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Population is an important basis for land and resource planning, and optimising the allocation of urban and rural public resources is conducive to the development of the regional economy and the protection of the regional ecological environment. Existing studies have mostly adopted the field research method, which mainly relies on researchers’ field visits to the population and public resources in the study area, and the data obtained by this method are relatively accurate, but only small-scale studies can be carried out, and it is difficult for researchers to grasp the overall state of the regional population and urban and rural public resources as a whole. This study is mainly based on multi-source nighttime light remote sensing data to analyse the population distribution and urban and rural public resources development in Luzhou City, Sichuan Province from 2012 to 2020, and the results of the study show that: 1.The total population of Luzhou City in 2020 is 314,100 more than the resident population of Luzhou City in the regression compared with the statistical data of Luzhou City, and the relative error is 7.38%, which shows that the overall accuracy of this study is high. 2. Luzhou city overall population, economy and public resources rapid development of the region is more dense, and shows the phenomenon of spatial aggregation. Good population development and balanced allocation of urban and rural public resources will be conducive to promoting the rapid development of the regional economy and providing sustainable power for regional development.

Laser plasma accelerators (LPAs) have become one of the frontiers of the accelerator community, mainly because they promise orders of magnitude improvement in the accelerating gradient. However, the energy stability and spread of the high-charge bunched beams (e.g. several hundred pC per bunch) from LPAs still strongly limit their application. In this work, we propose a novel method utilizing magnetic chicanes combined with both active and passive plasma dechirpers to simultaneously reduce the central energy deviation and the energy spread of high-charge bunched beams from LPAs. Start-to-end simulations demonstrate that the central energy deviation and the energy spread of approximately 500 pC bunches can be simultaneously reduced from approximately 2% and 1.2% to 0.1% and 0.5%, respectively, while maintaining almost perfect transmission efficiency (above 97%).

Climate change, especially through heatwaves, significantly affects human health and is a growing global concern. Concurrently, population aging is occurring worldwide, with many countries experiencing an increase in their elderly populations. As the elderly are particularly susceptible to extreme temperatures and unevenly distributed due to internal migration of younger populations, a spatio-temporal analysis integrating temperature changes and demographic data is essential. This study focuses on Japan, a super-aged society where over 25% of the total population is 65 years or older. We examined the effects of climate and the proportion of the elderly population on heatstroke deaths through spatio-temporal analysis within a Bayesian framework. We estimated the annual relative risk of heatstroke-related deaths at the prefecture level from 2008 to 2019. The results indicate a strong spatial autocorrelation in heatstroke deaths across Japan. The spatio-temporal interaction model was the best-performing, showing that regional and temporal variations significantly impact heatstroke mortality. In this model, a one-degree increase in temperature anomaly was linked to a 0.35 (95% CI 0.25 to 0.46) times higher odds of heatstroke deaths, while a 1% increase in the population aged 65 years or older was associated with 4.85 (95% CI 0.92 to 8.65) times higher odds. We found that not only metropolitan areas but also rural areas, such as the Tohoku and Shikoku regions, face a high risk of heatstroke, emphasizing the need to address the challenges in rural communities. Our study highlights the necessity of integrating temperature changes and demographic data in a spatio-temporal context for heatstroke risk assessment. It demonstrates the profound effects of temperature anomalies and the proportion of the elderly population on heatstroke mortality. This research framework could be applicable to other countries experiencing aging and heatwave issues, aiding in the development of targeted public health interventions.

