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Abstract Despite recent advances in systemic therapy for hepatocellular carcinoma (HCC), the prognosis of hepatitis B virus (HBV)-induced HCC patients remains poor. By screening a sgRNA library targeting human deubiquitinases, we find that ubiquitin-specific peptidase 26 (USP26) deficiency impairs HBV-positive HCC cell proliferation. Genetically engineered murine models with Usp26 knockout confirm that Usp26 drives HCC tumorigenesis. Mechanistically, we find that the HBV-encoded protein HBx binds to the promoter and induces the production of USP26, which is an X-linked gene exclusively expressed in the testis. HBx consequently promotes the association of USP26 with SIRT1 to synergistically stabilize SIRT1 by deubiquitination, which promotes cell proliferation and impedes cell apoptosis to accelerate HCC tumorigenesis. In patients with HBV-positive HCC, USP26 is robustly induced, and its levels correlate with SIRT1 levels and poor prognosis. Collectively, our study highlights a causative link between HBV infection, deubiquitinase induction and development of HCC, identifying a druggable target, USP26.

Abstract Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response. Multiple organs can develop fibrosis, including the liver, kidney, heart, and lung. Fibrosis such as liver cirrhosis, idiopathic pulmonary fibrosis, and cystic fibrosis caused substantial disease burden. Persistent abnormal activation of myofibroblasts mediated by various signals, such as transforming growth factor, platelet-derived growth factor, and fibroblast growh factor, has been recongized as a major event in the occurrence and progression of fibrosis. Although the mechanisms driving organ-specific fibrosis have not been fully elucidated, drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials. In this review, we briefly introduce the aetiology and epidemiology of several fibrosis diseases, including liver fibrosis, kidney fibrosis, cardiac fibrosis, and pulmonary fibrosis. Then, we summarise the abnormal cells (epithelial cells, endothelial cells, immune cells, and fibroblasts) and their interactions in fibrosis. In addition, we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation, extracellular matrix cross-linking, metabolism, and inflammation in fibrosis. Finally, we discuss the anti-fibrotic drugs based on their targets and clinical trials. This review provides reference for further research on fibrosis mechanism, drug development, and clinical trials.

With the rapid development of the social economy, the problem of environmental pollution has been widely concerned. The existing environmental monitoring system adopts a hierarchical centralized management structure, which has some problems, such as data silos and the risk of data falsification. Thus, this paper proposes an environmental monitoring data security model based on the blockchain, which uses the blockchain distributed storage mode to realize the secure sharing of monitoring data and curb the behavior of data forgery. A practical Byzantine fault tolerant mechanism based on credit grouping supervision is adopted to reduce the computation and communication overhead caused by data consensus. Through the cloud chain fusion technology, the encrypted monitoring data is stored on the cloud storage server, and the monitoring data credentials are stored on the blockchain to reduce the storage pressure. And AES(Advanced Encryption Standard) combined with the RSA (Rivest-Shamir-Adleman) encryption algorithm to ensure the security of data transmission and storage. Security analysis and experiments demonstrate that our proposed scheme achieves authenticity, integrity, and security for monitored data. In addition, it effectively reduces the computation, communication, and storage overhead of the block nodes.

Abstract Failures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.

To realize the unmanned automation of the full mechanized caving, the bottleneck problem of coal-gangue interface detection in top coal caving must be solved first. Targeting coal-gangue interface detection on fully mechanized mining face, an alternative scheme to detect coal-gangue interface based on vibration signal analysis of the tail boom support of the longwall mining machine. It is found that when coal and gangue fall, the characteristics of vibration signals generated by coal and gangue shocking the tail boom are different. First, EEMD algorithm is used to decompose the original vibration signals into intrinsic mode functions (IMFs). Each IMF represents the distribution of energy from high to low. EEMD algorithm can restrain the mode mixing phenomenon caused by empirical mode decomposition (EMD). The energy of vibration signals will change in different frequency bands when the top-coal fall down or the coal-gangue fall down. According the information theory, we define EEMD energy entropy to describe this change. Experimental results show that EEMD energy entropy of top-coal caving is always greater than that of coal-gangue caving. Thus, the Mahalanobis distance metric method based on EEMD energy entropy is proposed for coal-gangue interface detection. The results show the proposed method can be used as a robust empirical method for coal-gangue interface detection.

