1 on posttranscriptional gene regulation using both exon array and RNA-seq. Genes that potentially regulate oncogenesis, including CLK1 , CASP3 , PPFIBP1 , and TERT , validate as alternatively spliced by EWS-FLI1. In a CLIP-seq experiment, we find that EWS-FLI1 RNA-binding motifs most frequently occur adjacent to intron–exon boundaries. EWS-FLI1 also alters splicing by directly binding to known splicing factors including DDX5, hnRNP K, and PRPF6. Reduction of EWS-FLI1 produces an isoform of γ-TERT that has increased telomerase activity compared with wild-type (WT) TERT. The small molecule YK-4–279 is an inhibitor of EWS-FLI1 oncogenic function that disrupts specific protein interactions, including helicases DDX5 and RNA helicase A (RHA) that alters RNA-splicing ratios. As such, YK-4–279 validates the splicing mechanism of EWS-FLI1, showing alternatively spliced gene patterns that significantly overlap with EWS-FLI1 reduction and WT human mesenchymal stem cells (hMSC). Exon array analysis of 75 ES patient samples shows similar isoform expression patterns to cell line models expressing EWS-FLI1, supporting the clinical relevance of our findings. These experiments establish systemic alternative splicing as an oncogenic process modulated by EWS-FLI1. EWS-FLI1 modulation of mRNA splicing may provide insight into the contribution of splicing toward oncogenesis, and, reciprocally, EWS-FLI1 interactions with splicing proteins may inform the splicing code.
The orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; Nr2f2) is expressed in adipose tissue in vivo and declines during differentiation. Overexpression ...of COUP-TFII prevents adipogenesis, whereas shRNA-mediated reduction of COUP-TFII promotes differentiation, as shown by increased lipid accumulation and elevated expression of fat cell marker proteins. Furthermore, reduction of COUP-TFII allows uncommitted fibroblasts to be differentiated into fat cells. COUP-TFII represses the expression of a number of proadipogenic factors in adipocytes, with direct action noted at the CAAT enhancer-binding protein α promoter. We show that COUP-TFII acts downstream of hedgehog signaling and is required for the full antiadipogenic effect of this pathway. This effect is mediated in part by interaction with GATA factors. COUP-TFII and GATA2 are physically associated and repress target gene expression in an additive manner. Taken together, our data demonstrate that COUP-TFII represents an endogenous suppressor of adipogenesis, linking antiadipogenic extracellular signals to the core transcriptional cascade.
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