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In order to explore the effects of postharvest exogenous melatonin (MT) treatment on the storage quality of spaghetti squash, squash was treated with 0.2 mmol/L MT solution to investigate the changes in fruit quality and antioxidant capacity during storage at (9±1) ℃ with relative humidity of 65%~70%. The results showed that MT treatment delayed the occurrence of decay of spaghetti squash by 40 days during storage compared with the control group. At 160 d of storage, the decay rate of MT-treated fruit was only 15.56%, which was significantly lower than that of the control fruit (34.07%, P

Abstract Background Larval settlement and metamorphosis represent critical events in the life history of marine benthic animals. Myoinhibitory peptide (MIP) plays a pivotal role in larval settlement of marine invertebrates. However, the molecular mechanisms of MIP involved in this process are not well understood. Results In this study, we evaluated the effects of thirteen MIP mature peptides on triggering the larval settlement of Urechis unicinctus (Xenopneusta, Urechidae), and determined that MIP2 was the principal neuropeptide. Transcriptomic analysis was employed to identify differentially expressed genes (DEGs) between the MIP2-treated larvae and normal early-segmentation larvae. Both cAMP and calcium signaling pathways were enriched in the DEGs of the MIP2-treated larvae, and two neuropeptide receptor genes (Spr, Fmrfar) were up-regulated in the MIP2-treated larvae. The activation of the SPR-cAMP pathway by MIP2 was experimentally validated in HEK293T cells. Furthermore, fourteen cilia-related genes, including Tctex1d2, Cfap45, Ift43, Ift74, Ift22, Cav1 and Mns1, etc. exhibited down-regulated expression in the MIP2-treated larvae. Whole-mount in situ hybridization identified two selected ciliary genes, Tctex1d2 and Cfap45, were specially expressed in circumoral ciliary cells of the early-segmentation larvae. Knocking down Tctex1d2 mRNA levels by in vivo RNA interference significantly increased the larval settlement rate. Conclusion Our findings suggest that MIP2 inhibits the function of the cilia-related genes, such as Tctex1d2, through the SPR-cAMP-PKA pathway, thereby inducing larval settlement in U. unicinctus. The study contributes important data to the understanding of neuropeptide regulation in larval settlement.

The tourism network attention as a reflection of tourism demand is closely related to the tourism flow, the differences between the two has become an important criterion for judging the efficiency of destination tourism demand conversion, as well as a manifestation of the balance and coordination of destination tourism industry. Against the background of insufficient release of tourism demand in China, research on the development differences between tourism network attention and tourism flow can provide a basis for demand-side management and high-quality development. Based on the theory of spatial mismatch, this research analyzes the spatial development difference between the tourism network attention and the tourism flow in Shanghai from 2012 to 2021 using methods such as center of gravity model, spatial mismatch index, and two-dimensional combination matrix. The results show: (1) According to the analysis of the center of gravity model, there was a shift of the center of gravity of tourism network attention with the direction of ''south-north'', while the tourism flow shifted ''west-east''; the center of gravity between tourism network attention and tourism flow began to diverge from 2012 to 2016, gradually converged from 2016 to 2019, and then gradually deviated again after 2020. (2) According to the spatial mismatch index, the spatial mismatch types between tourism network attention and tourism flow in various Districts of Shanghai are mainly negative and low mismatch, with high mismatch areas mainly distributed in the eastern and southwestern parts of Shanghai. (3) Combining the two-dimensional combination matrix, it can be observed that the spatial development difference between tourism network attention and tourism flow in Shanghai show a characteristic of ''enlarging-shrinking-enlarging''. From 2012 to 2016, the spatial development difference between tourism network attention and tourism flow in Shanghai continuously expanded; from 2017 to 2019, the spatial development difference continuously shrank; and from 2020 to 2021, the spatial differences expanded again. (4) The analysis results of the panel data model show that the development of tourism resources and the level of tourism services have a positive promoting effect on the evolution of spatial mismatch, while the social basic development environment has a negative effect. The research results not only meet the needs of evaluating the high-quality development of the tourism industry in the current economic restructuring, providing direction for the high-quality development of the regional tourism industry, but also enrich the research content of network attention as a tourism element participating in the evaluation of tourism industry development quality, and deepen the relationship research between network attention and tourism flow.

Objective Syringomyelia is a common central nervous system disease characterized by the dilation of the central canal (CC). Regarding the pathogenesis of syringomyelia, cerebrospinal fluid (CSF) circulation obstruction in the subarachnoid space (SAS) of the spinal cord has been widely accepted. However, clinical and animal studies on obstructing the CSF in SAS failed to form syringomyelia, challenging the theory of SAS obstruction. The precise pathogenesis remains unknown. Methods We utilized an extradural compression rat model to investigate the pathogenesis underlying syringomyelia. Magnetic resonance imaging enabled detection of syringomyelia formation. To assess CSF flow within the SAS, Evans blue was infused into the cisterna magna. Histological analysis allowed morphological examination of the CC. Furthermore, CSF flow through the CC was traced using Ovalbumin Alexa-Flour 647 conjugate (OAF-647). Scanning electron microscopy (SEM) enabled visualization of ependymal cilia. Results The findings showed that the dura mater below the compression segment exhibited lighter coloration relative to the region above the compression, indicative of partial obstruction within the SAS. However, the degree of SAS occlusion did not significantly differ between syringomyelia (SM-Y group) and those without (SM-N group). Intriguingly, hematoxylin and eosin staining and CSF tracing revealed occlusion of the CC accompanied by reduced CSF flow in the SM-Y group compared to SM-N and control groups. SEM images uncovered impairment of ependymal cilia inside the syringomyelia. Conclusion CC occlusion may represent a physiological prerequisite for syringomyelia formation, while SAS obstruction serves to initiate disease onset. The impairment of ependymal cilia appears to facilitate progression of syringomyelia.