Background: Age-related vulnerable characteristics of pancoronary plaques in patients with ST-segment elevation myocardial infarction (STEMI) have not been systemically evaluated by optical coherence tomography (OCT). Therefore, we sought to explore the discrepancies in pancoronary characteristics between younger and older patients with STEMI through OCT. Methods: This retrospective single-center study included 588 patients who had STEMI and underwent three-vessel OCT through emergency percutaneous coronary intervention between October 2016 and September 2018. With a median age of 56 years as a cutoff, the patients were divided into a younger group (≤56 years, n = 298) and an older group (>56 years, n = 290). Results: A total of 795 non-culprit plaques were found in 298 of the younger patients, whereas 858 non-culprit plaques were identified in 290 of the older patients. Fewer high-risk OCT plaques (15.8% vs. 23.1%; P = 0.025), as well as other structures (cholesterol crystals, P = 0.001; microchannels, P = 0.032; calcifications, P < 0.001; spotty calcifications, P < 0.001; large calcifications, P < 0.001; and thrombi, P = 0.001) were identified in younger patients than older patients, at the patient level. In addition, pancoronary vulnerability in younger patients was independently predicted by culprit plaque rupture {CLIMA-defined high-risk plaques (odds ratio [OR]: 3.179; 95% CI: 1.501 to 6.733; P = 0.003), non-culprit rupture (OR: 3.802; 95% CI: 1.604 to 9.014; P = 0.002), non-culprit thin-cap fibroatheroma (OR: 3.536; 95% CI: 2.051 to 6.094; P < 0.001)}, hypertension (OR: 1.920; 95% CI: 1.099 to 3.355; P = 0.022), and total cholesterol (OR: 1.094; 95% CI: 1.002 to 1.195; P = 0.045). In older patients with STEMI, the predictor was male sex (OR: 3.031; 95% CI: 1.352 to 6.795; P = 0.007). Conclusions: Among patients with STEMI, younger patients had limited vulnerable plaque characteristics, and pancoronary vulnerability was associated with culprit plaque rupture, hypertension, and total cholesterol. In contrast, older patients had greater pancoronary vulnerability with the single predictor of male sex, thus suggesting that traditional risk factors have limited applicability in predicting pancoronary vulnerability in older patients.

AIM: To construct and evaluate a diagnostic model based on transfer learning and data augmentation as a non-invasive tool for fusarium identification of fungal keratitis. METHODS: A retrospective study. In this study, 2 157 images of fungal keratitis patients who underwent in vivo confocal microscopy examination in the Department of Ophthalmology of the people's Hospital of Guangxi Zhuang Autonomous Region from March 2017 to January 2020 were included as the dataset, which was classified according to the results of microbial culture. The dataset was subsequently randomly divided into training set(1 380 images), validation set(345 images)and test set(432 images). We used the transfer learning Inception-ResNet V2 network to construct a diagnostic model, and to compare the performance of the model trained on different datasets. The performance of the diagnostic model evaluated with specificity, sensitivity, accuracy, and area under the receiver operating characteristics curve(AUC).RESULTS: The model trained with the original training set had a specificity rate of 71.6%, a sensitivity rate of 72.0%, an accuracy rate of 71.8% and AUC of 0.785(95%CI: 0.742-0.828, P

The authors uncover synthetic lethality between TP53 and ENDOD1, which contains an atypical endonuclease domain. Co-depleted G1 cells accumulate single stranded DNA and die. Combined with xenograft data the work identifies ENDOD1 as a potential cancer-specific SL drug discovery target.

Abstract Background Calcified plaque is thought to adversely impact outcomes after percutaneous coronary intervention (PCI). This study sought to evaluate the impact of nodular calcification in patients with acute coronary syndrome treated with primary percutaneous coronary intervention. Methods Using optical coherence tomography (OCT), 500 culprit plaques with calcification were analyzed from 495 acute coronary syndrome (ACS) patients on whom PCI was performed. Based on morphology, we classified calcification into two subtypes: nodular calcification and non-nodular calcification. Nodular calcification was defined as protruding mass with an irregular surface, high backscattering, and signal attenuation while non-nodular calcification was defined as an area with low backscattering heterogeneous region with a well-delineated border without protrusion into the lumen on OCT. Results Calcified culprit plaques were divided into nodular calcification group (n = 238) and non-nodular calcification group (n = 262). Patients with nodular calcification were older (p

