Tumour cell-expressed PD-L1 reprograms lipid metabolism via EGFR/ITGB4/SREBP1c signalling in liver cancer.

Background & Aims: The programmed death-ligand 1 (PD-L1) is a major co-inhibitory checkpoint factor that controls T-cell activities in tumours. PD-L1 is expressed on immune cells and tumour cells. Whether tumour cell-expressed PD-L1 affects tumour cells in an immune cell-independent fashion remains largely elusive. In this study, we investigated the significance of tumour cell-expressed PD-L1 with a focus on downstream signals and changes in lipid metabolism. Methods: Immune-independent functions of PD-L1 in tumour growth were investigated in vitro and in immuno-deficient mice in vivo. The global influence of PD-L1 in targeted/untargeted lipidomic metabolites was studied by comprehensive mass spectrometry-based metabolomic analysis in liver cancer. Effects on lipid metabolism were confirmed by triglyceride and cholesterol assays as well as by Oil Red O staining in liver, pancreatic, breast, and oesophageal squamous cancer. Underlying mechanisms were investigated by real-time quantitative PCR, Western blot analysis, co-immunoprecipitation, pull-down assays, immunofluorescence staining, and RNA sequencing. Results: PD-L1 enhanced the accumulation of triglycerides, cholesterol, and lipid droplets in tumours. PD-L1 influenced targeted/untargeted lipidomic metabolites in hepatoma, including lipid metabolism, glucose metabolism, amino acid metabolism, nucleotide metabolism, and energy metabolism, suggesting that PD-L1 globally modulates the metabolic reprogramming of tumours. Mechanistically, PD-L1 activated epidermal growth factor receptor (EGFR) and/or integrin ß4 (ITGB4) by forming a complex of PD-L1/EGFR/ITGB4 in the cell membrane, prior to activating PI3K/mTOR/SREBP1c signalling, leading to reprogramming of lipid metabolism in tumours. Functionally, PD-L1-mediated lipid metabolism reprogramming supported the tumour growth in vitro and in vivo through EGFR and/or ITGB4 in an immune cell-independent manner. Conclusions: Our findings on lipogenesis and EGFR activation by tumour cell-expressed PD-L1 suggest that, in addition to its immunostimulatory effects, anti-PD-L1 may restrict lipid metabolism and EGFR/ITGB4 signalling in liver cancer therapy. Impact and implications: In this study, we present evidence that PD-L1 drives the reprogramming of lipid metabolism in tumours. PD-L1 forms a complex with epidermal growth factor receptor (EGFR) and ITGB4, activating the PI3K/Akt/mTOR/SREBP1c signalling pathway and thereby contributing to lipid metabolism in cancer progression. Our findings offer novel insights into the mechanisms by which PD-L1 initiates the reprogramming of lipid metabolism in tumours. From a clinical perspective, the anti-PD-L1 antibody may alleviate resistance to the anti-EGFR antibody cetuximab and inhibit the reprogramming of lipid metabolism in tumours.

Hepatitis B virus RNAs co-opt ELAVL1 for stabilization and CRM1-dependent nuclear export.

Hepatitis B virus (HBV) chronically infects 296 million people worldwide, posing a major global health threat. Export of HBV RNAs from the nucleus to the cytoplasm is indispensable for viral protein translation and genome replication, however the mechanisms regulating this critical process remain largely elusive. Here, we identify a key host factor embryonic lethal, abnormal vision, Drosophila-like 1 (ELAVL1) that binds HBV RNAs and controls their nuclear export. Using an unbiased quantitative proteomics screen, we demonstrate direct binding of ELAVL1 to the HBV pregenomic RNA (pgRNA). ELAVL1 knockdown inhibits HBV RNAs posttranscriptional regulation and suppresses viral replication. Further mechanistic studies reveal ELAVL1 recruits the nuclear export receptor CRM1 through ANP32A and ANP32B to transport HBV RNAs to the cytoplasm via specific AU-rich elements, which can be targeted by a compound CMLD-2. Moreover, ELAVL1 protects HBV RNAs from DIS3+RRP6+ RNA exosome mediated nuclear RNA degradation. Notably, we find HBV core protein is dispensable for HBV RNA-CRM1 interaction and nuclear export. Our results unveil ELAVL1 as a crucial host factor that regulates HBV RNAs stability and trafficking. By orchestrating viral RNA nuclear export, ELAVL1 is indispensable for the HBV life cycle. Our study highlights a virus-host interaction that may be exploited as a new therapeutic target against chronic hepatitis B.

