Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics. 相似文献
Electrochemical CO2 reduction reaction (CO2RR) is an efficient way in the utilization of CO2. In this work, single transition-metal (TM) atom (TM = Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn) anchored on two-dimensional (2D) Ti2CN2 are designed for CO2RR using density-functional-theory (DFT) calculation. We show that Ti2CN2 serves as an excellent substrate to support single atom catalysts (SACs), compared to Ti2CO2 and Ti2CF2. We find that the Sc, Ti and V supported on Ti2CN2 show high catalytic activities to produce CO with a low overpotential of 0.37, 0.27, and 0.23 eV, respectively. Differently, the Mn and Fe on Ti2CN2 are catalytically active for the production of HCOOH with a low overpotential of 0.32 and 0.43 eV, respectively. We further show that the negatively charged TM-Ti2CN2 can capture and activate CO2 more effectively, and the catalytic activity and selectivity can be significantly tuned by injecting extra electrons. 相似文献
Water Resources Management - The water evaluation and planning (WEAP) approach and the invasive weed optimization algorithm (IWOA) are herein employed to determine the optimal operating policies in... 相似文献
Water Resources Management - Environmental Impact Assessments (EIAs) of development projects are necessary to minimize negative impacts and maximize benefits. The objective of this paper is to... 相似文献
The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies. 相似文献
Security has always been a popular and critical topic. With the rapid development of information technology, it is always attracting people’s attention. However, since security has a long history, it covers a wide range of topics which change a lot, from classic cryptography to recently popular mobile security. There is a need to investigate security-related topics and trends, which can be a guide for security researchers, security educators and security practitioners. To address the above-mentioned need, in this paper, we conduct a large-scale study on security-related questions on Stack Overflow. Stack Overflow is a popular on-line question and answer site for software developers to communicate, collaborate, and share information with one another. There are many different topics among the numerous questions posted on Stack Overflow and security-related questions occupy a large proportion and have an important and significant position. We first use two heuristics to extract from the dataset the questions that are related to security based on the tags of the posts. And then we use an advanced topic model, Latent Dirichlet Allocation (LDA) tuned using Genetic Algorithm (GA), to cluster different security-related questions based on their texts. After obtaining the different topics of security-related questions, we use their metadata to make various analyses. We summarize all the topics into five main categories, and investigate the popularity and difficulty of different topics as well. Based on the results of our study, we conclude several implications for researchers, educators and practitioners. 相似文献
Sustainable water resources management aims at increasing the efficient use of water and achieving food security. This work proposes a generalized novel spatial fuzzy strategic planning (SFSP) in combination with multi-criteria decision making (MCDM) and a conceptual agricultural water use model for determining sustainable agricultural water management strategies. The proposed framework is applied to an irrigation and drainage network in Iran, which constitutes a large-scale water resource system. A spatial strength, weakness, opportunity, and threat (SWOT) analysis of internal and external factors related to agricultural water management is applied in this work. Possible water management strategies were ranked with the MCDM approach that combines the Analytic Hierarchy Process (AHP) and the Fuzzy technique for order-preference by similarity to ideal solution (TOPSIS). The AHP estimates the criteria weights and the TOPSIS model prioritizes the agricultural water management strategies. The results of SWOT analysis show that the final scores of the internal and external factors are equal to 2.9 and 2.73, respectively. Accordingly, the most attractive strategic type is a SO (aggressive) strategy, and a combination of structural and non-structural strategies (SO, ST, and WO strategies) are the top-ranked ones. Proposed strategies for water supply and demand management are the development and rehabilitation of the physical structure of water resources system of irrigation network, improvement of operation management and maintenance of water resources system, wastewater management, and inter-basin water transfer within the irrigation network. The results indicate that the total annual volume of agricultural water under normal conditions is about 1.8 billion cubic meters, of which about 1707 million cubic meters (95%) issue from surface water sources and 90 million cubic meters (5%) from groundwater sources. The proposed model and the calculated results provide viable and effective solutions for the implementation of sustainable management of water resources and consumption in large-scale water resources systems.