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Liver cancer, a result of multifactorial interplay between heredity and the environment, is one of the leading causes of cancer-related death worldwide. Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer. Here, we reported that deficiency in PCDHB14, a member of the cadherin superfamily, participates in the progression of HCC. We found that PCDHB14 is inactivated by aberrant methylation of its promoter in HCC patients and that PCDHB14 functions as a tumor suppressor to promote cell cycle arrest, inhibit cell proliferation, and induce ferroptosis. Furthermore, PCDHB14 ablation dramatically enhanced diethylenenitrite-induced HCC development. Mechanistically, PCDHB14 is induced by p53, and increased PCDHB14 downregulates the expression of SLC7A11, which is critical for ferroptosis. This effect is mediated by accelerated p65 protein degradation resulting from PCDHB14 promoting E3 ubiquitin ligase RNF182-mediated ubiquitination of p65 to block p65 binding to the promoter of SLC7A11. This study reports the new discovery that PCDHB14 serves as a potential prognostic marker for HCC.

Ferroptosis is an iron-dependent oxidative, nonapoptotic form of regulated cell death caused by the destruction of redox homeostasis. Recent studies have uncovered complex cellular networks that regulate ferroptosis. GINS4 is a promoter of eukaryotic G 1 /S - cell cycle as a regulator of initiation and elongation of DNA replication, but little is known about its impact on ferroptosis. Here, we found that GINS4 was involved in the regulation of ferroptosis in lung adenocarcinoma (LUAD). CRISPR/Cas9-mediated GINS4 KO facilitated ferroptosis. Interestingly, depletion of GINS4 could effectively induce G1, G 1 /S, S, and G 2 /M cells to ferroptosis, especially for G2/M cells. Mechanistically, GINS4 suppressed p53 stability through activating Snail that antagonized the acetylation of p53, and p53 lysine residue 351 (K351 for human p53) was the key site for GINS4-suppressed p53-mediated ferroptosis. Together, our data demonstrate that GINS4 is a potential oncogene in LUAD that functions to destabilize p53 and then inhibits ferroptosis, providing a potential therapeutic target for LUAD.

In the treatment of most malignancies, radiotherapy plays a significant role. However, the resistance of cancer cells to ionizing radiation (IR) is the main reason for the failure of radiotherapy, which causes tumor recurrence and metastasis. In this study, we confirmed that GPR162, an orphan receptor in the G-protein-coupled receptor family, acted as a novel radiotherapy sensitizer by interacting with the stimulator of interferon genes (STING), which targeted DNA damage responses, activated IRF3, accelerated the activation of type I interferon system, promoted the expression of chemokines including CXCL10 and CXCL4, and inhibited the occurrence and development of tumors. Interestingly, the activation of STING by overexpression of GPR162 was independent of the classical pathway of cGAS. STING inhibitors could resist the antitumor effect of overexpression of GPR162 in IR-induced mouse models. In addition, most solid tumors showed low expression of GPR162. And the higher expression of GPR162 indicated a better prognosis in patients with lung adenocarcinoma, liver cancer, breast cancer, etc. In summary, these results suggested that GPR162 may serve as a potential sensitizer of radiotherapy by promoting radiotherapy-induced STING-IFN production and increasing the expression of chemokines including CXCL10 and CXCL4 in DNA damage response, providing an alternative strategy for improving cancer radiotherapy.

Malicious web domains represent a serious threat to online users’ privacy and security, causing monetary loss, theft of private information, and malware attacks, among others. In recent years, machine learning methods have been widely used as prediction models to identify malicious web domains. In this study, we propose a Fuzzy-Weighted Least Squares Support Vector Machine (FW-LS-SVM) model for malicious web domain identification. In our proposed model, a fuzzy-weighted operation is applied to each data sample considering the fact that different samples may have different importance. This fuzzy-weighted operation is also able to alleviate the influence of noise data and improve the model’s robustness by assigning weights to error constraints. For comparison purposes, three commonly used single machine learning classifiers and three widely used ensemble models are included in our experiments, in order to assess the performance of our proposed FW-LS-SVM and its ensemble version. Hyperlink indicators and uniform resource locator-based features are used to train the prediction models. Experimental results show that our proposed approach is highly effective in identifying malicious web domains, outperforming the well-established single and ensemble models being compared.