In order to study the dynamic changes in volatile flavor components of walnut (Juglans regia L.) protein during enzymatic hydrolysis, single-enzyme hydrolysis was carried out using Protamex® protease. The headspace solid-phase microextraction and gas chromatography-mass spectrometry were used to analyze the volatile chemical components of the enzymatic hydrolysis solution at different time points, and the results were used to carried out relative odor activity analysis and principal component analysis (PCA). The results showed that fifty-five and sixty-eight aroma substances were detected before and after enzymolysis, including aldehydes, alcohols, ketones, esters and furans. With the progress of enzymatic hydrolysis, the key aroma components were gradually transformed from twenty-one compounds such as n-valeraldehyde, 1-octene-3-ol and isovaleraldehyde before enzymolysis into thirteen compounds such as isovaleraldehyde, dimethyl disulfide and (2E,4E)-decadienal. The PCA results showed that the aroma characteristics tended to be stable after enzymatic hydrolysis for 3 h, in addition, the aroma structure change of the enzymatic hydrolysis solution was mainly affected by the concentration change of 2-ethyl-1-hexanol, 2-ethyl furan, (2E,4E)-decadienal, 2-pentyl furan, (Z)-4-heptenal and dimethyl disulfide. These research results would provide a theoretical basis for the control of flavor quality during the preparation of walnut peptides by enzymolysis.

Although the expression of Mex3 RNA-binding family member B (MEX3B) is upregulated in human nasal epithelial cells (HNECs) predominately in the eosinophilic chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) subtype, its functions as an RNA binding protein in airway epithelial cells remain unknown. Here, we revealed the role of MEX3B based on different subtypes of CRS and demonstrated that MEX3B decreased the TGF-β receptor III (TGFBR3) mRNA level by binding to its 3′ UTR and reducing its stability in HNECs. TGF-βR3 was found to be a TGF-β2–specific coreceptor in HNECs. Knocking down or overexpressing MEX3B promoted or inhibited TGF-β2–induced phosphorylation of SMAD2 in HNECs, respectively. TGF-βR3 and phosphorylated SMAD2 levels were downregulated in CRSwNP compared with controls and CRS without nasal polyps with a more prominent downregulation in the eosinophilic CRSwNP. TGF-β2 promoted collagen production in HNECs. Collagen abundance decreased and edema scores increased in CRSwNP compared with control, again more prominently in the eosinophilic type. Collagen expression in eosinophilic CRSwNP was negatively correlated with MEX3B but positively correlated with TGF-βR3. These results suggest that MEX3B inhibits tissue fibrosis in eosinophilic CRSwNP by downregulating epithelial cell TGFBR3 expression; consequently, MEX3B might be a valuable therapeutic target against eosinophilic CRSwNP.

BackgroundThe benefits of virtual reality (VR)-based rehabilitation were reported in patients after stroke, but there is insufficient evidence about how VR promotes brain activation in the central nervous system. Hence, we designed this study to explore the effects of VR-based intervention on upper extremity motor function and associated brain activation in stroke patients.Methods/designIn this single-center, randomized, parallel-group clinical trial with a blinded assessment of outcomes, a total of 78 stroke patients will be assigned randomly to either the VR group or the control group. All stroke patients who have upper extremity motor deficits will be tested with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and clinical evaluation. Clinical assessment and fMRI will be performed three times on each subject. The primary outcome is the change in performance on the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE). Secondary outcomes are functional independence measure (FIM), Barthel Index (BI), grip strength, and changes in the blood oxygenation level-dependent (BOLD) effect in the ipsilesional and contralesional primary motor cortex (M1) on the left and right hemispheres assessed with resting-state fMRI (rs-fMRI), task-state fMRI (ts-fMRI), and changes in EEG at the baseline and weeks 4 and 8.DiscussionThis study aims to provide high-quality evidence for the relationship between upper extremity motor function and brain activation in stroke. In addition, this is the first multimodal neuroimaging study that explores the evidence for neuroplasticity and associated upper motor function recovery after VR in stroke patients.Clinical trial registrationChinese Clinical Trial Registry, identifier: ChiCTR2200063425.