Fabrication of self-assembled micelles based on amphiphilic oxidized sodium alginate grafted oleoamine derivatives via Schiff base reduction amination reaction for delivery of hydrophobic food active ingredients.

The application of hydrophobic ß-carotene in the food industry are limited due to its susceptibility to light, high temperature, pH value, and other factors, leading to poor stability and low bioavailability. To address this problem, we adopt a more green and environmentally friendly reducing agent, 2-methylpyridine borane complex (pic-BH3), instead of traditional sodium borohydride, to achieve the simple green and efficient synthesis of amphiphilic oxidized sodium alginate grafted oleoamine derivatives (OSAOLA) through the reduction amination reaction of Schiff base. The resultant OSAOLA with the degree of substitution (DS) of 7.2 %, 23.6 %, and 38.8 % were synthesized, and their CMC values ranged from 0.0095 to 0.062 mg/mL, indicating excellent self-assembly capability in aqueous solution. Meanwhile, OSAOLA showed no obvious cytotoxicity to RAW 264.7 cells, thus revealing good biocompatibility. Furthermore, ß-carotene, as the hydrophobic active ingredients in foods was successfully encapsulated in the OSAOLA micelles by ultrasonic-dialysis method. The prepared drug-loaded OSAOLA micelles could maintain good stability when stored at room temperature for 7 d. Additionally, they were able to continuously release ß-carotene and exert long-term effects in pH 7.4 PBS at 37 °C, effectively improving the bioavailability of ß-carotene, which exhibited tremendous application potential in functional food and biomedical fields.

Construction and Evaluation of Alginate Dialdehyde Grafted RGD Derivatives/Polyvinyl Alcohol/Cellulose Nanocrystals IPN Composite Hydrogels.

To enhance the mechanical strength and cell adhesion of alginate hydrogel, making it satisfy the requirements of an ideal tissue engineering scaffold, the grafting of Arg-Gly-Asp (RGD) polypeptide sequence onto the alginate molecular chain was conducted by oxidation of sodium periodate and subsequent reduction amination of 2-methylpyridine borane complex (2-PBC) to synthesize alginate dialdehyde grafted RGD derivatives (ADA-RGD) with good cellular affinity. The interpenetrating network (IPN) composite hydrogels of alginate/polyvinyl alcohol/cellulose nanocrystals (ALG/PVA/CNCs) were fabricated through a physical mixture of ion cross-linking of sodium alginate (SA) with hydroxyapatite/D-glucono-δ-lactone (HAP/GDL), and physical cross-linking of polyvinyl alcohol (PVA) by a freezing/thawing method, using cellulose nanocrystals (CNCs) as the reinforcement agent. The effects of the addition of CNCs and different contents of PVA on the morphology, thermal stability, mechanical properties, swelling, biodegradability, and cell compatibility of the IPN composite hydrogels were investigated, and the effect of RGD grafting on the biological properties of the IPN composite hydrogels was also studied. The resultant IPN ALG/PVA/CNCs composite hydrogels exhibited good pore structure and regular 3D morphology, whose pore size and porosity could be regulated by adjusting PVA content and the addition of CNCs. By increasing the PVA content, the number of physical cross-linking points in PVA increased, resulting in greater stress support for the IPN composite hydrogels of ALG/PVA/CNCs and consequently improving their mechanical characteristics. The creation of the IPN ALG/PVA/CNCs composite hydrogels' physical cross-linking network through intramolecular or intermolecular hydrogen bonding led to improved thermal resistance and reduced swelling and biodegradation rate. Conversely, the ADA-RGD/PVA/CNCs IPN composite hydrogels exhibited a quicker degradation rate, attributed to the elimination of ADA-RGD by alkali. The results of the in vitro cytocompatibility showed that ALG/0.5PVA/0.3%CNCs and ADA-RGD/PVA/0.3%CNCs composite hydrogels showed better proliferative activity in comparison with other composite hydrogels, while ALG/PVA/0.3%CNCs and ADA-RGD/PVA/0.3%CNCs composite hydrogels displayed obvious proliferation effects, indicating that PVA, CNCs, and ADA-RGD with good biocompatibility were conducive to cell proliferation and differentiation for the IPN composite hydrogels.

