The amino acid antiporter system Xc
is important for the synthesis of glutathione (GSH) that functions to prevent lipid peroxidation and protect cells from nonapoptotic, iron-dependent death (i.e., ...ferroptosis). While the activity of system Xc
often positively correlates with the expression level of its light chain encoded by SLC7A11, inhibition of system Xc
activity by small molecules (e.g., erastin) causes a decrease in the intracellular GSH level, leading to ferroptotic cell death. How system Xc
is regulated during ferroptosis remains largely unknown. Here we report that activating transcription factor 3 (ATF3), a common stress sensor, can promote ferroptosis induced by erastin. ATF3 suppressed system Xc
, depleted intracellular GSH, and thereby promoted lipid peroxidation induced by erastin. ATF3 achieved this activity through binding to the SLC7A11 promoter and repressing SLC7A11 expression in a p53-independent manner. These findings thus add ATF3 to a short list of proteins that can regulate system Xc
and promote ferroptosis repressed by this antiporter.
Online Social Networks generate a prodigious wealth of real-time information at an incessant rate. In this paper we study the empirical data that crawled from Twitter to describe the topology and ...information spreading dynamics of Online Social Networks. We propose a measurement with three measures to state the efforts of users on Twitter to get their information spreading, based on the unique mechanisms for information retransmission on Twitter. It is noticed that small fraction of users with special performance on participation can gain great influence, while most other users play a role as middleware during the information propagation. Thus a community analysis is performed and four categories of users are found with different kinds of participation that cause the information dissemination dynamics. These suggest that exiting topological measures alone may reflect little about the influence of individuals and provide new insights for information spreading.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar ...metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.
Based on the flipped classroom in the context of deep learning, this paper combines the teaching design of university mathematics in colleges and universities with the learning characteristics of ...college students and designs and builds a flipped classroom teaching model of university mathematics in colleges and universities in the context of deep learning. To analyze the application effect of the university mathematics flipped classroom teaching model in colleges and universities, we first analyze the differences in the deep learning level of college students and propose the evaluation model of the flipped classroom teaching model, evaluate the application of the model and analyze the evaluation results, then analyze the independent learning ability of college students in a pre and post-test, and finally analyze the participation of college students. There are significant differences in the four dimensions of students’ deep learning awareness, learning motivation, learning engagement, and learning strategies, i.e., p<0.05. The final scores of college mathematics in classes A and B are 40.11 and 36.98. It shows that the effect of flipped classroom teaching in college mathematics is better in class A than in class B. The total value of the independent learning ability of the students in this class before and after the practice increased by 6.8468 points. In the flipped classroom, 37.2 % of the students thought that they completed the task poorly, which was related to the content of practicing the flipped classroom. University math teachers should guide students at the right time to improve their ability to divergence and analogical reasoning.
Nickel-based superalloy is widely employed in aircraft engines and the hot end components of various types of gas turbines with its high strength, strong corrosion resistance and excellent thermal ...fatigue properties and thermal stability. However, nickel-based superalloy is one of the extremely difficult-to-cut materials. During the machining process, the interaction between the tool and the workpiece causes the severe plastic deformation in the local area of workpiece, and the intense friction at the tool–workpiece interface. The resulting cutting heat coupled with the serious work hardening leads to a series of flaws, such as excessive tool wear, frequent tool change, short tool life, low productivity, and large amount of power consumption etc., in which the excessive tool wear has become one of the main bottlenecks that constraints the machinability of nickel-based superalloys and its wide range of applications.
In this article, attention is mainly focused on the tool wear characteristics in the machining of nickel-based superalloys, and the state of the art in the fields of failure mechanism, monitoring and prediction, and control of tool wear are reviewed. The survey of existing works has revealed several gaps in the aspects of tool self-organizing process based on the non-equilibrium thermodynamics, tool wear considering the tool nose radius, thermal diffusion layer in coated tools, tool life prediction based on the thermal–mechanical coupling, and industrial application of tool wear online monitoring devices. The review aims at providing an insight into the tool wear characteristics in the machining of nickel-based superalloys and shows the great potential for further investigations and innovation in the field of tool wear.
A review of the causes, mechanisms, types and consequences of the tool wear in cutting of nickel-based superalloys Display omitted .