The inserts supporting run-flat tire (ISRFT) is mainly used in military off-road vehicles, which need to maintain high mobility after a blowout. Regulations show that the ISRFT can be driven safely for at least 100 km at a speed of 30 km/h to 40 km/h under zero-pressure conditions. However, the ISRFT generates serious heat during zero-pressure driving, which accelerates the aging of the tire rubber and degrades its performance. In order to study the thermo-mechanical coupling characteristics of the ISRFT, a three-dimensional finite element model verified by bench tests was established. Then, the stress–strain, energy loss and heat generation of the ISRFT were analyzed by the sequential thermo-mechanical coupling method to obtain the steady-state temperature field (SSTF). Finally, four kinds of honeycomb inserts bodies were designed based on the tangent method, and the SSTF of the honeycomb and the original ISRFT were compared. The results indicated that the high-temperature region of the ISRFT is concentrated in the shoulder area. For every 1 km/h increase in velocity, the temperature at the shoulder of the tire increases by approximately 1.6 °C. The SSTF of the honeycomb ISRFT is more uniformly distributed, and the maximum temperature of the shoulder decreases by about 30 °C, but the maximum temperature of the tread increases by about 40 °C. This study provides methodological guidance for investigating the temperature and mechanical characteristics of the ISRFT under zero-pressure conditions.

Abstract Background In the current treatment of non-small cell lung cancer (NSCLC), traditional chemotherapy causes high toxicity, so it is necessary to develop safe chemical drug delivery vehicles clinically. Chemotherapy monotherapy is prone to drug resistance. Chemotherapy combined with other therapies such as nucleic acid drugs is an effective way to avoid drug resistance and the toxicity of continuous chemotherapy. In this study, chemotherapy and siRNA therapy were combined to treat paclitaxel-resistant NSCLC in order to increase efficacy and reduce toxicity. This study aims to develop a cabazitaxel-loaded human serum albumin nanoparticles (CTX-HSA-NPs) to improve the toxicity of traditional CTX-Tween 80 and increase targeting, and to develop a TGFβ-1 siRNA lipid Nanoparticles (TGFβ-1 siRNA LNP) combined with chemotherapy in the treatment of paclitaxel-resistant NSCLC. Results This study prepared CTX-HSA-NPs and TGFβ-1 siRNA LNP had small particle size, high encapsulation efficiency (EE). CTX-HSA-NPs lyophilized powder has high stability after dissolved. The antitumor effect of CTX-HSA-NPs on paclitaxel-resistant NSCLC was higher than that of CTX-Tween, and the toxicity was 1.8 times lower than that of CTX-Tween. More importantly, the combined treatment of TGFβ-1 siRNA LNP and CTX-HSA-NPs could effectively improve the antitumor efficacy of paclitaxel-resistant NSCLC in vivo and in vitro. The results of tumor immunohistochemistry showed that TGFβ-1 siRNA LNP significantly inhibited the expression of TGFβ-1, and compared with other groups, the expression of P-gp after low-dose CTX-HSA-NPs treatment was lower, which did not cause obvious drug resistance. Conclusions The antitumor effect of CTX-HSA-NPs on paclitaxel-resistant NSCLC was higher than that of CTX-Tween, and the toxicity was lower than that of CTX-Tween. TGFβ-1 siRNA LNP can treat paclitaxel-resistant NSCLC by inhibiting the express of TGFβ-1 mRNA. The combined treatment of TGFβ-1 siRNA LNP and CTX-HSA-NPs could effectively improve the antitumor efficacy of paclitaxel-resistant NSCLC. A combination therapy of chemotherapy and nucleic acid drugs could be an effective approach for treating paclitaxel-resistant NSCLC.

Glioblastoma multiforme, a highly aggressive and lethal brain tumor, is a substantial clinical challenge and a focus of increasing concern globally. Hematological toxicity and drug resistance of first-line drugs underscore the necessity for new anti-glioma drug development. Here, 43 anthracenyl skeleton compounds as p53 activator XI-011 analogs were designed, synthesized, and evaluated for their cytotoxic effects. Five compounds (13d, 13e, 14a, 14b, and 14n) exhibited good anti-glioma activity against U87 cells, with IC50 values lower than 2 μM. Notably, 13e showed the best anti-glioma activity, with an IC50 value up to 0.53 μM, providing a promising lead compound for new anti-glioma drug development. Mechanistic analyses showed that 13e suppressed the MDM4 protein expression, upregulated the p53 protein level, and induced cell cycle arrest at G2/M phase and apoptosis based on Western blot and flow cytometry assays.