Antibiotic-induced gut bacteria depletion has no effect on HBV replication in HBV immune tolerance mouse model.

Commensal microbiota is closely related to Hepatitis B virus (HBV) infection. Gut bacteria maturation accelerates HBV immune clearance in hydrodynamic injection (HDI) HBV mouse model. However, the effect of gut bacteria on HBV replication in recombinant adeno-associated virus (AAV)-HBV mouse model with immune tolerance remains obscure. We aim to investigate its role on HBV replication in AAV-HBV mouse model. C57BL/6 mice were administrated with broad-spectrum antibiotic mixtures (ABX) to deplete gut bacteria and intravenously injected with AAV-HBV to establish persistent HBV replication. Gut microbiota community was analyzed by fecal qPCR assay and 16S ribosomal RNA (rRNA) gene sequencing. HBV replication markers in blood and liver were determined by ELISA, qPCR assay and Western blot at indicated time points. Immune response in AAV-HBV mouse model was activated through HDI of HBV plasmid or poly(I:C) and then detected by quantifying the percentage of IFN-γ+/CD8+ T cells in the spleen via flow cytometry as well as the splenic IFN-γ mRNA level via qPCR assay. We found that antibiotic exposure remarkably decreased gut bacteria abundance and diversity. Antibiotic treatment failed to alter the levels of serological HBV antigens, intrahepatic HBV RNA transcripts and HBc protein in AAV-HBV mouse model, but contributed to HBsAg increase after breaking of immune tolerance. Overall, our data uncovered that antibiotic-induced gut bacteria depletion has no effect on HBV replication in immune tolerant AAV-HBV mouse model, providing new thoughts for elucidating the correlation between gut bacteria dysbiosis by antibiotic abuse and clinical chronic HBV infection.

Hepatitis B virus hijacks TSG101 to facilitate egress via multiple vesicle bodies.

Hepatitis B virus (HBV) chronically infects 296 million individuals and there is no cure. As an important step of viral life cycle, the mechanisms of HBV egress remain poorly elucidated. With proteomic approach to identify capsid protein (HBc) associated host factors and siRNA screen, we uncovered tumor susceptibility gene 101 (TSG101). Knockdown of TSG101 in HBV-producing cells, HBV-infected cells and HBV transgenic mice suppressed HBV release. Co-immunoprecipitation and site mutagenesis revealed that VFND motif in TSG101 and Lys-96 ubiquitination in HBc were essential for TSG101-HBc interaction. In vitro ubiquitination experiment demonstrated that UbcH6 and NEDD4 were potential E2 ubiquitin-conjugating enzyme and E3 ligase that catalyzed HBc ubiquitination, respectively. PPAY motif in HBc and Cys-867 in NEDD4 were required for HBc ubiquitination, TSG101-HBc interaction and HBV egress. Transmission electron microscopy confirmed that TSG101 or NEDD4 knockdown reduces HBV particles count in multivesicular bodies (MVBs). Our work indicates that TSG101 recognition for NEDD4 ubiquitylated HBc is critical for MVBs mediated HBV egress.

Histone acetyltransferase 1 is a succinyltransferase for histones and non-histones and promotes tumorigenesis.

