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UBE2M, a NEDD8-conjugating enzyme, is dysregulated in various human cancers and promotes tumor cell proliferation. However, its role in estrogen receptor-positive (ER+) breast cancer remains unknown. We found that UBE2M expression was significantly higher in ER+ breast cancer tissues than in ER-negative (ER-) breast cancer tissues. Higher expression of UBE2M indicated a poorer prognosis in patients with ER+ breast cancer but not in those with ER- breast cancer. Of interest, a positive feedback loop was observed between UBE2M and ERα. Specifically, ERα enhanced the HIF-1α-mediated transcription of UBE2M. In turn, UBE2M maintained ERα expression by inhibiting its ubiquitination and degradation through UBE2M-CUL3/4A-E6AP-ERα axis. Functionally, silencing of UBE2M suppressed the growth of breast cancer cells by inducing cell cycle arrest and apoptosis and improved their sensitivity to fulvestrant both in vitro and in vivo. Altogether, our findings reveal that the UBE2M-ERα feedback loop drives breast cancer progression and fulvestrant resistance, suggesting UBE2M as a viable target for endocrine therapy of ER+ breast cancer.
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Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio , Retroalimentação Fisiológica , Enzimas de Conjugação de Ubiquitina , Humanos , Enzimas de Conjugação de Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Feminino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Animais , Progressão da Doença , Camundongos Nus , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Camundongos , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fulvestranto/farmacologia , Ubiquitinação , Células MCF-7RESUMO
The high-intactness and ultraclean fabrication of suspended 2D materials has always been a challenge due to their atomically thin nature. Here, we present a universal polymer-free transfer approach for fabricating suspended 2D materials by using volatile micro-molecule cyclododecane as the transfer medium, thus ensuring the ultraclean and intact surface of suspended 2D materials. For the fabricated monolayer suspended graphene, the intactness reaches 99% for size below 10 µm and suspended size reaches 36 µm. Owing to the advantages of ultra-cleanness and large size, the thermal conductivity reaches 4914 W m - 1 K - 1 at 338 K. Moreover, this strategy can also realize efficient batch transfer of suspended graphene and is applicable for fabricating other 2D suspended materials such as MoS2. Our research not only establishes foundation for potential applications and investigations of intrinsic properties of large-area suspended 2D materials, but also accelerates the wide applications of suspended graphene grid in ultrahigh-resolution TEM characterization.
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The disparity between growth substrates and application-specific substrates can be mediated by reliable graphene transfer, the lack of which currently strongly hinders the graphene applications. Conventionally, the removal of soft polymers, that support the graphene during the transfer, would contaminate graphene surface, produce cracks, and leave unprotected graphene surface sensitive to airborne contaminations. In this work, it is found that polyacrylonitrile (PAN) can function as polymer medium for transferring wafer-size graphene, and encapsulating layer to deliver high-performance graphene devices. Therefore, PAN, that is compatible with device fabrication, does not need to be removed for subsequent applications. The crack-free transfer of 4 in. graphene onto SiO2/Si wafers, and the wafer-scale fabrication of graphene-based field-effect transistor arrays with no observed clear doping, uniformly high carrier mobility (≈11 000 cm2 V-1 s-1), and long-term stability at room temperature, are achieved. This work presents new concept for designing the transfer process of 2D materials, in which multifunctional polymer can be retained, and offers a reliable method for fabricating wafer-scale devices of 2D materials with outstanding performance.