Fraudulent online sellers often collude with reviewers to garner fake reviews for their products. This act undermines the trust of buyers in product reviews, and potentially reduces the effectiveness of online markets. Being able to accurately detect fake reviews is, therefore, critical. In this study, we investigate several preprocessing and textual-based featuring methods along with machine learning classifiers, including single and ensemble models, to build a fake review detection system. Given the nature of product review data, where the number of fake reviews is far less than that of genuine reviews, we look into the results of each class in detail in addition to the overall results. We recognise from our preliminary analysis that, owing to imbalanced data, there is a high imbalance between the accuracies for different classes (e.g., 1.3% for the fake review class and 99.7% for the genuine review class), despite the overall accuracy looking promising (around 89.7%). We propose two dynamic random sampling techniques that are possible for textual-based featuring methods to solve this class imbalance problem. Our results indicate that both sampling techniques can improve the accuracy of the fake review class—for balanced datasets, the accuracies can be improved to a maximum of 84.5% and 75.6% for random under and over-sampling, respectively. However, the accuracies for genuine reviews decrease to 75% and 58.8% for random under and over-sampling, respectively. We also discover that, for smaller datasets, the Adaptive Boosting ensemble model outperforms other single classifiers; whereas, for larger datasets, the performance improvement from ensemble models is insignificant compared to the best results obtained by single classifiers.

Posttranslational modifications (PTMs) of proteins, including chromatin modifiers, play crucial roles in the dynamic alteration of various protein properties and functions including stem-cell properties. However, the roles of Lymphoid-specific helicase (LSH), a DNA methylation modifier, in modulating stem-like properties in cancer are still not clearly clarified. Therefore, exploring PTMs modulation of LSH activity will be of great significance to further understand the function and activity of LSH. Here, we demonstrate that LSH is capable to undergo PTMs, including methylation and phosphorylation. The arginine methyltransferase PRMT5 can methylate LSH at R309 residue, meanwhile, LSH could as well be phosphorylated by MAPK1 kinase at S503 residue. We further show that the accumulation of phosphorylation of LSH at S503 site exhibits downregulation of LSH methylation at R309 residue, which eventually promoting stem-like properties in lung cancer. Whereas, phosphorylation-deficient LSH S503A mutant promotes the accumulation of LSH methylation at R309 residue and attenuates stem-like properties, indicating the critical roles of LSH PTMs in modulating stem-like properties. Thus, our study highlights the importance of the crosstalk between LSH PTMs in determining its activity and function in lung cancer stem-cell maintenance.

BackgroundThe stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase MDM2. The chromatin modifier lymphoid-specific helicase (LSH) is essential for DNA methylation and cancer progression as a transcriptional repressor. The potential interplay between chromatin modifiers and transcription factors remains largely unknown.ResultsHere, we present data suggesting that LSH regulates p53in cisthrough two pathways: prevention proteasomal degradation through its deubiquitination, which is achieved by reducing the lysine 11-linked, lysine 48-linked polyubiquitin chains (K11 and K48) on p53; and revival of the transcriptional activity of p53 by forming a complex with PKM2 (pyruvate kinase 2). Furthermore, we confirmed that the LSH–PKM2 interaction occurred at the intersubunit interface region of the PKM2 C-terminal region and the coiled-coil domains (CC) and ATP-binding domains of LSH, and this interaction regulated p53-mediated transactivationin cisin lipid metabolism, especially lipid catabolism.ConclusionThese findings suggest that LSH is a novel regulator of p53 through the proteasomal pathway, thereby providing an alternative mechanism of p53 involvement in lipid metabolism in cancer.

Ferroptosis is primarily caused by intracellular iron catalytic activity and lipid peroxidation. The potential interplay between ferroptosis and apoptosis remains poorly understood. Here, we show that the expression of a nuclear long non-coding RNA (lncRNA), LINC00618, is reduced in human leukemia and strongly increased by vincristine (VCR) treatment. Furthermore, LINC00618 promotes apoptosis by increasing the levels of BCL2-Associated X (BAX) and cleavage of caspase-3. LINC00618 also accelerates ferroptosis by increasing the levels of lipid reactive oxygen species (ROS) and iron, two surrogate markers of ferroptosis, and decreasing the expression of solute carrier family 7 member 11 (SLC7A11). Interestingly, VCR-induced ferroptosis and apoptosis are promoted by LINC00618, and LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis. LINC00618 attenuates the expression of lymphoid-specific helicase (LSH), and LSH enhances the transcription of SLC7A11 after the recruitment to the promoter regions of SLC7A11, further inhibiting ferroptosis. Knowledge of these mechanisms demonstrates that lncRNAs related to ferroptosis and apoptosis are critical to leukemogenesis and chemotherapy., Graphical Abstract, We identified a previously unknown function of a specific lncRNA, LINC00618, which we show promotes apoptosis and ferroptosis by epigenetic mechanisms, thereby linking apoptosis and ferroptosis. In cooperation with vincristine, LINC00618 may represent a promising target for leukemia therapy.