► Machining of nickel-based superalloys often results in excessive tool wear. ► Tool wear is considered to be a result of mechanical and chemical interactions. ► Analytical, experimental, and FE methods are employed for analysis of tool wear. ► Novel assisted technologies can be applied into the effective control of tool wear. ► Thermal wear of tools should be of widespread concern in machining process.
Remediation of contaminated soil and sediment is important for improving the eco-environmental quality. Electro-kinetic remediation (EKR) is an environmentally friendly technology to migrate and ...remove pollutants from the soil and sediment matrix. This paper analyses the mechanism and performance of EKR of heavy metals, organic pollutants, and compound pollutants. Moreover, the effect of optimizing individual EKR through soil and sediment pre-treatment (adding acid/oxidant/co-solvent/surfactant, stirring, heating, etc.), electrode optimization (exchange electrode, anode approximation, electrode matrix, etc.), and applying multi-technology combination (electro-kinetic permeable reaction barrier/Fenton/ion, exchange membrane/ultrasonic/electrolyte enhancement, etc.) was evaluated. Factors including incomplete separation of pollutants, variation in physico-chemical properties and microstructure of soil/sediment, and difficulties in in situ practice have restrained the field application of EKR. To solve the above technical challenge, an integrated EKR technology based on pollutant in situ separation, followed by separated contaminant treatment, and subsequent valuable elements recovery is proposed.
Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models ...and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse renal hypertrophy, tubular damage, inflammation, fibrosis, and albuminuria in diabetic mice, indicating a protective role of autophagy in DKD. Autophagy impairment in DKD was associated with the downregulation of unc-51-like autophagy-activating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression and autophagy impairment in diabetic kidneys, resulting in less renal hypertrophy and albuminuria. Furthermore, blockade of p53 attenuated miR-214 induction in DKD, leading to higher levels of ULK1 and autophagy, accompanied by an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD.
Robotic grinding is considered as an alternative towards the efficient and intelligent machining of complex components by virtue of its flexibility, intelligence and cost efficiency, particularly in ...comparison with the current mainstream manufacturing modes. The advances in robotic grinding during the past one to two decades present two extremes: one aims to solve the problem of precision machining of small-scale complex surfaces, the other emphasizes on the efficient machining of large-scale complex structures. To achieve efficient and intelligent grinding of these two different types of complex components, researchers have attempted to conquer key technologies and develop relevant machining system. The aim of this paper is to present a systematic, critical, and comprehensively review of all aspects of robotic grinding of complex components, especially focusing on three research objectives.
For the first research objective, the problems and challenges arising out of robotic grinding of complex components are identified from three aspects of accuracy control, compliance control and cooperative control, and their impact on the machined workpiece geometrical accuracy, surface integrity and machining efficiency are also identified. For the second aim of this review, the relevant research work in the field of robotic grinding till the date are organized, and the various strategies and alternative solutions to overcome the challenges are provided. The research perspectives are concentrated primarily on the high-precision online measurement, grinding allowance control, constant contact force control, and surface integrity from robotic grinding, thereby potentially constructing the integration of “measurement – manipulation – machining” for the robotic grinding system. For the third objective, typical applications of this research work to implement successful robotic grinding of turbine blades and large-scale complex structures are discussed. Some research interests for future work to promote robotic grinding of complex components towards more intelligent and efficient in practical applications are also suggested.
amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as ...potential drug targets. Here we report that neuroblastoma cells with
amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to
-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in
-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy. SIGNIFICANCE: This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.
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Neuroblastoma is a pediatric cancer responsible for approximately 15% of all childhood cancer deaths. Aberrant MYCN activation, as a result of genomic MYCN amplification, is a major driver of ...high-risk neuroblastoma, which has an overall survival rate of less than 50%, despite the best treatments currently available. Metabolic reprogramming is an integral part of the growth-promoting program driven by MYCN, which fuels cell growth and proliferation by increasing the uptake and catabolism of nutrients, biosynthesis of macromolecules, and production of energy. This reprogramming process also generates metabolic vulnerabilities that can be exploited for therapy. In this review, we present our current understanding of metabolic reprogramming in neuroblastoma, focusing on transcriptional regulation as a key mechanism in driving the reprogramming process. We also highlight some important areas that need to be explored for the successful development of metabolism-based therapy against high-risk neuroblastoma.
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