Abstract Chronic inflammation and dyslipidemia are important risk factors in developing atherosclerotic cardiovascular disease, such as coronary heart disease. Acute coronary syndrome (ACS) is one of the most dangerous syndromes in coronary heart disease. Type 2 diabetes mellitus (T2DM) is considered equal to coronary heart disease owing to the high cardiac risk induced by chronic inflammation and dyslipidemia. The neutrophil to high-density lipoprotein cholesterol ratio (NHR) is a novel and straightforward marker that reflects inflammation and lipid metabolic disorder. However, few studies have been on the role of NHR in assessing the risk of ACS in T2DM patients. Here we analyzed NHR level in ACS patients with T2DM, exploring its predictive and diagnostic values. 211 hospitalized ACS patients with T2DM were recruited as the case group, and 168 hospitalized T2DM patients as the control group (all patients collected from 6/2020 to 12/2021 in Xiangya Hospital). Biochemical test results and echocardiograms, as well as demographic information such as age, BMI, diabetes mellitus, smoking, drinking, and history of hypertension, were recorded. Frequencies, percentages, means, and standard deviations were used to describe the data. The shapiro–Wilk test was used to assess the normality of the data. Normally distributed data were compared using the independent sample T-test, and non-normally distributed data were compared using Mann–Whitney U test. Correlation analysis was performed using the Spearman rank correlation test, and receiver operating characteristic (ROC) curve analysis and multivariable logistic regression analysis were performed by SPSS version 24.0 (SPSS Inc) and GraphPad Prism 9.0 (GraphPad Software Inc). p

Sepsis is a life-threatening multiple organ dysfunction syndrome (MODS) caused by a microbial infection that leads to high morbidity and mortality worldwide. Sepsis-induced cardiomyopathy (SIC) and coagulopathy promote the progression of adverse outcomes in sepsis. Here, we reported that ACT001, a modified compound of parthenolide, improved the survival of sepsis mice. In this work, we used cecal ligation and puncture (CLP) model to induce SIC. Transthoracic echocardiography and HE staining assays were adopted to evaluate the influence of ACT001 on sepsis-induced cardiac dysfunction. Our results showed that ACT001 significantly improved heart function and reduced SIC. Coagulation accelerates organ damage in sepsis. We found that ACT001 decreased blood clotting in the FeCl3-induced carotid artery thrombosis experiment. ACT001 also reduced the production of neutrophil extracellular traps (NETs). RNA-sequencing of heart tissues revealed that ACT001 significantly downregulated the expression of pro-inflammatory cytokines and the JAK-STAT signaling pathway. These results were confirmed with real-time PCR and ELISA. In summary, we found ACT001 rescued mice from septic shock by protecting the cardiovascular system. This was partially mediated by inhibiting pro-inflammatory cytokine production and down-regulating the JAK-STAT signaling.

The aim of this study was to explore the efficacy and safety of TGFβ1 siRNA lipid nanoparticles (LNPs) modified with different PEG derivatives (PEG5000 cholesterol, abbreviated as CE; tocopherol polyethylene glycol 1000 succinate, abbreviated as TPGS) in the treatment of paclitaxel-resistant non-small-cell lung cancer. Three kinds of TGFβ1 siRNA LNPs were prepared via microfluidics technology, using different PEG derivatives and dosages (CE1.5, CE2.5, TPGS2.5) as variables. Their particle size, zeta potential, contents, and encapsulation efficiencies were determined. The inhibition of TGFβ1 mRNA and protein expression and the effects of the three kinds of LNPs on the proliferation of paclitaxel-resistant non-small-cell lung cancer cells (A549/T cell) were characterized. The distributions of the three siRNA LNPs in nude mice bearing A549/T tumors, especially at the tumor site, were observed using in vivo mouse imaging technology, and their corresponding efficacies were evaluated. The average particle size of the three kinds of TGFβ1 siRNA LNPs was about 70–80 nm, and they were capable of charge flipping. All three siRNA LNPs could effectively inhibit the expression of TGFβ1 mRNA and protein in A549/T cells and inhibit the proliferation of A549/T cells in vitro. The results of in vivo mice imaging showed that the three kinds of siRNA LNPs, when labeled with cypate, retain strong fluorescence in the tumor at 24 h. The pharmacodynamic results, such as for relative tumor volumes and tumor inhibition rates, reveal that TGFβ1 siRNA LNPs modified with CE1.5, CE2.5, or TPGS2.5 can be used to effectively treat paclitaxel-resistant lung adenocarcinoma. The histopathological results showed that the three kinds of LNPs have a certain toxicity but are relatively safe compared to common forms of chemotherapy such as cabazitaxel. TGFβ1 siRNA LNPs modified with CE1.5, CE2.5, and TPGS2.5 can inhibit TGFβ1 mRNA and protein expression in A549/T cells in vitro and can accumulate and play a role in the tumor tissue of nude mice, features that can be exploited for treating paclitaxel-resistant lung adenocarcinoma.

Here Kim et al. show that primary BMECs can be maintained ex vivo as distinct sinusoidal- and arterial-like populations and that the presence of macrophages is critical to preserve their native transcriptomic profiles and functional heterogeneity.

Chaperonin containing TCP1 subunit 2 (CCT2) is essential in various neurodegenerative diseases, albeit its role in the pathogenesis of Alzheimer’s disease (AD) remains elusive. This study aimed to evaluate the role of CCT2 in Alzheimer’s disease. First, bioinformatics database analysis revealed that CCT2 was significantly downregulated in patients with Alzheimer’s disease and associated with autophagic clearance of β-amyloid. The 789 differentially expressed genes overlapped in AD-group and CCT2-low/high group, and the CCT2-high-associated genes screened by Pearson coefficients were enriched in protein folding, autophagy, and messenger RNA stability regulation pathways. These results suggest that CCT2 is significantly and positively associated with multiple pathways linked to autophagy and negatively associated with neuronal death. The logistic prediction model with 13 key genes, such as CCT2, screened in this study better predicts Alzheimer’s disease occurrence (AUC = 0.9671) and is a favorable candidate for predicting potential biological targets of Alzheimer’s disease. Additionally, this study predicts reciprocal micro RNAs and small molecule drugs for hub genes. Our findings suggest that low CCT2 expression may be responsible for the autophagy suppression in Alzheimer’s disease, providing an accurate explanation for its pathogenesis and new targets and small molecule inhibitors for its treatment.