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Based on multi-scale characteristics inherent in the cracking process of cementitious composites, fibers with different geometric dimensions are simultaneously used to restrain the formation and development of cracks at different scales. Accordingly, hybrid fiber-reinforced cementitious composites (HyFRCCs) exhibit excellent bond behavior and deformation capacity in terms of tension and compression, accompanied by higher damage tolerance. Using these benefits of the mechanical properties of HyFRCCs, the structural performance of HyFRCC structures under complex loading conditions can be improved. To objectively evaluate the contributions of all fibers to the mechanical properties of HyFRCCs, steel macro-fibers, and polyvinyl alcohol (PVA) micro-fibers were used to design several reinforced cementitious composites. Four of the specimens were mono-fibrous cementitious composites, three specimens were cementitious composites reinforced with hybrid fibers, and one was a non-fibrous cementitious composite. The synergy effect of the steel and PVA fibers was analyzed using various fiber combinations. The results indicated a significant enhancement of the bonding properties of HyFRCCs through the incorporation of PVA and steel fibers. Specifically, the peak bond strength, peak slip displacement, and residual bond strength exhibited increments ranging from 31.0% to 41.7%, 60.6% to 118.4%, and 34.6% to 391.3%, respectively, in comparison to the reference test block. Notably, the combined presence of the PVA and steel fibers consistently demonstrated a positive confounding effect on the residual bond strength. However, negative confounding effects were observed in terms of the peak bond strength and peak slip displacement, particularly with 1.0% steel fiber content and 0.5% PVA fiber content.
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The dissection of the genetic architecture and the detection of the loci for adaptive traits are important for marker-assisted selection (MAS) for breeding. A spring wheat diversity panel with 251 cultivars, mainly from China, was obtained to conduct a genome-wide association study (GWAS) to detect the new loci, including the heading date (HD), maturating date (MD), plant height (PH), and lodging resistance (LR). In total, 41 loci existing in all 21 chromosomes, except for 4A and 6B, were identified, and each explained 4.3-18.9% of the phenotypic variations existing in two or more environments. Of these, 13 loci are overlapped with the known genes or quantitative trait loci (QTLs), whereas the other 28 are likely to be novel. The 1A locus (296.9-297.7 Mb) is a multi-effect locus for LR and PH, whereas the locus on chromosome 6D (464.5-471.0 Mb) affects both the HD and MD. Furthermore, four candidate genes for adaptive traits were identified, involved in cell division, signal transduction, and plant development. Additionally, two competitive, allele-specific PCR (KASP) markers, Kasp_2D_PH for PH and Kasp_6D_HD for HD, were developed and validated in another 162 spring wheat accessions. Our study uncovered the genetic basis of adaptive traits and provided the associated SNPs and varieties with more favorable alleles for wheat MAS breeding.
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The real applications of chemical vapor deposition (CVD)-grown graphene films require the reliable techniques for transferring graphene from growth substrates onto application-specific substrates. The transfer approaches that avoid the use of organic solvents, etchants, and strong bases are compatible with industrial batch processing, in which graphene transfer should be conducted by dry exfoliation and lamination. However, all-dry transfer of graphene remains unachievable owing to the difficulty in precisely controlling interfacial adhesion to enable the crack- and contamination-free transfer. Herein, through controllable crosslinking of transfer medium polymer, the adhesion is successfully tuned between the polymer and graphene for all-dry transfer of graphene wafers. Stronger adhesion enables crack-free peeling of the graphene from growth substrates, while reduced adhesion facilitates the exfoliation of polymer from graphene surface leaving an ultraclean surface. This work provides an industrially compatible approach for transferring 2D materials, key for their future applications, and offers a route for tuning the interfacial adhesion that would allow for the transfer-enabled fabrication of van der Waals heterostructures.