Lysine succinylation (Ksucc) is an evolutionarily conserved and widespread post-translational modification. Histone acetyltransferase 1 (HAT1) is a type B histone acetyltransferase, regulating the acetylation of both histone and non-histone proteins. However, the role of HAT1 in succinylation modulation remains unclear. Here, we employ a quantitative proteomics approach to study succinylation in HepG2 cancer cells and find that HAT1 modulates lysine succinylation on various proteins including histones and non-histones. HAT1 succinylates histone H3 on K122, contributing to epigenetic regulation and gene expression in cancer cells. Moreover, HAT1 catalyzes the succinylation of PGAM1 on K99, resulting in its increased enzymatic activity and the stimulation of glycolytic flux in cancer cells. Clinically, HAT1 is significantly elevated in liver cancer, pancreatic cancer, and cholangiocarcinoma tissues. Functionally, HAT1 succinyltransferase activity and the succinylation of PGAM1 by HAT1 play critical roles in promoting tumor progression in vitro and in vivo. Thus, we conclude that HAT1 is a succinyltransferase for histones and non-histones in tumorigenesis.

Chronic ethanol consumption and HBV induce abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activate Tregs in HBV-Tg mice.

Rationale: Chronic ethanol consumption as a public health problem worldwide boosts the development of chronic liver diseases in hepatitis B virus (HBV)-infected patients. Arachidonic acid metabolite prostaglandin E2 (PGE2) activates regulatory T cells (Tregs) function. Here, we aim to investigate the underlying mechanism by which chronic ethanol consumption enriches the HBV-induced abnormal lipid metabolism and Tregs. Methods: The si-RNAs were used to weaken the expression of SWELL1 in HepG2, HepG2.2.15 and K180 cancer cell lines, followed by RNA sequencing from HepG2 cells. Arachidonic acid metabolite PGE2 and LTD4 were measured by ELISA assay in vivo and in vitro. Western blot analysis and RT-qPCR were used to examine HBx and SWELL1 and transcriptional factor Sp1 in clinical HCC samples and cell lines. The effect of chronic ethanol consumption on Tregs was tested by flow cytometry in HBV-Tg mice. The splenic Tregs were collected and analyzed by RNA sequencing. Results: The cooperative effect of ethanol and HBV in abnormal lipid metabolism was observed in vivo and in vitro. The depression of SWELL1 (or HBx) resulted in the reduction of lipid content and arachidonic acid metabolite, correlating with suppression of relative gene atlas. Ethanol and SWELL1 elevated the levels of PGE2 or LTD4 in the liver of mice and cell lines. Interestingly, the ethanol modulated abnormal lipid metabolism through activating HBx/Sp1/SWELL1/arachidonic acid signaling. Chronic ethanol consumption remarkably increased the population of PBL Tregs and splenic Tregs in HBV-Tg mice, consistently with the enhanced expression of PD-L1 in vivo and in vitro. Mechanically, RNA-seq data showed that multiple genes were altered in the transcriptomic atlas of Tregs sorting from ethanol-fed mice or HBV-Tg mice. Conclusion: The chronic ethanol intake enriches the HBV-enhanced abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activates Tregs in mice.

IFN-α2b inhibits the ethanol enriched-HBV cccDNA through blocking a positive feedback loop of HBx/MSL2/cccDNA/HBV/HBx in liver.

Hepatitis B virus (HBV) is a major risk factor for liver diseases, in which HBV covalently closed circular DNA (cccDNA), as the genomic form that templates viral transcription, plays crucial roles in sustaining viral persistence. Clinically, the excessive ethanol intake accelerates the progression of liver diseases with HBV infection. Here, we supposed that ethanol might trigger HBV cccDNA in the liver. Interestingly, we observed that the ethanol remarkably elevated the levels of HBeAg, HBsAg, HBV DNA and cccDNA in HBV-expressing hepatoma cells. Mechanically, the ethanol increased the levels of HBx and MSL2 in vivo and in HBV-expressing HepG2 cells, but not in HBV-free HepG2 cells. Moreover, the down-regulation of MSL2 by small interference RNA could block the ethanol-promoted HBV cccDNA in HepG2.2.15 cells. As a commonly administered treatment for HBV, the effect of IFNα on ethanol-triggered HBV cccDNA remains poorly understood. Strikingly, we showed that the treatment with IFN-α2b inhibited the ethanol-promoted cccDNA through depressing MSL2 in the cells. Thus, we conclude that IFN-α2b inhibits the ethanol-enriched HBV cccDNA through blocking a positive feedback loop of HBx/MSL2/cccDNA/HBV/HBx. Our finding provides new insights into the mechanism by which IFN-α2b inhibits ethanol-enhanced HBV cccDNA. Therapeutically, IFNα may contribute to the cccDNA induced by ethanol in liver.