The mortality of sepsis and septic shock remains high worldwide. Neutrophil extracellular traps (NETs) release is a major cause of organ failure and mortality in sepsis. Targeting Gasdermin D (GSDMD) can restrain NETs formation, which is promising for sepsis management. However, no medicine is identified without severe safety concerns for this purpose. Xuebijing injection (XBJ) has been demonstrated to alleviate the clinical symptoms of COVID-19 and sepsis patients, but there are not enough animal studies to reveal its mechanisms in depth. Therefore, we wondered whether XBJ relieved pulmonary damage in sepsis by suppressing NETs formation and adopted a clinically relevant polymicrobial infection model to test this hypothesis. Firstly, XBJ effectively reversed lung injury caused by sepsis and restrained neutrophils recruitment to lung by down-regulating proinflammatory chemokines, such as CSF-3, CXCL-2, and CXCR-2. Strikingly, we found that XBJ significantly reduced the expressions of NETs component proteins, including citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase (NE). GSDMD contributes to the production of NETs in sepsis. Notably, XBJ exhibited a reduced effect on the expressions of GSDMD and its upstream regulators. Besides, we also revealed that XBJ reversed NETs formation by inhibiting the expressions of GSDMD-related genes. Collectively, we demonstrated XBJ protected against sepsis-induced lung injury by reversing GSDMD-related pathway to inhibit NETs formation.

Abstract Background During acute myeloid leukemia (AML) growth, the bone marrow (BM) niche acquires significant vascular changes that can be offset by therapeutic blast cytoreduction. The molecular mechanisms of this vascular plasticity remain to be fully elucidated. Herein, we report on the changes that occur in the vascular compartment of the FLT3-ITD+ AML BM niche pre and post treatment and their impact on leukemic stem cells (LSCs). Methods BM vasculature was evaluated in FLT3-ITD+ AML models (Mll PTD/WT/Flt3 ITD/ITD mouse and patient-derived xenograft) by 3D confocal imaging of long bones, calvarium vascular permeability assays, and flow cytometry analysis. Cytokine levels were measured by Luminex assay and miR-126 levels evaluated by Q-RT-PCR and miRNA staining. Wild-type (wt) and Mll PTD/WT/Flt3 ITD/ITD mice with endothelial cell (EC) miR-126 knockout or overexpression served as controls. The impact of treatment-induced BM vascular changes on LSC activity was evaluated by secondary transplantation of BM cells after administration of tyrosine kinase inhibitors (TKIs) to Mll PTD/WT/Flt3 ITD/ITD mice with/without either EC miR-126 KO or co-treatment with tumor necrosis factor alpha (TNFα) or anti-miR-126 miRisten. Results In the normal BM niche, CD31+Sca-1high ECs lining arterioles have miR-126 levels higher than CD31+Sca-1low ECs lining sinusoids. We noted that during FLT3-ITD+ AML growth, the BM niche lost arterioles and gained sinusoids. These changes were mediated by TNFα, a cytokine produced by AML blasts, which induced EC miR-126 downregulation and caused depletion of CD31+Sca-1high ECs and gain in CD31+Sca-1low ECs. Loss of miR-126high ECs led to a decreased EC miR-126 supply to LSCs, which then entered the cell cycle and promoted leukemia growth. Accordingly, antileukemic treatment with TKI decreased the BM blast-produced TNFα and increased miR-126high ECs and the EC miR-126 supply to LSCs. High miR-126 levels safeguarded LSCs, as shown by more severe disease in secondary transplanted mice. Conversely, EC miR-126 deprivation via genetic or pharmacological EC miR-126 knock-down prevented treatment-induced BM miR-126high EC expansion and in turn LSC protection. Conclusions Treatment-induced CD31+Sca-1high EC re-vascularization of the leukemic BM niche may represent a LSC extrinsic mechanism of treatment resistance that can be overcome with therapeutic EC miR-126 deprivation. Graphic abstract

BackgroundAlthough there is a growing consensus around the world that long-term care services and supports are important to help the aged population with disabilities achieve healthy aging, a misallocation of care resources and inefficiency in care delivery still exist in China. The absence or inadequate provision of long-term care services and supports among older adults with disabilities results in a range of adverse health consequences. However, the negative influence of unmet needs for assistance on healthy aging, based on functional perspectives including physiological, psychological, and societal domains, has been underestimated. This study aimed to measure healthy aging based on a person-centered approach and examine the relationship between unmet needs for assistance and healthy aging among older adults with disabilities in China.MethodsBased on the data from the Chinese Longitudinal Healthy Longevity Survey 2018, we used the latent profile analysis with three indicators to uncover distinctive types of older adults experiencing distinct levels of healthy aging, and applied the ordered logit regression to analyze the correlation between unmet needs for assistance and different levels of healthy aging. To further address the endogeneity bias, the robust test was conducted by the two-stage least-squares instrumental variable estimation and the conditional mixed process instrumental variable estimation.ResultsThree ordered latent classes were identified: a low level of healthy aging (42.83%), a middle level of healthy aging (47.27%), and a high level of healthy aging (9.90%). Disabled older adults with unmet needs had a lower probability of achieving the higher level of healthy aging (OR = 0.57, SE = 0.04, CI = 0.48–0.66, p < 0.001).ConclusionsThis study highlights the need to increase awareness among gerontological practitioners with respect to long-term care services and supports for disabled older adults as a potential for enhancing their healthy aging, and that unmet needs could be a basis for risk assessment and a means for determining the efficacy of long-term care interventions on maintaining health.

Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after Allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT). Although a series of immunosuppressant agents are routinely used as the first-line prevention, the morbidity and mortality rate remains high in allo-HSCT recipients. Our previous work indicated that combining Xuebijing (XBJ) with Cyclosporin A (CSA) is superior to CSA alone in preventing aGVHD. However, it was not clear which compounds in XBJ may prevent aGVHD. Whether the effective compounds in XBJ can be safely combined with CSA to prevent GVHD remain to be evaluated. Here, we accessed whether the combination of four main components in XBJ (C0127) had the same efficacy as XBJ in preventing aGVHD. In addition, the effectiveness of a novel combination therapy (C0127 + CSA) on aGVHD prophylaxis was evaluated using 16 s rRNA sequencing and RNA sequencing approaches in vitro and in vivo. In aGVHD mice, C0127 enhanced the preventive effects of CSA including decreasing mortality, maintaining weight, reducing GVHD score and reducing the expression of IL-6 and TNF-α in serum. Fatal GVHD is a frequent consequence of intestinal tract damage. We found combining C0127 with CSA alleviated the gut damage and maintained the normal physiological function of intestine by H&E staining, intestinal permeability and short chain fatty acid (SCFA) assays. Next, 16 S sequencing analysis of feces showed the combination treatment maintained the intestinal microbial diversity, normalized the intestinal microorganism and prevented flora disorder by reducing the relative abundances of Escherichia coli and Enterococcus. Further, RNA-seq analysis of colonic epithelium revealed C0127 combined with CSA chiefly regulated chemokines and cytokines in IL-17 signaling pathway. The combination treatment reduced the expression of G-CSF and its effector STAT3 (an axis that aggravated gut inflammation and flora disorder) in gut epithelium on mRNA and protein level. These findings indicated that C0127 improved the prevention of CSA in aGVHD mice partially by protecting the gut from damage through normalizing G-CSF signaling, which regulates the intestinal microbiota and the integrity of the epithelial barrier.

Pesticide residue in vegetables has been considered as a serious food safety problem across the whole world. This study investigates a novel advanced oxidation process (AOP), namely the coupled free chlorine/ultrasound (FC/US) process for the removal of three typical pesticides from lettuce. The removal efficiencies of dimethoate (DMT), trichlorfon (TCF) and carbofuran (CBF) from lettuce reached 86.7%, 79.8% and 71.3%, respectively by the FC/US process. There existed a synergistic effect in the coupled FC/US process for pesticide removal and the synergistic factors reached 22.3%, 19.0% and 36.4% for DMT, TCF and CBF, respectively. Based on the analysis of mass balance of pesticides, the synergistic effect was probably attributed to the efficient oxidation of pesticides both in vegetables and in water by the generated free radicals and FC. The surface area and surface structure of vegetables strongly affected the removal of pesticides by FC/US. The removal efficiency of DMT increased from 80.9% to 88.1% as solution pH increased from 5.0 to 8.0, and then decreased to 84.1% when solution pH further increased to 9.0. When the ultrasonic frequency changed from 20 to 40 kHz, a remarkable improvement in pesticide removal by FC/US was observed. As the FC concentration increased from 0 to 15 mg L–l, the removal efficiencies of pesticides increased firstly, and then became stagnant when the FC concentration further increased to 25 mg L–l. The pesticide degradation pathways based on the identified intermediates were proposed. The total chlorophyll content was reduced by less than 5% after the FC/US process, indicating a negligible damage to the quality of vegetables. It suggests that the FC/US process is a promising AOP for pesticides removal from vegetables.

This paper concerns the nonlinear filter designing methods in the information space of the nonlinear systems with non-Gaussian noises. Firstly, the prediction information vector is obtained by the traditional square root cubature information filtering algorithm. Then, under the maximum correntropy criterion, the prediction information vector is corrected with the contribution information vector obtained by the non-Gaussian measurement. The information filtering gain is obtained by utilizing the state information correntropy matrix and the measurement information correntropy matrix, in which, the state prediction is taken as the state value. In order to improve the advantage of the above nonlinear non-Gaussian information filter in filtering accuracy, with the help of fixed-point theory, an iterative computation method is further developed to update the estimation information vector and the state estimate. The effectiveness of the two proposed nonlinear non-Gaussian filtering methods is illustrated in final four simulation examples.