The visible light and Eosin B-catalyzed direct sulfenylation of sp2 C–H bonds with sulfinic acids through a photoredox process has been demonstrated at room temperature under transition metal-free conditions for the first time. Diverse heteroaryl sulfides were obtained in moderate to good yields. This is the first example of the sulfenylation of sp2 C–H bonds using arylsulfinic acids as odorless sulfur reagents under visible light-induced conditions. More interestingly, the reductive products could be obtained under visible light-induced oxidative conditions. This protocol demonstrates a new model for C–S bond formation, which serves as a novel approach toward the synthesis of heteroaryl sulfides.

Cancer stem cells (CSCs) exhibit highly aggressive and metastatic features and resistance to chemotherapy and radiotherapy. Aryl hydrocarbon receptor (AhR) expression varies among non-small cell lung cancers (NSCLCs), and the mechanisms that support abnormal AhR expression in CSCs remain elusive. Here, we identified ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, as a bona fide deubiquitylase of the AhR in NSCLC. UCHL3 was shown to interact with, deubiquitylate, and stabilize AhR in a manner dependent on its deubiquitylation activity. Moreover, we showed that UCHL3 promotes the stem-like characteristics and potent tumorigenic capacity of NSCLC cells. UCHL3 increased AhR stability and the binding of AhR to the promoter regions of the “stemness” genes ATP-binding cassette subfamily G member 2 (ABCG2), KLF4, and c-Myc. Depletion of UCHL3 markedly downregulated the “stemness” genes ABCG2, KLF4, and c-Myc, leading to the loss of self-renewal and tumorigenesis in NSCLCs. Furthermore, the UCHL3 inhibitor TCID induced AhR degradation and exhibited significantly attenuated efficacy in NSCLC cells with stem cell-like properties. Additionally, UCHL3 was shown to indicate poor prognosis in patients with lung adenocarcinoma. In general, our results reveal that the UCHL3 deubiquitylase is pivotal for AhR protein stability and a potential target for NSCLC-targeted therapy.

Online learning is the main implementation of distance education and adult education. A pertinence and timely online teaching intervention could determine the persistence and quality of online learning. However, the existing intervention mechanism is mainly determined by teachers and focus on offline intervention which cannot be compatible with the online learning system well. In this paper we propose a model of online intervention which based on the learning behavior features. After interveners selection, the adaptive intervention measures could be generated in the intervention strategy library and executed automated. We emphasis on the construction of the intervention strategy library which combines with historical intervention experiences in strategy forming and representation. Besides this, we take a decision-making algorithm to classify the strategies and make adaptive and accurate strategies to different kinds of interveners. Adaptive online intervention strategy library is the premise and basis of automated online intervention, which can reduce the gap between the large number of online learners and the limited number of teachers. It also can improve the awareness of learners and teachers, thus gain the better effect on online learning ultimately.

Additional file 1. Additional figures and tables.

The financial impact of positive reviews has prompted some fraudulent sellers to generate fake product reviews for either promoting their products or discrediting competing products. Many e-commerce portals have implemented measures to detect such fake reviews, and these measures require excellent detectors to be effective. In this work, we propose 133 unique features from the combination of content and behaviour-based features to detect fake reviews using machine learning classifiers. Preliminary results show that these features can provide good results for all datasets tested. Detailed analysis of the results, however, reveals the existence of class imbalance issues for two of the bigger datasets - there is a high imbalance between the accuracies of different classes (e.g., 7.73% for the fake class and 99.3% for the genuine class using a Multilayer Perceptron classifier). We therefore introduce two sampling methods that can improve the accuracy of the fake review class on balanced datasets. The accuracies can be improved to a maximum of 89% for both random under and over-sampling on Convolutional Neural Networks. Additionally, we propose a parallel cross-validation method that can speed up the validation process in a parallel environment.

Intelligent vehicle is a complex system includes at least three parts of information, the vehicles themselves, driving surroundings and drivers which has different formats, different properties, and different collection methods. These differences bring difficulties to communication and knowledge sharing among vehicles and drivers, and also create barriers to vehicle safety research. To address these problems, we propose a novel intelligent vehicle knowledge framework to contain all of related information of intelligent vehicle with clear hierarchical architecture and unified SOEKS structure. Based on the framework the anomaly detection approach using past driving experience and the neural knowledge DNA (NK-DNA) is proposed. And then we introduce the Long Short-Term Memory (LSTM) neural network into the Networks of NK-DNA, to detect abnormal CAN packages. We examine our approach with real car data and simulated attack data. The simulation results shown our framework and detection method can share easily and found anomalies of CAN bus flow.