Temperature variation structures the composition and diversity of gut microbiomes in ectothermic animals, key regulators of host physiology, with potential benefit to host or lead to converse results (i.e., negative). So, the significance of either effect may largely depend on the length of time exposed to extreme temperatures and how rapidly the gut microbiota can be altered by change in temperature. However, the temporal effects of temperature on gut microbiota have rarely been clarified. To understand this issue, we exposed two juvenile fishes (Cyprinus carpio and Micropterus salmoides), which both ranked among the 100 worst invasive alien species in the world, to increased environmental temperature and sampled of the gut microbiota at multiple time points after exposure so as to determine when differences in these communities become detectable. Further, how temperature affects the composition and function of microbiota was examined by comparing predicted metagenomic profiles of gut microbiota between treatment groups at the final time point of the experiment. The gut microbiota of C. carpio was more plastic than those of M. salmoides. Specifically, communities of C. carpio were greatly altered by increased temperature within 1 week, while communities of M. salmoides exhibit no significant changes. Further, we identified 10 predicted bacterial functional pathways in C. carpio that were temperature-dependent, while none functional pathways in M. salmoides was found to be temperature-dependent. Thus, the gut microbiota of C. carpio was more sensitive to temperature changes and their functional pathways were significantly changed after temperature treatment. These results showed the gut microbiota of the two invasive fishes differ in response to temperature change, which may indicate that they differ in colonization modes. Broadly, we have confirmed that the increased short-term fluctuations in temperatures are always expected to alter the gut microbiota of ectothermic vertebrates when facing global climate change.

Interference with quorum sensing (QS) represents an antivirulence strategy with a significant promise for the treatment of bacterial infections and a new approach to restoring antibiotic tolerance. Over the past two decades, a novel series of studies have reported that quorum quenching approaches and the discovery of quorum sensing inhibitors (QSIs) have a strong impact on the discovery of anti-infective drugs against various types of bacteria. The discovery of QSI was demonstrated to be an appropriate strategy to expand the anti-infective therapeutic approaches to complement classical antibiotics and antimicrobial agents. For the discovery of QSIs, diverse approaches exist and develop in-step with the scale of screening as well as specific QS systems. This review highlights the latest findings in strategies and methodologies for QSI screening, involving activity-based screening with bioassays, chemical methods to seek bacterial QS pathways for QSI discovery, virtual screening for QSI screening, and other potential tools for interpreting QS signaling, which are innovative routes for future efforts to discover additional QSIs to combat bacterial infections.

Abstract Nuclear receptors (NR) are ligand-modulated transcription factors that regulate multiple cell functions and thus represent excellent drug targets. However, due to a considerable NR structural homology, NR ligands often interact with multiple receptors. Here, we describe a multiplex reporter assay (the FACTORIAL NR) that enables parallel assessment of NR ligand activity across all 48 human NRs. The assay comprises one-hybrid GAL4-NR reporter modules transiently transfected into test cells. To evaluate the reporter activity, we assessed their RNA transcripts. We used a homogeneous RNA detection approach that afforded equal detection efficacy and permitted the multiplex detection in a single-well format. For validation, we examined a panel of selective NR ligands and polypharmacological agonists and antagonists of the progestin, estrogen, PPAR, ERR, and ROR receptors. The assay produced highly reproducible NR activity profiles (r > 0.96) permitting quantitative assessment of individual NR responses. The inferred EC50 values agreed with the published data. The assay showed excellent quality ( = 0.73) and low variability ( = 7.2%). Furthermore, the assay permitted distinguishing direct and non-direct NR responses to ligands. Therefore, the FACTORIAL NR enables comprehensive evaluation of NR ligand polypharmacology.