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.

The influenza A virus is highly contagious and often causes global pandemics. The prevalence of strains of the influenza A virus that are resistant to approved drugs is a huge challenge for the current clinical treatment of influenza A. RNA polymerase is a pivotal enzyme in the replication of the influenza A virus, and it is a promising target for anti-influenza A therapies. In this paper, we report a novel and potent anti-influenza-A-virus inhibitor, ZSP1273, targeting the influenza A virus RNA polymerase, especially for multidrug-resistant strains. The inhibitory activity of ZSP1273 on RNA polymerase activity was 0.562 ± 0.116 nM (IC50 value), which was better than that of the clinical candidate compound VX-787 with the same target. In vitro, the EC50 values of ZSP1273 on normal influenza A virus strains (i.e., H1N1 and H3N2) varied from 0.01 nM to 0.063 nM, which were better than those of the licensed drug oseltamivir. Moreover, oseltamivir-resistant strains, baloxavir-resistant strains, and highly pathogenic avian influenza strains were also sensitive to ZSP1273. In vivo, ZSP1273 effectively reduced influenza A virus titers in a dose-dependent manner in a murine model and maintained a high survival rate in mice. In addition, the inhibitory activity of ZSP1273 on influenza A virus infection was also observed in a ferret model. Pharmacokinetic studies showed the favorable pharmacokinetic characteristics of ZSP1273 in mice, rats, and beagle dogs after single-dose and continuous multiple-dose administration. In conclusion, ZSP1273 is a highly effective anti-influenza A virus replication inhibitor, especially against multidrug-resistant strains. ZSP1273 is currently being studied in phase III clinical trials.

Nicotinamide mononucleotide (NMN) is a natural antioxidant approved as a nutritional supplement and food ingredient, but its protective role in silicosis characterized by oxidative damage remains unknown. In this study, we generated a silicosis model by intratracheal instillation of silica, and then performed histopathological, biochemical, and transcriptomic analysis to evaluate the role of NMN in silicosis. We found that NMN mitigated lung damage at 7 and 28 days, manifested as a decreasing coefficient of lung weight and histological changes, and alleviated oxidative damage by reducing levels of reactive oxygen species and increasing glutathione. Meanwhile, NMN treatment also reduced the recruitment of inflammatory cells and inflammatory infiltration in lung tissue. Transcriptomic analysis showed that NMN treatment mainly regulated immune response and glutathione metabolism pathways. Additionally, NMN upregulated the expression of antioxidant genes Gstm1, Gstm2, and Mgst1 by promoting the expression and nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Gene interaction analysis showed that Nrf2 interacted with Gstm1 and Mgst1 through Gtsm2. Promisingly, oxidative damage mediated by these genes occurred mainly in fibroblasts. In summary, NMN alleviates silica-induced oxidative stress and lung injury by regulating the endogenous glutathione metabolism pathways. This study reveals that NMN supplementation might be a promising strategy for mitigating oxidative stress and inflammation in silicosis.

Assessing the quality of agricultural products is an essential step to reduce food waste. The problems of overly complex models, difficult to deploy to mobile devices, and slow real-time detection in the application of deep learning in agricultural product quality assessment requiring solutions. This paper proposes a lightweight method based on ShuffleNetV2 to identify phenotypic diseases in corn seeds and conduct experiments on a corn seed dataset. Firstly, Cycle-Consistent Adversarial Networks are used to solve the problem of unbalanced datasets, while the Efficient Channel Attention module is added to enhance network performance. After this, a 7×7 depthwise convolution is used to increase the effective receptive field of the network. The repetitions of basic units in ShuffleNetV2 are also reduced to lighten the network structure. Finally, experimental results indicate that the number of model parameters are 0.913 M, the computational volume is 44.75 MFLOPs and 88.5 MMAdd, and the recognition accuracy is 96.28%. The inference speed of about 9.71 ms for each image was tested on a mobile portable laptop with only a single CPU, which provides a reference for mobile deployment.

