Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly ...inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.
Esophageal squamous cell carcinomas (ESCC) have become a severe threat to health and the current treatments for ESCC are frequently not effective. Recent epidemiological studies suggest that the ...anti-hyperglycemic agent metformin may reduce the risk of developing cancer, including ESCC, among diabetic patients. However, the antitumor effects of metformin on ESCC and the mechanisms underlying its cell cycle regulation remain elusive. The findings reported herein show that the anti-proliferative action of metformin on ESCC cell lines is partially mediated by AMPK. Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1. In vivo experiments further showed that metformin inhibited tumor growth in a ESCC xenograft model. Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo. In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model. AMPK, p53, p21CIP1, p27KIP1 and cyclinD1 are involved in the inhibition of tumor growth that is induced by metformin and cell cycle arrest in ESCC. These findings indicate that metformin has the potential for use in the treatment of ESCC.
AMP-activated protein kinase (AMPK) is a central metabolic sensor and plays an important role in regulating glucose, lipid and cholesterol metabolism. Therefore, AMPK is a key therapeutic target in ...diabetes. Recent pilot studies have suggested that diabetes drugs may reduce the risk of cancer by affecting the AMPK pathway. However, the association between AMPK and the proliferation of hepatocellular carcinoma (HCC) is unknown. In this study, we investigated the relationship between AMPK activity and the proliferation of HCC in cell lines, nude mice and human clinic samples. We first investigated the relationship between AMPK activity and cell proliferation in two HCC cell lines, PLC/PRF/5 and HepG2, by two AMPK activators, 5-aminoimidazole-4-carboxamide-1-h-D-ribofuranoside (AICAR) and metformain. AICAR and metformin treatment significantly inhibited the proliferation of HCC cells and induced cell cycle arrest at G1-S checkpoint. We then observed that metformin abrogated the growth of HCC xenografts in nude mice. The clinical pathology of AMPK activity in HCC, including cell proliferation, differential grade, tumor size and microvessel density, was studied by using 30 clinical tissue samples. In HCC tissue samples, phosphorylated AMPK was expressed mainly in cytoplasm. AMPK activity decreased significantly in HCC in comparison with paracancerous liver tissues (P<0.05). AMPK activity was negatively correlated with the level of Ki-67 (a marker of cell proliferation), differential degradation and tumor size (P<0.05), but not with microvessel density, hemorrhage or necrosis in HCC. Our findings suggest that AMPK activity inhibits the proliferation of HCC and AMPK might be an effective target for prevention and treatment of HCC.
Zn2Ti3O8, as a new type of anode material for lithium-ion batteries, is attracting enormous attention because of its low cost and excellent safety. Though decent capacities have been reported, the ...electrochemical reaction mechanism of Zn2Ti3O8 has rarely been studied. In this work, a porous Zn2Ti3O8 anode with considerably high capacity (421 mAh/g at 100 mA/g and 209 mAh/g at 5000 mA/g after 1500 cycles) was reported, which is even higher than ever reported titanium-based anodes materials including Li4Ti5O12, TiO2 and Li2ZnTi3O8. Here, for the first time, the accurate theoretical capacity of Zn2Ti3O8 was confirmed to be 266.4 mAh/g. It was also found that both intercalation reaction and pseudocapacitance contribute to the actual capacity of Zn2Ti3O8, making it possibly higher than the theoretical value. Most importantly, the porous structure of Zn2Ti3O8 not only promotes the intercalation reaction, but also induces high pseudocapacitance capacity (225.4 mAh/g), which boosts the reversible capacity. Therefore, it is the outstanding pseudocapacitance capacity of porous Zn2Ti3O8 that accounts for high actual capacity exceeding the theoretical one. This work elucidates the superiorities of porous structure and provides an example in designing high-performance electrodes for lithium-ion batteries.
The porous structure of Zn2Ti3O8 not only promotes the intercalation reaction, but also induces high pseudocapacitance capacity, which boosts the reversible capacity.
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Wind power belongs to sustainable and clean energy sources which play a vital role of reducing environment pollution and addressing energy crisis. However, wind power outputs are quite difficult to ...predict because they are derived from wind speeds, which vary irregularly and greatly all the time. The uncertainty of wind power causes variation of the variables of power grids, which threatens the power grids’ operating security. Therefore, it is significant to provide the accurate ranges of power grids’ variables, which can be used by the operators to guarantee the power grid’s operating security. To achieve this goal, the present paper puts forward the interval power flow with wind farms model, where the generation power outputs of wind farms are expressed by intervals and three types of control modes are considered for imitating the operation features of wind farms. To solve the proposed model, the affine arithmetic-based method and optimizing-scenarios method are modified and employed, where three types of constraints of wind control modes are considered in their solution process. The former expresses the interval variables as affine arithmetic forms, and constructs optimization models to contract the affine arithmetic forms to obtain the accurate intervals of power flow variables. The latter regards active power outputs of the wind farms as variables, which vary in their corresponding intervals, and accordingly builds the minimum and maximum programming models for estimating the intervals of the power flow variables. The proposed methods are applied to two case studies, where the acquired results are compared with those acquired by the Monte Carlo simulation, which is a traditional method for handling interval uncertainty. The simulation results validate the advantages, effectiveness and the applicability of the two methods.