To explore the mechanism of citrus pulp in absorption of flavor compounds, the composition, nitrogen adsorption-desorption isotherm of sweet orange pulp powder was tested, its microstructure was observed by scanning electron microscope (SEM), its adsorption capacity for flavor components in orange oil was tested and analyzed by gas chromatography-mass spectrometry (GC-MS). The results of component analysis showed that the sweet orange pulp powder was mainly composed of dietary fiber (51.87%±3.12%), protein (20.47%±0.58%), lipid (11.33%±1.60%), and starch (4.06%±0.59%). SEM observations and analysis of the nitrogen adsorption-desorption isotherm indicated that there were lots of wedges, slits and other irregular structures in the sweet orange pulp powder. The specific surface area of the sweet pulp powder was 2.98 m2/g. The results of GC-MS analysis showed that the sweet orange pulp powder had an obvious effect on the adsorption of typical aroma components of orange oil such as limonene, γ-terpinene, β-myrcene, β-phellandrene, linalool, octanal, nonanal, etc., especially of linear fatty aldehydes and oxygenated terpenoid, while had a relatively weak effect for bicyclic monoterpenoids such as α-pinene, sabinene. In summary, the wedges, slits formed by the cross-linking of the components in the sweet orange pulp powder were the key foundation for its absorption of flavor compounds. The results could provide a reference for the further development and utilization of sweet orange pulp.

Abstract Background Depletion of oocytes leads to ovarian aging-associated infertility, endocrine disruption and related diseases. Excitingly, unlimited oocytes can be generated by differentiation of primordial germ cell like cells (PGCLCs) from pluripotent stem cells. Nevertheless, development of oocytes and follicles from PGCLCs relies on developmentally matched gonadal somatic cells, only available from E12.5 embryos in mice. It is therefore imperative to achieve an in vitro source of E12.5 gonadal somatic cells. Methods We explored to identify small molecules, which can induce female embryonic stem cells (ESCs) into gonadal somatic cell like cells. Results Using RNA-sequencing, we identified signaling pathways highly upregulated in E12.5_gonadal somatic cells (E12.5_GSCs). Through searching for the activators of these pathways, we identified small-molecule compounds Vitamin C (Vc) and AM580 in combination (V580) for inducing differentiation of female embryonic stem cells (ESCs) into E12.5_GSC-like cells (E12.5_GSCLCs). After V580 treatment for 6 days and sorted by a surface marker CD63, the cell population yielded a transcriptome profile similar to that of E12.5_GSCs, which promoted meiosis progression and folliculogenesis of primordial germ cells. This approach will contribute to the study of germ cell and follicle development and oocyte production and have implications in potentially treating female infertility. Conclusion ESCs can be induced into embryonic gonadal somatic cell like cells by small molecules.

IntroductionKnowledge of the morphological features of the anterior cruciate ligament (ACL) is critical for accurate reconstruction of it. This study aimed to explore the quantitative correlations among different morphological features of the ACL, thus to provide useful information for improving anatomical reconstruction techniques and designing artificial ligaments.Methods19 porcine knees were fixed at full extension using 10% formalin and were dissected to expose the ACL. ACL lengths were measured using a caliper. Mid-substances of the ACL were cut and scanned using X-ray microscopy, and the cross-sectional area (CSA) was measured at the isthmus. Margins of direct and indirect bone insertion sites were distinguished and marked. Measurements were performed on digital photographs to obtain the areas of bone insertions. Statistical analysis using nonlinear regression was used to identify potential correlations among the measurements.ResultsThe results showed that the CSA at the isthmus was significantly correlated with the total area of the bone insertion sites and the area of tibial insertion. The area of the tibial insertion was significantly correlated with the area of its direct insertion site. In contrast, the area of the femoral insertion was significantly correlated with the area of its indirect insertion site. The area of the indirect tibial insertion showed a weak correlation with the length of ACL, whereas the length of the ACL was not able to predict or be predicted by any other parameters.ConclusionsThe CSA at the ACL isthmus is more representative for assessing the size of the ACL. However, ACL length has little correlation with the CSA of the isthmus or bone insertion sites, and thus should be evaluated independently for ACL reconstruction.

