Hypoxia development in tumor is closely associated with its increased aggressiveness and strong resistance to therapy, leading to the poor prognosis in several cancer types. Clinically, invasive ...oxygen microelectrode and high dosage radiotherapy are often utilized to accurately detect and effectively fight hypoxia. Recently, however, there has been a surge of interdisciplinary research aiming at developing functional molecules and nanomaterials that can be used to noninvasively image and efficiently treat hypoxic tumors. In this review, we will provide an overview of the reports published to date on the imaging and therapy of hypoxic tumors. First, we will present the design concepts and engineering of various hypoxia-responsive probes that can be applied to image hypoxia noninvasively, in an order of fluorescent imaging, positron emission tomography, magnetic resonance imaging, and photoacoustic imaging. Then, we will summarize the up-to-date functional nanomaterials which can be used for the effective treatments of tumor hypoxia. The well-established chemical functions of these elaborately designed nanostructures will enable clinicians to adopt specific treatment concepts by overcoming or even utilizing hypoxia. Finally, challenges and future perspectives facing the researchers in the field will be discussed.
► We review the literature on FMEA published between 1992 and 2012. ► We use a classification framework to classify 75 papers by the approaches used. ► The most important shortcomings, the most ...popular approaches and their inadequacies are identified. ► We offer directions for future research to address the FMEA deficiencies.
Failure mode and effects analysis (FMEA) is a risk assessment tool that mitigates potential failures in systems, processes, designs or services and has been used in a wide range of industries. The conventional risk priority number (RPN) method has been criticized to have many deficiencies and various risk priority models have been proposed in the literature to enhance the performance of FMEA. However, there has been no literature review on this topic. In this study, we reviewed 75 FMEA papers published between 1992 and 2012 in the international journals and categorized them according to the approaches used to overcome the limitations of the conventional RPN method. The intention of this review is to address the following three questions: (i) Which shortcomings attract the most attention? (ii) Which approaches are the most popular? (iii) Is there any inadequacy of the approaches? The answers to these questions will give an indication of current trends in research and the best direction for future research in order to further address the known deficiencies associated with the traditional FMEA.
Crowdsourcing systems which utilize the human intelligence to solve complex tasks have gained considerable interest and adoption in recent years. However, the majority of existing crowdsourcing ...systems rely on central servers, which are subject to the weaknesses of traditional trust-based model, such as single point of failure. They are also vulnerable to distributed denial of service (DDoS) and Sybil attacks due to malicious users involvement. In addition, high service fees from the crowdsourcing platform may hinder the development of crowdsourcing. How to address these potential issues has both research and substantial value. In this paper, we conceptualize a blockchain-based decentralized framework for crowdsourcing named CrowdBC, in which a requester's task can be solved by a crowd of workers without relying on any third trusted institution, users’ privacy can be guaranteed and only low transaction fees are required. In particular, we introduce the architecture of our proposed framework, based on which we give a concrete scheme. We further implement a software prototype on Ethereum public test network with real-world dataset. Experiment results show the feasibility, usability, and scalability of our proposed crowdsourcing system.
Objective
This study was undertaken to uncover the pathophysiologic role of discoidin domain receptor 2 (DDR‐2), a putative fibrillar collagen receptor, in inflammation promotion and joint ...destruction in rheumatoid arthritis (RA).
Methods
In synovial tissue from patients with RA and from mice with collagen antibody–induced arthritis (CAIA) (using Ddr2−/− and DBA/1 mice), gene and protein expression levels of DDR‐2, interleukin‐15 (IL‐15), and Dkk‐1 were measured by quantitative reverse transcription–polymerase chain reaction, Western blotting, and immunohistochemistry. Gene knockdown of DDR2 in human RA fibroblast‐like synoviocytes (FLS) was conducted via small interfering RNA. Interaction between the long noncoding RNA H19 and microRNA 103a (miR‐103a) was assessed in RA FLS using RNA pulldown assays. Cellular localization of H19 was examined using fluorescence in situ hybridization assays. Chromatin immunoprecipitation and dual luciferase reporter assays were applied to verify H19 transcriptional and posttranscriptional regulation by miR‐103a.
Results
DDR2 messenger RNA (mRNA) expression was significantly associated with the levels of IL‐15 and Dkk‐1 mRNA in the synovial tissue of RA patients (r2 = 0.2022–0.3293, all P < 0.05; n = 33) and with the serum levels of IL‐15 and Dkk‐1 in mice with CAIA (P < 0.05). In human RA FLS, activated DDR‐2 induced the expression of H19 through c‐Myc. Moreover, H19 directly interacted with and promoted the degradation of miR‐103a.
Conclusion
These results indicate a novel role for activated DDR‐2 in RA FLS, showing that DDR‐2 is responsible for regulating the expression of IL‐15 and Dkk‐1 in RA FLS and is involved in the promotion of inflammation and joint destruction during pathophysiologic development of RA. Moreover, DDR‐2 inhibition, acting through the H19–miR‐103a axis, leads to reductions in the inflammatory reaction and severity of joint destruction in mice with CAIA, suggesting that inhibition of DDR‐2 may be a potential therapeutic strategy for RA.