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Objectives: Observational studies have demonstrated that household income is associated with morbidity of mental disorders. However, a causal relationship between the two factors remains unclear. Therefore, we investigated the causal relationship between household income status and genetic liability of mental disorders using a bidirectional Mendelian randomization (MR) study. Methods: This MR study included a large cohort of the European population from publicly available genome-wide association study datasets. A random-effects inverse-variance weighting model was used as the main standard, with MR-Egger regression, weighted median, and maximum likelihood estimations performed concurrently as supplements. Sensitivity analysis, consisting of heterogeneity and horizontal pleiotropy tests, was performed using Cochran's Q test, MR-Egger intercept, and MR-PRESSO tests to ensure the reliability of the conclusions. Results: A higher household income tended to be associated with a lower risk of genetic liability for depression (odds ratio [OR]: 0.655, 95% confidence interval [CI] = 0.522-0.822, p < 0.001) and anxiety disorder (OR: 0.666, 95% CI = 0.526-0.843, p < 0.001). No associations were observed for schizophrenia (OR: 0.678, 95% CI = 0.460-1.000, p = 0.05), panic disorder (OR: 0.837, 95% CI = 0.445-1.577, p = 0.583), insomnia (OR: 1.051, 95% CI = 0.556-1.986, p = 0.877), obsessive-compulsive disorder (OR: 1.421, 95% CI = 0.778-2.596, p = 0.252), and bipolar disorder (OR: 1.126, 95% CI = 0.757-1.677, p = 0.556). A reverse MR study showed no reverse causal relationship between psychiatric disorders and household income. Sensitivity analysis verified the reliability of the results. Conclusion: Our results revealed that the population with a higher household income tended to have a minor risk of genetic liability in depression and anxiety disorders.
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Acute kidney injury (AKI) is a serious disorder associated with significant morbidity and mortality. AKI and ischemia/reperfusion (hypoxia/reoxygenation, H/R) injury can be induced due to several reasons. Paeoniflorin (PF) is a traditional herbal medicine derived from Paeonia lactiflora Pall. It exerts diverse therapeutic effects, including anti-inflammatory, antioxidative, antiapoptotic, and immunomodulatory properties; thus, it is considered valuable for treating several diseases. However, the effects of PF on H/R injury-induced AKI remain unknown. In this study, we established an in vitro H/R model using COCL2 and investigated the functions and underlying mechanisms of PF on H/R injury in HK-2 cells. The cell vitality was evaluated using the cell count kit-8 assay. The DCFH-DA fluorescence probe was used to measure the levels of reactive oxygen species (ROS). Oxidative damage was detected using superoxide dismutase (SOD) and malondialdehyde (MDA) assay kits. Apoptotic relative protein and Keap1/Nrf2/HO-1 signaling were evaluated by Western blotting. Our results indicated that PF increased cell viability and SOD activity and decreased the ROS and MDA levels in HK-2 cells with H/R injury. PF inhibits apoptosis by increasing Bcl-2 and decreasing Bax. Furthermore, PF significantly upregulated the expression of HO-1 and Nrf2, but downregulated the expression of HIF-1α and Keap1. PF considerably increased Nrf2 nuclear translocation and unregulated the HO-1 expression. The Nrf2 inhibitor (ML385) could reverse the abovementioned protective effects of PF, suggesting that Nrf2 can be a critical target of PF. To conclude, we found that PF attenuates H/R injury-induced AKI by decreasing the oxidative damage via the Nrf2/HO-1 pathway and inhibiting apoptosis.
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Injúria Renal Aguda , Traumatismo por Reperfusão , Humanos , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Fator 2 Relacionado a NF-E2/uso terapêutico , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Transdução de Sinais , Estresse Oxidativo , Apoptose , Hipóxia , Superóxido Dismutase , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismoRESUMO
BACKGROUND: Fluorofenidone (AKF-PD) is a novel pyridone agent and has potent anti-NLRP3 inflammasome and anti-fibrotic activities. However, the mechanisms underlying its pharmacological actions are not fully understood. METHODS: A renal fibrosis rat model was established by the unilateral ureteral obstruction (UUO) procedure and the rats were randomized and treated with, or without, AKF-PD for 3 and 7 days. The levels of renal fibrosis, NLRP3 inflammasome activation, mitochondrial function, and autophagy were tested in rat kidney tissues. Macrophages following lipopolysaccharides (LPS) and adenosine 5'-triphosphate (ATP) stimulation were examined by Western blot, spectrophotometry, and TEM. RESULTS: Compared with the untreated UUO rats, AKF-PD treatment significantly mitigated the UUO procedure-induced renal fibrosis in rats. AKF-PD treatment decreased mitochondrial dysfunction and IL-Iß and caspase-1 expression in rat kidney tissues and reduced mitochondrial reactive oxygen species production in activated macrophages. Mechanistically, AKF-PD treatment significantly attenuated the PI3K/AKT/mTOR signaling, increased Beclin-1 and LC3 II expression and autophagosome formation, and ameliorated the mitochondrial damage in renal tissues and activated macrophages. CONCLUSION: The results indicated that AKF-PD treatment inhibited renal interstitial fibrosis by regulating the autophagy-mitochondria-NLRP3 inflammasome pathway.