IntroductionThe natural disasters and climate anomalies caused by increasing global carbon emissions have seriously threatened public health. To solve increasingly serious environmental pollution problems, the Chinese government has committed itself to achieving the goals of peak carbon emissions and carbon neutrality. The low-carbon patent application is an important means to achieve these goals and promote public health.MethodsThis study analyzes the basic situation, spatial network, and influencing factors of low-carbon patent applications in China since 2001 at the provincial and urban agglomeration levels using social network analysis based on data from the Incopat global patent database.ResultsThe following findings are established. (1) From the number of low-carbon patent applications, the total number of low-carbon patent applications in China increased year by year, while the number of applications in the eastern region was larger than those in the central and western regions, but such regional differences had been decreasing. (2) At the interprovincial level, low-carbon patent applications showed a complex and multithreaded network structure. In particular, the eastern coastal provinces occupied the core position in the network. The weighted degree distribution of China's interprovincial low-carbon patent cooperation network is affected by various factors, including economic development, financial support, local scientific research level, and low-carbon awareness. (3) At the urban agglomeration level, the eastern coastal urban agglomerations showed a radial structure with the central city as the core. Urban innovation capability, economic development, low-carbon development awareness, level of technology import from overseas, and informatization level are highly correlated with the weighted degree of low-carbon cooperation networks of urban agglomerations.DiscussionThis study provides ideas for the construction and governance of low-carbon technology innovation system and perspectives for theoretical research on public health and high-quality development in China.

Objective. Many stroke victims have severe swallowing problems. Previous neuroimaging studies have found that several brain regions scattered in the frontal, temporal, and parietal lobes, such as Brodmann’s areas (BA) 6, 21, and 40, are associated with swallowing function. This study sought to investigate changes in swallowing function and resting-state functional magnetic resonance imaging (rs-fMRI) in stroke patients with dysphagia following action observation treatment. It also sought to detect changes in brain regions associated with swallowing in stroke patients. Methods. In this study, 12 healthy controls (HCs) and 12 stroke patients were recruited. Stroke patients were given 4 weeks of action observation therapy. In order to assess the differences in mfALFF values between patients before treatment and HCs, the fractional amplitude of low-frequency fluctuations (fALFF) in three frequency bands (conventional frequency band, slow-4, and slow-5) were calculated for fMRI data. The significant brain regions were selected as regions of interest (ROIs) for subsequent analysis. The mfALFF values were extracted from ROIs of the three groups (patients before and after treatment and HCs) and compared to assess the therapeutic efficacy. Results. In the conventional band, stroke patients before treatment had higher mfALFF in the inferior temporal gyrus and lower mfALFF in the calcarine fissure and surrounding cortex and thalamus compared to HCs. In the slow-4 band, there was no significant difference in related brain regions between stroke patients before treatment and HCs. In the slow-5 band, stroke patients before treatment had higher mfALFF in inferior cerebellum, inferior temporal gyrus, middle frontal gyrus, and lower mfALFF in calcarine fissure and surrounding cortex compared to HCs. We also assessed changes in aberrant brain activity that occurred both before and after action observation therapy. The mfALFF between stroke patients after therapy was closed to HCs in comparison to the patients before treatment. Conclusion. Action observation therapy can affect the excitability of certain brain regions. The changes in brain function brought about by this treatment may help to further understand the potential mechanism of network remodeling of swallowing function.