RNA polymerase II (Pol II) binds to promoter-proximal regions of inducible target genes that are controlled and not transcribed by several negative elongation factors, which is known as Pol II stalling. The occurrence of stalling is due to particular modification signatures and structural conformations of chromatin that affect Pol II elongation. The existence and physiological importance of Pol II stalling implies that there is a dynamic balance in chromatin regulation prior to endogenous or exogenous stimulation. In this review, we discuss the effects of ATP-dependent chromatin remodeling complexes and histone modification via transcriptional machinery Pol II C-terminal domain phosphorylated at serine 5 (S5P RNAPII) initiation and S2P RNAPII elongation on the expression or silence of specific genes after the production of activated or differentiated signals or cytokines. The response occurs immediately during immune cell development and function, and it also includes the generation of immunological memories. This summary suggests that the host immune response genes involve a novel mechanism of selectively regulatory chromatin remodeling, a fundamental and crucial aspect of epigenetic regulation.

Merrifield resin supported ionic liquids/L-proline as effcient and recyclable catalyst systems for asymmetric aldol reaction have been developed. L -Proline with Merrifield resin supported ionic liquids can catalyze asymmetric aldol reaction smoothly and generate the corresponding products in good to excellent yields and ee values. In addition, the supported catalyst systems can be recycled simply by filtration and reused for five times without significant decrease in activity.

The immobilization of palladium on silica gel in Heck reaction has been developed. Iodobenzenes, bromobenzenes and activated chlorobenzenes were coupled with olefins (Heck reaction) smoothly to afford the corresponding cross-coupling products in good to excellent yields under phosphine- and amine-free reaction conditions in the presence of silica gel supported palladium, Silica-Ap-Pd cat. as catalyst, potassium carbonate as base and DMF as solvent. Furthermore, the silica-supported palladium catalyst 3 could be recovered and recycled by a simple filtration of the reaction solution and used for 6 consecutive trials without significant loss of its catalytic activity.

A novel silica-anchored proline-copper(I) organic-inorganic hybrid material as an efficient catalyst for the Sonoga-shira reaction was developed. Terminal alkynes were reacted with aryl iodides and bromides smoothly in the presence of a proline-functionalized silica-anchored copper(I) catalyst in DMF to afford the corresponding cross-coupling products in good to excellent yields. Furthermore, silica-anchored proline-copper(I) catalyst was recovered and recycled by a simple filtration of the reaction solution and reused for six times without significant decreases in activity.

Background The hemodynamic balloon model describes the change in coupling from underlying neural activity to observed blood oxygen level dependent (BOLD) response. It plays an increasing important role in brain research using magnetic resonance imaging (MRI) techniques. However, changes in the BOLD signal are sensitive to the resting blood volume fraction (i.e., \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0) associated with the regional vasculature. In previous studies the value was arbitrarily set to a physiologically plausible value to circumvent the ill-posedness of the inverse problem. These approaches fail to explore actual \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 value and could yield inaccurate model estimation. Methods The present study represents the first empiric attempt to derive the actual \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 from data obtained using cerebral blood volume imaging, with the aim of augmenting the existing estimation schemes. Bimanual finger tapping experiments were performed to determine how \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 influences the model estimation of BOLD signals within a single-region and multiple-regions (i.e., dynamic causal modeling). In order to show the significance of applying the true \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0, we have presented the different results obtained when using the real \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 and assumed \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 in terms of single-region model estimation and dynamic causal modeling. Results The results show that \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 significantly influences the estimation results within a single-region and multiple-regions. Using the actual \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 might yield more realistic and physiologically meaningful model estimation results. Conclusion Incorporating regional venous information in the analysis of the hemodynamic model can provide more reliable and accurate parameter estimations and model predictions, and improve the inference about brain connectivity based on fMRI data.

The prediction of emergency event occupies an important position in the network public opinion. In this paper, an improved algorithm for emergency event based on statistics of word frequency is presented, which takes BBS, blog, news sites with commentary function as investigated subjects. The experiment shows it can provide the useful ideas and exploration for analysis of public opinion and early warning of mass group incidents.

The immobilization of palladium on silica gel in Heck reaction has been developed. Iodobenzenes, bromobenzenes and activated chlorobenzenes were coupled with olefins (Heck reaction) smoothly to afford the corresponding cross-coupling products in good to excellent yields under phosphine- and amine-free reaction conditions in the presence of silica gel supported palladium, Silica-Ap-Pd cat. as catalyst, potassium carbonate as base and DMF as solvent. Furthermore, the silica-supported palladium catalyst 3 could be recovered and recycled by a simple filtration of the reaction solution and used for 6 consecutive trials without significant loss of its catalytic activity.