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Nefropatias , Obstrução Ureteral , Ratos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fosfatidilinositol 3-Quinases , Ratos Sprague-Dawley , Nefropatias/tratamento farmacológico , Fibrose , Piridonas/farmacologia , Piridonas/uso terapêutico , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Autofagia , Mitocôndrias/metabolismoRESUMO
Graphene films that can theoretically block almost all molecules have emerged as promising candidate materials for moisture barrier films in the applications of organic photonic devices and gas storage. However, the current barrier performance of graphene films does not reach the ideal value. Here, we reveal that the interlayer distance of the large-area stacked multilayer graphene is the key factor that suppresses water permeation. We show that by minimizing the gap between the two monolayers, the water vapor transmission rate of double-layer graphene can be as low as 5 × 10-3 g/(m2 d) over an A4-sized region. The high barrier performance was achieved by the absence of interfacial contamination and conformal contact between graphene layers during layer-by-layer transfer. Our work reveals the moisture permeation mechanism through graphene layers, and with this approach, we can tailor the interlayer coupling of manually stacked two-dimensional materials for new physics and applications.
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Viewing government-public relationships as important antecedents of individuals' health protection behaviors, this study uses a relationship management approach to examine COVID-19 vaccine promotion among local government agencies. The study hypothesizes that the quality of local government-public relationships is positively associated with pro-vaccine outcomes, including more frequent risk information seeking, pro-vaccine attitudes, and greater vaccination intention. In addition, an important pathway through which the government-public relationship promotes vaccination acceptance is by enhancing the public's risk perceptions. Using a representative community sample, findings support the positive roles of certain but not all relationship quality variables in predicting vaccine acceptance. Meanwhile, risk perceptions consistently predict risk information seeking, pro-vaccine attitudes, and vaccination intention.
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COVID-19 , Vacinas , Humanos , Vacinas contra COVID-19 , Governo Local , COVID-19/epidemiologia , COVID-19/prevenção & controle , Órgãos Governamentais , Comportamentos Relacionados com a Saúde , VacinaçãoRESUMO
Triboelectric nanogenerators (TENGs) and dielectric elastomer generators (DEGs) are potentially promising energy conversion technologies, but they still have limitations due to their own intrinsic characteristics, including the low energy output of TENGs caused by the air breakdown effect, and external polarization voltage requirement for DEGs, which severely limit their practical applications. Herein, coupling TENG with DEG is proposed to build a mutual beneficial self-excitation hybrid generator (named TDHG) for harvesting distributed and low-quality mechanical energy (high entropy energy). Experimental results demonstrate that the output charges of this TDHG are enhanced by fivefold of that of the conventional charge-excitation TENG, and continuous operation of DEG is also realized by simple mechanical triggering. More importantly, owing to the high peak power contributed by TENG and the long output pulse duration guaranteed by DEG, the TDHG realizes a much higher energy conversion efficiency of 32% in comparison to either the TENG (3.6%) or DEG (13.2%). This work proposes a new design concept for hybridized energy harvester toward highly efficient mechanical energy harvesting.