Aromatic ketones are important pharmaceutical intermediates, especially the pyridin-2-yl-methanone motifs. Thus, synthetic methods for these compounds have gained extensive attention in the last few years. Transition metals catalyze the oxidation of Csp3-H for the synthesis of aromatic ketones, which is arresting. Here, we describe an efficient copper-catalyzed synthesis of pyridin-2-yl-methanones from pyridin-2-yl-methanes through a direct Csp3-H oxidation approach with water under mild conditions. Pyridin-2-yl-methanes with aromatic rings, such as substituted benzene, thiophene, thiazole, pyridine, and triazine, undergo the reaction well to obtain the corresponding products in moderate to good yields. Several controlled experiments are operated for the mechanism exploration, indicating that water participates in the oxidation process, and it is the single oxygen source in this transformation. The current work provides new insights for water-involving oxidation reactions.

The space–air–ground integrated network (SAGIN) represents a pivotal component within the realm of next-generation mobile communication technologies, owing to its established reliability and adaptable coverage capabilities. Central to the advancement of SAGIN is propagation channel research due to its critical role in aiding network system design and resource deployment. Nevertheless, real-world propagation channel research faces challenges in data collection, deployment, and testing. Consequently, this paper designs a comprehensive simulation framework tailored to facilitate SAGIN propagation channel research. The framework integrates the open source QuaDRiGa platform and the self-developed satellite channel simulation platform to simulate communication channels across diverse scenarios, and also integrates data processing, intelligent identification, algorithm optimization modules in a modular way to process the simulated data. We also provide a case study of scenario identification, in which typical channel features are extracted based on channel impulse response (CIR) data, and recognition models based on different artificial intelligence algorithms are constructed and compared.

We propose to use tightly focused lasers to generate high quality electron beams in laser wakefield accelerators. In this scheme, the expansion of the laser beam after the focal position enlarges the size of wakefield bubble, which reduces the effective phase velocity of the wake and triggers injection of plasma electrons. This scheme injects a relatively long beam with high charge. The energy spread of the injected beam can be minimized if an optimal acceleration distance is chosen so that the beam chirp is suppressed. Particle-in-cell simulations indicate that electron beams with the charge on the order of nanocoulomb, the energy spread of ∼1%, and the normalized emittance of ∼0.1 mm mrad can be generated in uniform plasma using ∼100 TW laser pulses. An empirical formula is also given for predicting the beam charge. This injection scheme, with a very simple setup, paves the way toward practical high-quality laser wakefield accelerators for table-top electron and radiation sources.

Natural antioxidants represented by quercetin have been documented to be effective against atherosclerosis. However, the related mechanisms remain largely unclear. In this study, we identified a novel anti-atherosclerotic mechanism of quercetin inhibiting macrophage pyroptosis by activating NRF2 through binding to the Arg483 site of KEAP1 competitively. In ApoE−/− mice fed with high fat diet, quercetin administration attenuated atherosclerosis progression by reducing oxidative stress level and suppressing macrophage pyroptosis. At the cellular level, quercetin suppressed THP-1 macrophage pyroptosis induced by ox-LDL, demonstrated by inhibiting NLRP3 inflammasome activation and reducing ROS level, while these effects were reversed by the specific NRF2 inhibitor (ML385). Mechanistically, quercetin promoted NRF2 to dissociate from KEAP1, enhanced NRF2 nuclear translocation as well as transcription of downstream antioxidant protein. Molecular docking results suggested that quercetin could bind with KEAP1 at Arg415 and Arg483. In order to verify the binding sites, KEAP1 mutated at Arg415 and Arg483 to Ser (R415S and R483S) was transfected into THP-1 macrophages, and the anti-pyroptotic effect of quercetin was abrogated by Arg483 mutation, but not Arg415 mutation. Furthermore, after administration of adeno associated viral vector (AAV) with AAV-KEAP1-R483S, the anti-atherosclerotic effects of quercetin were almost abolished in ApoE−/− mice. These findings proved quercetins suppressed macrophage pyroptosis by targeting KEAP1/NRF2 interaction, and provided reliable data on the underlying mechanism of natural antioxidants to protect against atherosclerosis.