A mild ischemic stroke may cause both debilitating locomotor and cognitive decline, for which the mechanism is not fully understood, and no therapies are currently available. In this study, a nonfatal stroke model was constructed in mice by a modified middle cerebral artery occlusion (MCAO) procedure, allowing an extended recovery period up to 28 days. The extended MCAO model successfully mimicked phenotypes of a recovery phase post-stroke, including locomotor motor and cognitive deficiencies, which were effectively improved after Shuxuening injection (SXNI) treatment. Tissue slices staining showed that SXNI repaired brain injury and reduced neuronal apoptosis, especially in the hippocampus CA3 region. Transcriptomics sequencing study revealed 565 differentially expressed genes (DEGs) in the ischemic brain after SXNI treatment. Integrated network pharmacological analysis identified Neurotrophin/Trk Signaling was the most relevant pathway, which involves 15 key genes. Related DEGs were further validated by RT-PCR. Western-blot analysis showed that SXNI reversed the abnormal expression of BDNF, TrkB, Mek3 and Jnk1after stroke. ELISA found that SXNI increased brain level of p-Erk and Creb. At sub-brain level, the expression of BDNF and TrkB was decreased and GFAP was increased on the hippocampal CA3 region in the post-stroke recovery phase and this abnormality was improved by SXNI. In vitro experiments also found that oxygen glucose deprivation reduced the expression of BDNF and TrkB, which was reversed by SXNI. In summary, we conclude that SXNI facilitates the recovery of cognitive and locomotor dysfunction by modulating Neurotrophin/Trk Signaling in a mouse model for the recovery phase of post-ischemic stroke.

Sepsis-induced myocardial dysfunction is a major contributor to the poor outcomes of septic shock. As an add-on with conventional sepsis management for over 15 years, the effect of Xuebijing injection (XBJ) on the sepsis-induced myocardial dysfunction was not well understood. The material basis of Xuebijing injection (XBJ) in managing infections and infection-related complications remains to be defined. A murine cecal ligation and puncture (CLP) model and cardiomyocytes in vitro culture were adopted to study the influence of XBJ on infection-induced cardiac dysfunction. XBJ significantly improved the survival of septic-mice and rescued cardiac dysfunction in vivo. RNA-seq revealed XBJ attenuated the expression of proinflammatory cytokines and related signalings in the heart which was further confirmed on the mRNA and protein levels. Xuebijing also protected cardiomyocytes from LPS-induced mitochondrial calcium ion overload and reduced the LPS-induced ROS production in cardiomyocytes. The therapeutic effect of XBJ was mediated by the combination of paeoniflorin and hydroxysafflor yellow A (HSYA) (C0127-2). C0127-2 improved the survival of septic mice, protected their cardiac function and cardiomyocytes while balancing gene expression in cytokine-storm-related signalings, such as TNF-α and NF-κB. In summary, Paeoniflorin and HSYA are key active compounds in XBJ for managing sepsis, protecting cardiac function, and controlling inflammation in the cardiac tissue partially by limiting the production of IL-6, IL-1β, and CXCL2.

Effective therapies for stroke are still limited due to its complex pathological manifestations. QiShenYiQi (QSYQ), a component-based Chinese medicine capable of reducing organ injury caused by ischemia/reperfusion, may offer an alternative option for stroke treatment and post-stroke recovery. Recently, we reported a beneficial effect of QSYQ for acute stroke via modulation of the neuroinflammatory response. However, if QSYQ plays a role in subacute stroke remains unknown. The pharmacological action of QSYQ was investigated in experimental stroke rats which underwent 90 min ischemia and 8 days reperfusion in this study. Neurological and locomotive deficits, cerebral infarction, brain edema, and BBB integrity were assessed. TMT-based quantitative proteomics were performed to identify differentially expressed proteins following QSYQ treatment. Immunohistochemistry, western blot analysis, RT-qPCR, and ELISA were used to validate the proteomics data and to reveal the action mechanisms. Therapeutically, treatment with QSYQ (600 mg/kg) for 7 days significantly improved neurological recovery, attenuated infarct volume and brain edema, and alleviated BBB breakdown in the stroke rats. Bioinformatics analysis indicated that protein galectin-3 and its mediated inflammatory response was closely related to the beneficial effect of QSYQ. Specially, QSYQ (600 mg/kg) markedly downregulated the mRNA and protein expression levels of galectin-3, TNF-α, and IL-6 in CI/RI brain as well as serum levels of TNF-α and IL-6. Overall, our findings showed that the effective action of QSYQ against the subacute phase of CI/RI occurs partly via regulating galectin-3 mediated inflammatory reaction.

Haze can cause a significant reduction in the contrast and brightness of images. CNN-based methods have achieved benign performance on synthetic data. However, they show weak generalization performance on real data because they are only trained on fully labeled data, ignoring the role of natural data in the network. That is, there exists distribution shift. In addition to using little real data for training image dehazing networks in the literature, few studies have designed losses to constrain the intermediate latent space and the output simultaneously. This paper presents a semi-supervised neural process dehazing network with asymmetry pseudo labels. First, we use labeled data to train a backbone network and save intermediate latent features and parameters. Then, in the latent space, the neural process maps the latent features of real data to the latent space of synthetic data to generate one pseudo label. One neural process loss is proposed here. For situations where the image may be darker after dehazing, another pseudo label is created, and one new loss is used to guide the dehazing result at the output end. We combine the two pseudo labels with designed losses to suppress the distribution shift and guide better dehazing results. Finally, the artificial and hazy natural images are tested experimentally to demonstrate the method’s effectiveness.