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Entropia , Frequência Cardíaca , Células Híbridas , Fenômenos FísicosRESUMO
The triboelectric nanogenerator (TENG) as an ideal low-frequency mechanical energy harvester has received extensive attention, while low output charge density limits its application. A charge excitation strategy is one of the techniques to effectively improve the surface charge density of the TENG. However, there is little in-depth research on the matching factors between the TENG and excitation circuit. Herein, a soft-contact charge excitation rotary TENG (SCER-TENG) is developed to explore the matching mechanism of different charge excitation strategies. The total output power transferred by the voltage-multiplying circuit (VMC) is 2.13 times that of the full-wave bridge rectifier, which effectively improves the output performance of the SCER-TENG. Moreover, through the established capacitor model and the theoretically calculated maximum output charge of the SCER-TENG with VMC and Zener diodes (VMC-Z), it is found that the output of the Main TENG is mainly affected by capacitors and Zener diodes. The theories have been verified by experiments. After optimization, the output charge of the Main TENG with VMC-Z (1.54 µC) is 3850% higher than that without excitation (0.04 µC). The SCER-TENG successfully harvests low-speed (2.5 m s-1) wind energy to form a self-powered system. This work has crucial instructive implications for using charge excitation strategies to improve the performance of the rotary TENG.
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Identification of the gene for agronomic traits is important for the wheat marker-assisted selection (MAS) breeding. To identify the new and stable loci for agronomic traits, including flag leaf length (FLL), flag leaf width (FLW), uppermost internode length (UIL), and plant morphology (PM, including prostrate, semi-prostrate, and erect). A total of 251 spring wheat accessions collected from the Northeast of China were used to conduct genome-wide association study (GWAS) by 55K SNP arrays. A total of 30 loci for morphological traits were detected, and each explained 4.8-17.9% of the phenotypic variations. Of these, 13 loci have been reported by previous studies, and the other 17 are novel. We have identified seven genes involved in the signal transduction, cell-cycle progression, and plant development pathway as candidate genes. This study provides new insights into the genetic basis of morphological traits. The associated SNPs and accessions with more of favorable alleles identified in this study could be used to promote the wheat breeding progresses.
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Triboelectric nanogenerator (TENG) is a promising strategy for harvesting low frequency mechanical energy. However, the bottlenecks of limited electric output by air/dielectric breakdown and poor durability by material abrasion seriously restrict its further improvement. Herein, we propose a liquid lubrication promoted sliding mode TENG to address both issues. Liquid lubrication greatly reduces interface material abrasion, and its high breakdown strength and charge transmission effect further enhance device charge density. Besides, the potential decentralization design by the voltage balance bar effectively suppresses the dielectric breakdown. In this way, the average power density up to 87.26 W·m-2·Hz-1, energy conversion efficiency of 48%, and retention output of 90% after 500,000 operation cycles are achieved, which is the highest average power density and durability currently. Finally, a cell phone is charged to turn on by a palm-sized TENG device at 2 Hz within 25 s. This work has a significance for the commercialization of TENG-based self-powered systems.
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The availability of graphene and other two-dimensional (2D) materials on a wide range of substrates forms the basis for large-area applications, such as graphene integration with silicon-based technologies, which requires graphene on silicon with outperforming carrier mobilities. However, 2D materials were only produced on limited archetypal substrates by chemical vapor deposition approaches. Reliable after-growth transfer techniques, that do not produce cracks, contamination, and wrinkles, are critical for layering 2D materials onto arbitrary substrates. Here we show that, by incorporating oxhydryl groups-containing volatile molecules, the supporting films can be deformed under heat to achieve a controllable conformal contact, enabling the large-area transfer of 2D films without cracks, contamination, and wrinkles. The resulting conformity with enhanced adhesion facilitates the direct delamination of supporting films from graphene, providing ultraclean surfaces and carrier mobilities up to 1,420,000 cm2 V-1 s-1 at 4 K.