Solution and rheological properties of cationic cellulose/gemini surfactant: Effect of the alkyl chain and spacer length.

In this paper, three sulfonate-containing gemini surfactants, sodium 1,1'-(4,4'-methylenebis(4,1-phenylene))bis(1-oxooctane-2-sulfonate) (C8-M1-C8), sodium 1,1'-(4,4'-(ethane-1,2-diyl)bis(4,1-phenylene))bis(1-oxooctane-2-sulfonate) (C8-M2-C8), sodium 1,1'-(4,4'-methylenebis(4,1-phenylene))-bis(1-oxododecane-2-sulfonate) (C12-M2-C12), were synthesized and characterized with FT-IR, 1H NMR and MS. Furthermore, interaction between a cationic cellulose-based polyelectrolyte, PQ-10, and gemini surfactants were investigated by surface tension, turbidity, flow and low-amplitude oscillation rheology analysis. For comparing, the interaction of their corresponding monomeric counterpart sodium dodecyl sulfate (SDS), sodium 1-octanesulfate (SOS) was also studied. Results showed that the concentration value at T1, defined as critical surface complex concentration, for the PQ-10/surfactant was in order of PQ-10/C8-M2-C8> PQ-10/C8-M1-C8 > PQ-10/C12-M2-C12. Precipitation appeared at low concentration for Gemini surfactants than their monomeric counterparts, and for the gemini surfactants with shorter spacer or longer hydrocarbon chain. The increase/decrease of the crossover frequency (ωc) (the relaxation time, τc) for PQ-10/C12-M2-C12 indicated the formation/collapse of network structures, while PQ-10/SDS showed no obvious change.

SPIN1 triggers abnormal lipid metabolism and enhances tumor growth in liver cancer.

Abnormal lipid metabolism plays crucial roles in the development of cancer. Spindlin 1 (SPIN1) involving the process of spindle organization and chromosomal stability serves as an important player in the carcinogenesis. In this study, we try to identify the new function of SPIN1 in lipid metabolism of liver cancer. Tissue microarray showed that 75% (60/80) of hepatocellular carcinoma (HCC) tissues were positive for SPIN1, which was highly expressed in clinical HCC samples and positively associated with malignancy of HCC. Strikingly, SPIN1 could modulate abnormal lipid metabolism by increasing intracellular triglycerides, cholesterols, and lipid droplets in hepatoma cells, which could remarkably enhance the proliferation of hepatoma cells. Mechanistically, SPIN1 up-regulated FASN in hepatoma cells. SPIN1 co-activated transcriptional factor SREBP1c in the promoter of FASN through interaction with SREBP1c. Moreover, SPIN1 promoted the growth of liver cancer in vitro and in vivo and the levels of intracellular triglycerides, cholesterols and lipid droplets were increased in the tumor tissues from mice. In conclusion, SPIN1 modulates abnormal lipid metabolism and enhances growth of liver cancer through SREBP1c-triggered FASN signaling. Therapeutically, SPIN1 may serve as a novel target for HCC.

HAT1 signaling confers to assembly and epigenetic regulation of HBV cccDNA minichromosome.