Acute gut graft-versus-host disease (aGVHD) is a leading threat to the survival of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Abnormal gut microbiota is correlated with poor prognosis in allo-HSCT recipients. A disrupted intestinal microenvironment exacerbates dysbiosis in GVHD patients. We hypothesized that maintaining the integrity of the intestinal barrier may protect gut microbiota and attenuate aGVHD. This hypothesis was tested in a murine aGVHD model and an in vitro intestinal epithelial culture. Millipore cytokine array was utilized to determine the expression of proinflammatory cytokines in the serum. The 16S rRNA sequencing was used to determine the abundance and diversity of gut microbiota. Combining Xuebijing injection (XBJ) with a reduced dose of cyclosporine A (CsA) is superior to CsA alone in improving the survival of aGVHD mice and delayed aGVHD progression. This regimen also reduced interleukin 6 (IL-6) and IL-12 levels in the peripheral blood. 16S rRNA analysis revealed the combination treatment protected gut microbiota in aGVHD mice by reversing the dysbiosis at the phylum, genus, and species level. It inhibited enterococcal expansion, a hallmark of GVHD progression. It inhibited enterococcal expansion, a hallmark of GVHD progression. Furthermore, Escherichia coli expansion was inhibited by this regimen. Pathology analysis revealed that the combination treatment improved the integrity of the intestinal tissue of aGVHD mice. It also reduced the intestinal permeability in aGVHD mice. Besides, XBJ ameliorated doxorubicin-induced intestinal epithelial death in CCK-8 assay. Overall, combining XBJ with CsA protected the intestinal microenvironment to prevent aGVHD. Our findings suggested that protecting the intestinal microenvironment could be a novel strategy to manage aGVHD. Combining XBJ with CsA may reduce the side effects of current aGVHD prevention regimens and improve the quality of life of allo-HSCT recipients.

Phosphorus in the form of phosphate (Pi) is an essential element for metabolic processes, including lipid metabolism. In yeast, the inositol polyphosphate kinase vip1 mediated synthesis of inositol heptakisphosphate (IP7) regulates the phosphate-responsive (PHO) signaling pathway, which plays an important role in response to Pi stress. The role of vip1 in Pi stress and lipid metabolism of Candida albicans has not yet been studied. We found that when vip1Δ/Δ was grown in glucose medium, if Pi was supplemented in the medium or mitochondrial Pi transporter was overexpressed in the strain, the lipid droplet (LD) content was reduced and membrane damage was alleviated. However, further studies showed that neither the addition of Pi nor the overexpression of the Pi transporter affected the energy balance of vip1Δ/Δ. In addition, the LD content of vip1Δ/Δ grown in Pi limitation medium PNMC was lower than that grown in SC, and the metabolic activity of vip1Δ/Δ grown in PNMC was also lower than that grown in SC medium. This suggests that the increase in Pi demand by a high energy metabolic rate is the cause of LD accumulation in vip1Δ/Δ. In addition, in the vip1Δ/Δ strains, the core transcription factor PHO4 in the PHO pathway was transported to the vacuole and degraded, which reduced the pathway activity. However, this does not mean that knocking out vip1 completely blocks the activation of the PHO pathway, because the LD content of vip1Δ/Δ grown in the medium with β-glycerol phosphate as the Pi source was significantly reduced. In summary, the increased Pi demand and the decreased PHO pathway activity in vip1Δ/Δ ultimately lead to LD accumulation and cell membrane damage.

Post-stroke neural damage is a serious health concern which does not yet have an effective treatment. We have shown previously that Shuxuening injection (SXNI), a Ginkgo biloba extract-based natural medicine, protects brain after an acute ischemic stroke, but its efficacy for post-stroke recovery is not known. This study was to investigate whether SXNI can improve the prognosis of stroke at a subacute phase. Mice with cerebral ischemia-reperfusion injury (CIRI) were established by middle cerebral artery occlusion (MCAO), and drugs or saline were injected by the tail vein every 12 h after reperfusion. The therapeutic effect of SXNI was evaluated by survival rate, modified neurologic severity scores (mNSS), open-field test, locomotive gait patterns, cerebral infarction volume, brain edema and histopathological changes. Subsequently, a combined method of RNA-seq and Ingenuity® Pathway Analysis (IPA) was performed to identify key targets and pathways of SXNI facilitating the prognosis of stroke in mouse brain. The results of the transcriptome analysis were verified by real time reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), western blot (WB) and immunohistochemistry (IHC). The experimental results showed that in the new subacute stroke model, SXNI markedly improves the survival rate, neurological and motor functions and histopathological changes, and significantly reduces cerebral infarction and edema volume. RNA-seq analysis of subacute stroke mice with or without SXNI (3 mL/kg) indicated 963 differentially expressed genes (DEGs) with a fold change ≥ 1.5 and a P-value ≤ 0.01. IPA analysis of DEGs showed that granulocyte adhesion and diapedesis ranked first in the pathway ranking, and the most critical gene regulated by SXNI was G-csf. Simultaneously, RT-PCR, ELISA, WB and IHC results demonstrated that SXNI not only obviously reduced the mRNA expression levels of key genes G-csf, Sele and Mac-1 in this pathway, but also significantly decreased the protein expression levels of G-CSF in serum and E-selectin and MAC-1 in brain tissues. In summary, our research suggested that SXNI can exert a remarkable neurofunctional therapeutic effect on stroke mice via down-regulating G-CSF to inhibit granulocyte adhesion and diapedesis. This study provides experimental evidence that SXNI may fulfill the need for stroke medicine targeting specifically at the recovery stage.