The pathogenesis of diabetes is accompanied by increased levels of inflammatory factors, also known as “metabolic inflammation”, which runs through the whole process of the occurrence and development ...of the disease. Mitochondria, as the key site of glucose and lipid metabolism, is often accompanied by mitochondrial function damage in type 2 diabetes mellitus (T2DM). Damaged mitochondria release pro‐inflammatory factors through damage‐related molecular patterns that activate inflammation pathways and reactions to oxidative stress, further aggravate metabolic disorders, and form a vicious circle. Currently, the pathogenesis of diabetes is still unclear, and clinical treatment focuses primarily on symptomatic intervention of the internal environment of disorders of glucose and lipid metabolism with limited clinical efficacy. The proinflammatory effect of mitochondrial damage‐associated molecular pattern (mtDAMP) in T2DM provides a new research direction for exploring the pathogenesis and intervention targets of T2DM. Therefore, this review covers the most recent findings on the molecular mechanism and related signalling cascades of inflammation caused by mtDAMP in T2DM and discusses its pathogenic role of it in the pathological process of T2DM to search potential intervention targets.
The internal simulation market system can stimulate employee initiative, reduce costs and improve information processing efficiency. However, the complexity of the internal simulation market poses a ...challenge to computing resources. Efficient data processing techniques are crucial for internal simulation market systems. In this paper, the internal simulation market model and the value chain theory are first put forward. Second, the internal simulation market construction within power grid enterprises is proposed. Then we propose a data mining-based collaborative fusion and processing method for multi-value chain quantitative data in power grid internal simulation markets to conduct data processing, including data fusion, abnormal data elimination and data dimensionality reduction, thereby improving the accuracy of information processing and data sharing. Finally, we validate the superior performance of the proposed method through simulations.
Commercial advertisement (ad) dissemination has been proliferating on connected vehicles, allowing users to promote their products via vehicle-to-vehicle/-infrastructure communications. Despite the ...prospect of ad dissemination in vehicular networks, it faces challenges upon deployment especially on security and privacy. Particularly, vehicles may collude to defraud the advertiser to obtain rewards without disseminating ads, which may cause unfair "free-riding" issue in these activities. Furthermore, concerns on possible privacy leakage may discourage vehicles to participate in the process of ad dissemination. In addition, external DDoS attacks and internal single point of failure may also affect service availability. To address these issues, we explore the potential of blockchain technology to construct a fair and anonymous scheme for advertising in vehicular networks. We first present the overview of the blockchain-based ad dissemination framework. Then, under the framework, we design a concrete, fair and anonymous scheme. To ensure fairness, we utilize the Merkle hash tree together with smart contracts to achieve the "proof-of-ad-receiving" property (i.e., check whether a vehicle indeed receives an ad without deception or introducing significant storage cost) to mitigate the "free-riding" attack. On the other hand, any ad receiver who acquires a dissemination reward per ad more than once can be effectively detected and will be punished which is achieved by using smart contracts. Additionally, the proposed scheme can protect vehicles' privacy in terms of anonymity and conditional linkability based on zero-knowledge proof techniques. Lastly, extensive security analysis and implementations demonstrate the feasibility and efficiency of the scheme.
Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified that small-molecule ...erastin specifically inhibits transmembrane cystine-glutamate antiporter system x
, prevents extracellular cystine import and ultimately causes ferroptosis in certain cancer cells. In this study, we aimed to investigate the molecular mechanism underlying erastin-induced ferroptosis resistance in ovarian cancer cells.
We treated ovarian cancer cells with erastin and examined cell viability, cellular ROS and metabolites of the transsulfuration pathway. We also depleted cystathionine β-synthase (CBS) and NRF2 to investigate the CBS and NRF2 dependency in erastin-resistant cells.
We found that prolonged erastin treatment induced ferroptosis resistance. Upon exposure to erastin, cells gradually adapted to cystine deprivation via sustained activation of the reverse transsulfuration pathway, allowing the cells to bypass erastin insult. CBS, the biosynthetic enzyme for cysteine, was constantly upregulated and was critical for the resistance. Knockdown of CBS by RNAi in erastin-resistant cells caused ferroptotic cell death, while CBS overexpression conferred ferroptosis resistance. We determined that the antioxidant transcriptional factor, NRF2 was constitutively activated in erastin-resistant cells and NRF2 transcriptionally upregulated CBS. Genetically repression of NRF2 enhanced ferroptosis susceptibility.
Based on these results, we concluded that constitutive activation of NRF2/CBS signalling confers erastin-induced ferroptosis resistance. This study demonstrates a new mechanism underlying ferroptosis resistance, and has implications for the therapeutic response to erastin-induced ferroptosis.
Cascade radical cyclization constitutes an atom‐ and step‐economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox‐active metal catalysts has recently shown ...robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium‐based N‐heterocyclic carbene (NHC)‐boryl radical is capable of catalyzing cascade cyclization reactions in both intra‐ and intermolecular pathways, assembling 5,5 fused bicyclic and 6,6,6 fused tricyclic molecules, respectively. The catalytic reactions start with the chemo‐ and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal 3+2 or an intermolecular 2+2+2 cycloaddition process to construct bicyclo3.3.0octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a β‐elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.
Benzimidazolium‐based N‐heterocyclic carbene (NHC)‐boryl radical catalyzes cascade cyclization reactions to construct polycyclic compounds both intra‐ and intermolecularly. This catalytic cascade radical reaction allows rapid construction of complex molecular architectures through the formation of two or three bonds in a single operation, respectively.
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