Rationale: Hepatitis B virus (HBV) is a leading cause of liver diseases. HBV covalently closed circular DNA (cccDNA) is a critical obstacle of complete elimination by anti-HBV therapy. HBV cccDNA accumulates in nucleus as a chromatin-like cccDNA minichromosome assembled by histones and non-histones. However, the underlying mechanism of modulation of cccDNA minichromosome in hepatocytes is poorly understood. Methods: A human liver-chimeric mouse model was established. The cccDNA-ChIP, Southern blot analysis, confocal assays, RIP assays and RNA pull-down assays, et al. were performed to assess the mechanism of assembly and epigenetic regulation of cccDNA minichromosome in human liver-chimeric mouse model, human primary hepatocytes (PHH), dHepaRG, HepG2-NTCP cell lines and clinical liver tissues. Results: Importantly, the expression levels of HAT1, CAF-1 and lncRNA HULC were significantly elevated in the liver from HBV-infected human liver-chimeric mice. Strikingly, the depletion of HAT1 reduced HBV replication and cccDNA accumulation, and impaired the assembly of histone H3/H4 and the deposition of HBx and p300 onto cccDNA to form cccDNA minichromosome in the cells. Mechanically, chromatin assembly factor-1 (CAF-1) was involved in the events. Interestingly, HAT1 modified the acetylation of histone H3K27/H4K5/H4K12 on cccDNA minichromosome. Moreover, lncRNA HULC-scaffold HAT1/HULC/HBc complex was responsible for the modification on cccDNA minichromosome. Additionally, HBV activated HAT1 through HBx-co-activated transcriptional factor Sp1 in a positive feedback manner. Conclusion: HAT1 signaling contributes to assembly and epigenetic regulation of HBV cccDNA minichromosome.

LncRNA PCNAP1 modulates hepatitis B virus replication and enhances tumor growth of liver cancer.

Rationale: Hepatitis B virus (HBV) is a major risk factor for liver cancer, in which HBV covalently closed circular DNA (cccDNA) plays crucial roles. However, the effect of pseudogene-derived long noncoding RNAs (lncRNAs) acting as functional regulators of their ancestral gene expression on HBV replication and hepatocellular carcinoma (HCC) remains unclear. In this study, we speculated that the pseudogene-derived lncRNA PCNAP1 and its ancestor PCNA might modulate HBV replication and promote hepatocarcinogenesis. Methods: We investigated the roles of lncRNA PCNAP1 in contribution of HBV replication through modulating miR-154/PCNA/HBV cccDNA signaling in hepatocarcinogenesis by using CRISPR/Cas9, Southern blot analysis, confocal assays, et al. in primary human hepatocytes (PHH), HepaRG cells, HepG2-NTCP cells, hepatoma carcinoma cells, human liver-chimeric mice model, transgenetic mice model, in vitro tumorigenicity and clinical patients. Results: Interestingly, the expression levels of PCNAP1 and PCNA were significantly elevated in the liver of HBV-infectious human liver-chimeric mice. Clinically, the mRNA levels of PCNAP1 and PCNA were increased in the liver of HBV-positive/HBV cccDNA-positive HCC patients. Mechanistically, PCNA interacted with HBV cccDNA in a HBc-dependent manner. PCNAP1 enhanced PCNA through sponging miR-154 targeting PCNA mRNA 3'UTR. Functionally, PCNAP1 or PCNA remarkably enhanced HBV replication and accelerated the growth of HCC in vitro and in vivo. Conclusion: We conclude that lncRNA PCNAP1 enhances the HBV replication through modulating miR-154/PCNA/HBV cccDNA signaling and the PCNAP1/PCNA signaling drives the hepatocarcinogenesis. Our finding provides new insights into the mechanism by which lncRNA PCNAP1 enhances HBV replication and hepatocarcinogenesis.

Long non-coding RNA HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related hepatocellular carcinoma.