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The genomic and carbohydrate metabolic features of Pseudoalteromonas agarivorans Hao 2018 (P. agarivorans Hao 2018) were investigated through pan-genomic and transcriptomic analyses, and key enzyme genes that may encode the process involved in its extracellular polysaccharide synthesis were screened. The pan-genome of the P. agarivorans strains consists of a core-genome containing 2331 genes, an accessory-genome containing 956 genes, and a unique-genome containing 1519 genes. Clusters of Orthologous Groups analyses showed that P. agarivorans harbors strain-specifically diverse metabolisms, probably representing high evolutionary genome changes. The Kyoto Encyclopedia of Genes and Genomes and reconstructed carbohydrate metabolic pathways displayed that P. agarivorans strains can utilize a variety of carbohydrates, such as d-glucose, d-fructose, and d-lactose. Analyses of differentially expressed genes showed that compared with the stationary phase (24 h), strain P. agarivorans Hao 2018 had upregulated expression of genes related to the synthesis of extracellular polysaccharides in the logarithmic growth phase (2 h), and that the expression of these genes affected extracellular polysaccharide transport, nucleotide sugar synthesis, and glycosyltransferase synthesis. This is the first investigation of the genomic and metabolic features of P. agarivorans through pan-genomic and transcriptomic analyses, and these intriguing discoveries provide the possibility to produce novel marine drug lead compounds with high biological activity.
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Pseudoalteromonas , Transcriptoma , Carboidratos , Genoma Bacteriano/genética , Genômica , Filogenia , Pseudoalteromonas/genética , Pseudoalteromonas/metabolismoRESUMO
Exopolysaccharides (EPSs) are carbohydrate polymers produced and secreted by microorganisms. In a changing marine environment, EPS secretion can reduce damage from external environmental disturbances to microorganisms. Meanwhile, EPSs have promising application prospects in the fields of food, cosmetics, and pharmaceuticals. Changes in external environmental pH have been shown to affect the synthesis of EPSs in microorganisms. In this study, we analyzed the effects of different initial fermentation pHs on the production, monosaccharide composition, and antioxidant activity of the EPSs of Pseudoalteromonas agarivorans Hao 2018. In addition, the transcriptome sequence of P. agarivorans Hao 2018 under different initial fermentation pH levels was determined. GO and KEGG analyses showed that the differentially expressed genes were concentrated in the two-component regulatory system and bacterial chemotaxis pathways. We further identified the expression of key genes involved in EPS synthesis during pH changes. In particular, the expression of genes encoding the glucose/galactose MFS transporter, phosphomannomutase, and mannose-1-phosphate guanylyltransferase was upregulated when the environmental pH increased, thus promoting EPS synthesis. This study not only contributes to elucidating the environmental adaptation mechanisms of P. agarivorans, but also provides important theoretical guidance for the directed development of new products using biologically active polysaccharides.
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Antioxidantes/isolamento & purificação , Polissacarídeos Bacterianos/isolamento & purificação , Pseudoalteromonas/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Fermentação , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Concentração de Íons de Hidrogênio , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/farmacologia , Pseudoalteromonas/genéticaRESUMO
Boosting output charge density is top priority for achieving high-performance triboelectric nanogenerators (TENGs). The charge-excitation strategy is demonstrated to be a superior approach to acquire high output charge density. Meanwhile, the molecular charge behaviors in the dielectric under a strong electric field from high charge density bring new physics that are worth exploring. Here, a rapid self-polarization effect of a polar dielectric material by the superhigh electric field in a charge-excitation TENG is reported, by which the permittivity of the polar dielectric material realizes self-increase to a saturation, and thus enhances the output charge density. Consequently, an ultrahigh charge density of 3.53 mC m-2 is obtained with 7 µm homemade lead zirconate titanate-poly(vinylidene fluoride) composite film in the atmosphere with 5% relative humidity, which is the highest charge density for TENGs with high durability currently. This work provides new guidance for dielectric material optimization under charge excitation to boost the output performance of TENGs toward practical applications.