With the rapid development of economy and technology, large-scale integrated energy buildings account for an increasing proportion of urban load. However, the randomness of EV owner behaviors, ...electricity price and outdoor temperature have brought challenges to the energy management of integrated energy buildings. This paper proposes a stochastic dynamic programming-based online algorithm to address the energy management of integrated energy buildings with electric vehicles and flexible thermal loads under multivariate uncertainties. First, an online energy management framework is established, which is further formulated as a multi-stage stochastic sequential decision-making problem. To address the complexities of the problem, a novel stochastic dynamic programming is employed to develop a distribution-free, computationally efficient, and scalable solution. By using extensive training samples, the algorithm is trained offline to learn how to deal with multivariate uncertainties and get the approximate optimal solution, which no longer depends on intraday forecast information. Numerical tests demonstrate the effectiveness of the proposed algorithm compared with other online algorithms in terms of optimality and computation efficiency.
The design and physical implementation of an embedded memory utilising bit-area efficient hybrid gain cell is presented. The memory cells in this work are composed of a high-threshold NMOS write ...transistor and a standard-threshold NMOS read transistor. The bit data are stored on the parasitic capacitances within the cells. Owing to the combination of low subthreshold-leakage write device and high mobility read device, this NMOS-based hybrid 2T gain cell exhibits much improved data retention and read performance in a compact bit area. The memory arrays operate with a logic-compatible supply voltage; SRAM-like I/O interface; chip-select-controlled 128-row refresh; and non-destructive read with speed comparable with 6T SRAM, but 65% smaller cell area. Measurement results from a 32 kbit pseudo-SRAM test chip implemented in a 130 nm logic CMOS technology demonstrate the effectiveness of the proposed embedded memory techniques.
Ferroptosis, a form of regulated cell death triggered by lipid peroxidation, was recently identified as an important mechanism in radiotherapy (RT)-mediated tumor suppression and radioresistance, ...although the exact genetic contexts in which to target ferroptosis in RT remains to be defined. p53 is the most commonly mutated gene in human cancers and a major effector to RT. Here, we identify ferroptosis as a critical mechanism to mediate p53 function in tumor radiosensitivity. Mechanistically, RT-mediated p53 activation antagonizes RT-induced SLC7A11 expression and represses glutathione synthesis, thereby promoting RT-induced lipid peroxidation and ferroptosis. p53 deficiency promotes radioresistance in cancer cells or tumors at least partly through SLC7A11-mediated ferroptosis inhibition. Ferroptosis inducers (FINs) that inhibit SLC7A11 exert significant radiosensitizing effects in tumor organoids and patient-derived xenografts with p53 mutation or deficiency. Finally, we show that RT-induced ferroptosis correlates with p53 activation and better clinical outcomes to RT in cancer patients. Together, our study uncovers a previously unappreciated role of ferroptosis in p53-mediated radiosensitization and suggest using FINs in combination with RT to treat p53-mutant cancers.
•Porous plate-like Li2ZnTi3O8 was prepared in a low energy consumption method.•The nanostructure formation mechanism was analyzed in detail.•The kinetics properties was enhanced due to the advanced ...microstructure.•Enhanced Li+ storage with a mass of pseudocapacitance was achieved.•Its reversible capacity exceeds all current reports of LZTO-based anodes.
Spinel Li2ZnTi3O8 (LZTO) is widely studied in the field of anode materials for lithium-ion batteries (LIBs) in recent years because of its stable cycling performance, no volume expansion and higher theoretical capacity than that of Li4Ti5O12. In this work, porous plate-like LZTO is synthesized via a simple in situ topological reaction with layered Titanic acid as the precursor. Due to its special morphology, a large amount of pseudocapacitance is introduced for lithium-ion storage in conjunction with the intercalation reaction. This co-storage mode allows more Li+ to be stored, resulting in the plate-like LZTO getting the highest capacity in the LZTO-based anode. It shows a reversible capacity of 338 mAh/g at 0.1 A/g and maintains excellent performance in long cycle tests under high current density (208 mAh/g after 1000 cycles at 1 A/g and 118 mAh/g after 2000 cycles at 5 A/g). In terms of electrochemical reaction kinetics, the two-dimensional plate structure provides a flat path for electron transport and the micropores on its surface provide many fast channels for the Li+ diffusion. Its simple synthesis method and excellent electrochemical properties prove that it has a great potential to become the new generation of anode materials for LIBs.
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SnSe/r-GO composite with SnSe nanorods anchoring on the r-GO surface by Sn–O–C and Sn–C bonds was prepared successfully by in-situ selenization of SnO2/r-GO precursor. When employed as lithium ion ...battery anode, SnSe/r-GO exhibits more superior electrochemical performance than SnO2/r-GO composite.
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•SnSe/r-GO is prepared by in-situ selenization transformation from SnO2/r-GO.•SnSe nanorods are anchored on r-GO surface homogeneously via the Sn–O–C and Sn–C bonds.•The SnSe/r-GO demonstrates much better cycling and rate performance than SnO2/r-GO.
SnSe is regarded as one of the promising anodes for the next-generation lithium ion batteries (LIBs) due to high theoretical capacity and good conductivity. Herein, SnSe/r-GO composite is synthesized by in-situ selenization transformation from SnO2/r-GO and it displays the structure that SnSe nanorods are dispersed on the surface of r-GO homogeneously via the Sn–O–C and Sn–C bonds. The chemically bonded SnSe/r-GO demonstrates much better cycling and rate performance than SnO2/r-GO when used as LIBs anode. It can afford a high discharge capacity of 1196.4 mAh·g−1 in the first cycle and maintained at 606.6 mAh·g−1 after 100 cycles. Even at high current density of 1000 mA·g−1, the specific capacity of SnSe/r-GO can reach to 423.8 mAh·g−1. This work provides an in situ synthesis strategy for high-performance tin-based material in the application of energy storage.
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