Long noncoding RNA HULC is identified and highly expressed in hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) is a key driver of liver cancer. In the present study, we found that HULC remarkably elevated the levels of HBeAg, HBsAg, HBcAg, pgRNA, HBx, HBV DNA and covalently closed circular DNA (cccDNA), which activated the HBV replication in HBV-expressing hepatoma cells or de novo HBV-infected cell lines (PHH, HepG2-NTCP and dHepaRG). Mechanistically, HULC enhanced HBV cccDNA stability by down-regulating the APOBEC3B in hepatoma cells. HULC significantly up-regulated microRNA-539, which targeted the 3'UTR of APOBEC3B mRNA. Luciferase reporter gene assays revealed a putative STAT3-binding site located in the upstream of miR-539 promoter. Moreover, we identified that HULC was able to elevate HBx, which co-activated the STAT3 to stimulate the miR-539 promoter. Then, miR-539 down-regulated APOBEC3B and promoted HBV replication. Functionally, HULC enhanced the growth of hepatoma cells by activating HBV in vitro and in vivo, which could be blocked by overexpressing APOBEC3B. In conclusion, HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related HCC.

Aspirin inhibits the proliferation of hepatoma cells through controlling GLUT1-mediated glucose metabolism.

Aspirin can efficiently inhibit liver cancer growth, but the mechanism is poorly understood. In this study, we report that aspirin modulates glucose uptake through downregulating glucose transporter 1 (GLUT1), leading to the inhibition of hepatoma cell proliferation. Our data showed that aspirin significantly decreased the levels of reactive oxygen species (ROS) and glucose consumption in hepatoma cells. Interestingly, we identified that GLUT1 and HIF1α could be decreased by aspirin. Mechanically, we demonstrated that the -1008/-780 region was the regulatory element of transcriptional factor NF-κB in GLUT1 promoter by luciferase report gene assays. PDTC, an inhibitor of NF-κB, could suppress the expression of GLUT1 in HepG2 and H7402 cells, followed by affecting the levels of ROS and glucose consumption. CoCl2-activated HIF1α expression could slightly rescue the GLUT1 expression inhibited by aspirin or PDTC, suggesting that aspirin depressed GLUT1 through targeting NF-κB or NF-κB/HIF1α signaling. Moreover, we found that GLUT1 was highly expressed in clinical HCC tissues relating to their paired adjacent normal tissues. Importantly, we observed that high level of GLUT1 was significantly correlated with the poor relapse-free survival of HCC patients by analysis of public data. Functionally, overexpression of GLUT1 blocked the PDTC-induced or aspirin-induced inhibition of glucose metabolism in HepG2 cells. Conversely, aspirin failed to work when GLUT1 was stably knocked down in the cells. Administration of aspirin could depress the growth of hepatoma cells through controlling GLUT1 in vitro and in vivo. Thus, our finding provides new insights into the mechanism by which aspirin depresses liver cancer.

A Feasibility Study of Transformer Winding Temperature and Strain Detection Based on Distributed Optical Fibre Sensors.

The temperature distribution and deformation of the transformer windings cannot be measured in a distributed manner by the traditional method and failure location cannot be performed. To solve these problems, we present a transformer winding temperature and strain based on a distributed optical fibre sensing detection method. The design of the optical fibre winding composite model is developed and simulated winding temperature rise test and local deformation test distinguish between measuring the winding temperature and the strain curve. The test results show that the distributed optical fibre can transmit wire strain efficiently. Optical fibres, in the process of winding, have a certain pre-stress. Using the Brillouin⁻Raman joint measuring method, one can effectively extract the optical fibre temperature and strain information and measure the length of the winding direction of the temperature and strain distribution curve to a temperature measurement precision of ±2 °C and strain detection accuracy of ±50 µÎµ. The system can carry out local hot spot and deformation localisation, providing new ideas for the transformer winding state monitoring technology.

Direct Electrophysiological Mapping of Shape-Induced Affective Perception.