Peroxisome proliferator-activated receptor α/δ (PPAR α/δ), regulating glucolipid metabolism and immune inflammation, has been identified as an effective therapeutic target in non-alcoholic steatohepatitis (NASH). Dual PPAR α/δ agonist, such as GFT505 (also known as elafibranor), demonstrated potential therapeutic effect for NASH in clinical trials. To profile the regulatory network of PPAR α/δ agonist in NASH, the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) induced NASH model was used to test the pharmacodynamics and transcriptome regulation of GFT505 in this study. The results showed that GFT505 ameliorated hepatic steatosis, inflammation and fibrosis in CDAHFD mice model. RNA-sequencing yielded 3995 up-regulated and 3576 down-regulated genes with GFT505 treatment. And the most significant differentialy expressed genes involved in glucolipid metabolism (Pparα, Acox1, Cpt1b, Fabp4, Ehhadh, Fabp3), inflammation (Ccl6, Ccl9, Cxcl14) and fibrosis (Timp1, Lamc3, Timp2, Col3a1, Col1a2, Col1a1, Hapln4, Timp3, Pik3r5, Pdgfα, Pdgfβ, Tgfβ1, Tgfβ2) were confirmed by RT-qPCR. The down-regulated genes were enriched in cytokine-cytokine receptor interaction pathway and ECM-receptor interaction pathway, while the up-regulated genes were enriched in PPAR signaling pathway and fatty acid degradation pathway. This study provides clues and basis for further understanding on the mechanism of PPAR α/δ agonist on NASH.

Background Non-alcoholic steatohepatitis (NASH) is a progressive liver disease characterized by hepatic steatosis, lobular inflammation and fibrosis. Acetyl-CoA carboxylase (ACC) isoform 1 and 2 involved in de novo lipogenesis (DNL) and fatty acid oxidation have been identified as a therapeutic target in NASH. GS-0976, the inhibitor of ACC1 and ACC2, has achieved favorable therapeutic effects in clinical trials with NASH. The purpose of this study was to explore the transcriptional alterations regulated by GS-0976 in NASH. Methods C57BL/6 mice were fed on a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) or normal diet for 12 weeks. Mice were treated with or without GS-0976 (3 mg/kg per day) in the last 8 weeks. Oil Red O, Haematoxylin-eosin (H & E), and Sirius Red were used to evaluate hepatic steatosis, inflammation and fibrosis. The comparative RNA-sequencing was conducted to analyse the hepatic gene expression profiles in mice. Reverse transcription–polymerase chain reaction analysis was performed to validate the differential expression of representative genes. Results GS-0976 attenuated the steatosis, inflammation, and fibrosis of NASH in CDAHFD mouse model. High-throughput sequencing and differential gene expression analysis showed that there were 516 up-regulated genes and 525 down-regulated genes after GS-0976 treatment. Genes involved in the metabolic process, extracellular matrix formation, immune response, and angiogenesis were significantly enriched. The “Metabolic pathways” and “ECM-receptor interaction” pathways were the most significantly enriched KEGG pathways in the up-regulated and down-regulated differentially expressed genes (DEGs), respectively. Conclusions Transcriptome analysis showed that GS-0976 could regulate the expression of genes related to metabolism, inflammation and fibrosis in NASH. The global transcriptomic changes in gene expression promote the further understanding for the inhibition mechanisms of GS-0976 in NASH.

The dependency of cancer cells on iron increases their susceptibility to ferroptosis, thus providing new opportunities for patients with treatment-resistant tumors. However, we show that lipid peroxidation, a hallmark of ferroptosis, was found in various areas of patient samples, indicating the potential resistance of ferroptosis. Using whole deubiquitinases (DUBs) sgRNA screening, we found that loss of ZRANB1 confers cancer cell resistance to ferroptosis. Intriguingly, functional studies revealed that ZRANB1 ubiquitinates and represses SLC7A11 expression as an E3 ubiquitin ligase and that ZRANB1 inhibits glutathione (GSH) synthesis through SLC7A11 degradation, leading to elevated lipid peroxidation and ferroptosis. Deletion of the region (residues 463–584) abolishes the E3 activity of ZRANB1. Moreover, we show that ZRANB1 has lower expression in tumors, which is positively correlated with lipid peroxidation. Collectively, our results demonstrate the role of ZRANB1 in ferroptosis resistance and unveil mechanisms involving modulation of E3 ligase activity through an unconventional catalytic domain. [ABSTRACT FROM AUTHOR]