Visual information may convey different affective valences and induce our brain into different affective perceptions. Many studies have found that unpleasant stimuli could produce stronger emotional effects than pleasant stimuli could. Although there has been a notion that triangle is perceived as negative and circle as positive, there has been no systematic study to map the degrees of valence of shapes with different affective perceptions. Here, we employed four shapes (ellipse, triangle, and line-drawn happy and angry faces) to investigate the behavior and electrophysiological responses, in order to systematically study shape-induced affective perception. The reaction time delay and the event-related potential (ERP), particularly the early ERP component, were applied to find the associations with different affective perceptions. Our behavioral results showed that reaction time for angry face was significantly shorter than those for the other three types of stimuli (p < 0.05). In the ERP results, P1, N1, P2, and N2 amplitudes for angry face were significantly larger than those for happy face. Similarly, P1, N1, P2, and N2 amplitudes for triangle were significantly larger than those for ellipse. Particularly, P1 amplitude in the parietal lobe for angry face was the strongest, followed by happy face, triangle, and ellipse. Hence, this work found distinct electrophysiological evidence to map the shape-induced affective perception. It supports the hypothesis that affective strain would induce larger amplitude than affective ease does and strong affective stimuli induce larger amplitude than mild affective stimuli do.

Detection and identification of transformer winding strain based on distributed optical fiber sensing.

At present, transformer winding strain monitoring is divided mainly into off-line detection and on-line detection. Due to the interference of the complex electromagnetic environment, on-line detection has not been widely used. Although off-line detection is more mature, it can not accurately judge the winding strain form. Based on the above problems, this research investigated a strain gauge strain detection method based on distributed fiber optic sensing, and proposes a winding strain identification method based on the S-transform and an extreme learning machine (ELM). First, the deformation of the winding in the process of transformer operation is simulated, and the corresponding Brillouin frequency shift is collected. Then, the time-frequency analysis of the strain signal is carried out using an S-transform, and the transformed time-frequency feature is extracted as the input sample to the neural network. An ELM was used for training identification. Experimental results show that the method can effectively identify the common winding deformation form, and that the recognition effect is better and the accuracy is high.

Electrophoretic deposition of graphene oxide onto carbon fibers for in-tube solid-phase microextraction.

Carbon fibers (CFs) were functionalized with graphene oxide (GO) by an electrophoretic deposition (EPD) method for in-tube solid-phase microextraction (SPME). GO-CFs were filled into a poly(ether ether ketone) (PEEK) tube to obtain a fibers-in-tube SPME device, which was connected with high performance liquid chromatography (HPLC) equipment to build online SPME-HPLC system. Compared with CFs, GO-CFs presented obviously better extraction performance, due to excellent adsorption property and large surface area of GO. Using ten polycyclic aromatic hydrocarbons (PAHs) as model analytes, the important extraction conditions were optimized, such as sample flow rate, extraction time, organic solvent content and desorption time. An online analysis method was established with wide linear range (0.01-50µgL-1) and low detection limits (0.001-0.004µgL-1). Good sensitivity resulted from high enrichment factors (1133-3840) of GO-CFs in-tube device towards PAHs. The analysis method was used to online determination of PAHs in wastewater samples. Some target analytes were detected and relative recoveries were in the range of 90.2-112%. It is obvious that the proposed GO-CFs in-tube device was an efficient extraction device, and EPD could be used to develop nanomaterials functionalized sorbents for sample preparation.

An organically modified silica aerogel for online in-tube solid-phase microextraction.

Aerogels have received considerable attentions because of its porous, high specific surface, unique properties and environmental friendliness. In this work, an organically modified silica aerogel was functionalized on the basalt fibers (BFs) and filled into a poly(ether ether ketone) (PEEK) tube, which was coupled with high performance liquid chromatography (HPLC) for in-tube solid-phase microextraction (IT-SPME). The aerogel was characterized by scanning electron microscopy (SEM) and fourier transform infrared spectrometry (FT-IR). The extraction efficiency of the tube was systematically investigated and shown enrichment factors from 2346 to 3132. An automated, sensitive and selective method was developed for the determination of five estrogens. The linear range was from 0.03 to 100µgL-1 with correlation coefficients (r) higher than 0.9989, and low detection limits (LODs) were 0.01-0.05µgL-1. The relative standard deviations (RSDs) for intra-day and inter-day were less than 4.5% and 6.7% (n=6), respectively. Finally, the analysis method was successfully applied to detect estrogens in sewage and emollient water samples.