Cerebral ischemia/reperfusion injury (CI/RI) is a common feature of ischemic stroke, involving a period of impaired blood supply to the brain, followed by the restoration of cerebral perfusion through medical intervention. Although ischemia and reperfusion brain damage is a complex pathological process with an unclear physiological mechanism, more attention is currently focused on the neuroinflammatory response of an ischemia/reperfusion origin, and anti-inflammatory appears to be a potential therapeutic strategy following ischemic stroke. QiShenYiQi (QSYQ), a component-based Chinese medicine with Qi-tonifying and blood-activating property, has pharmacological actions of anti-inflammatory, antioxidant, mitochondrial protectant, anti-apoptosis, and antiplatelet aggregation. We have previously reported that the cardioprotective effect of QSYQ against ischemia/reperfusion injury is via improvement of mitochondrial functional integrity. In this research work, we aimed to investigate the possible mechanism involved in the neuroprotection of QSYQ in mice model of cerebral ischemia/reperfusion injury based on the inflammatory pathway. The cerebral protection was evaluated in the stroke mice after 24 h reperfusion by assessing the neurological deficit, cerebral infarction, brain edema, BBB functionality, and via histopathological assessment. TCM-based network pharmacology method was performed to establish and analyze compound-target-disease & function-pathway network so as to find the possible mechanism linking to the role of QSYQ in CI/RI. In addition, RT-qPCR was used to verify the accuracy of predicted signaling gene expression. As a result, improvement of neurological outcome, reduction of infarct volume and brain edema, a decrease in BBB disruption, and amelioration of histopathological alteration were observed in mice pretreated with QSYQ after experimental stroke surgery. Network pharmacology analysis revealed neuroinflammatory response was associated with the action of QSYQ in CI/RI. RT-qPCR data showed that the mice pretreated with QSYQ could significantly decrease IFNG-γ, IL-6, TNF-α, NF-κB p65, and TLR-4 mRNA levels and increase TGF-β1 mRNA level in the brain compared to the untreated mice after CI/RI (p < 0.05). In conclusion, our study indicated the cerebral protective effect of pretreatment with QSYQ against CI/RI, which may be partly related to its potential to the reduction of neuroinflammatory response in a stroke subject.

Paeoniflorin (PF) possesses multiple biological functions including anti-oxidization. PF is the major bioactive ingredient of total glycosides of paeony (TGP), which could promote re-pigmentation of vitiligo. The study was sought to investigate the effects and potential signaling pathways of PF on hydrogen peroxide (H2O2)-induced oxidative stress in melanocytes. The results showed that pretreatment with 50 µM PF significantly inhibited cell apoptosis, enhanced cell viability, and suppressed reactive oxygen species (ROS) accumulation by enhancing the productions of superoxide dismutase (SOD) and antioxidant enzymes catalase (CAT). Furthermore, PF activated c-Jun amino terminal kinase (JNK) and the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway to counteract H2O2-induced oxidative damage in PIG1 and PIG3V. Taken together, our study firstly demonstrates that PF resists H2O2-induced oxidative stress in melanocytes probably by activating JNK/Nrf2/HO-1 signaling, suggesting a potential therapeutic application of PF on vitiligo.

Sepsis and septic shock threaten the survival of millions of patients in the intensive care unit. Secondary fungal infections significantly increased the risk of mortality in sepsis patients. Chinese medicine Xuebijing injection (XBJ) has been routinely used as an add-on treatment to sepsis and septic shock in China. Our network pharmacology analysis predicted that XBJ also influences fungal infection, consisting with results of pioneer clinical studies. We conducted in vivo and in vitro experiments to verify this prediction. To our surprise, XBJ rescued mice from lethal Candida sepsis in a disseminated Candida albicans infection model and abolished the colonization of C. albicans in kidneys. Although XBJ did not inhibit the growth and the virulence of C. albicans in vitro, it enhanced the viability of 293T cells upon C. albicans insults. Further RNA-seq analysis revealed that XBJ activated the endoplasmic reticulum (ER) stress pathway upon C. albicans infection. Western blot confirmed that XBJ maintained the expression of GRP78 in the presence of C. albicans. Interestingly, key active ingredients in XBJ (C0127) mirrored the effects of XBJ. C0127 not only rescued mice from lethal Candida sepsis and prevented the colonization of C. albicans in kidneys, but also sustained the survival of kidney epithelial cells partially by maintaining the expression of GRP78. These results suggested that XBJ may prevent fungal infection in sepsis patients. Pre-activation of ER stress pathway is a novel strategy to control C. albicans infection. Network pharmacology may accelerate drug development in the field of infectious diseases.

Summary: RHOA, a founding member of the Rho GTPase family, is critical for actomyosin dynamics, polarity, and morphogenesis in response to developmental cues, mechanical stress, and inflammation. In murine small intestinal epithelium, inducible RHOA deletion causes a loss of epithelial polarity, with disrupted villi and crypt organization. In the intestinal crypts, RHOA deficiency results in reduced cell proliferation, increased apoptosis, and a loss of intestinal stem cells (ISCs) that mimic effects of radiation damage. Mechanistically, RHOA loss reduces YAP signaling of the Hippo pathway and affects YAP effector epiregulin (EREG) expression in the crypts. Expression of an active YAP (S112A) mutant rescues ISC marker expression, ISC regeneration, and ISC-associated Wnt signaling, but not defective epithelial polarity, in RhoA knockout mice, implicating YAP in RHOA-regulated ISC function. EREG treatment or active β-catenin Catnblox(ex3) mutant expression rescues the RhoA KO ISC phenotypes. Thus, RHOA controls YAP-EREG signaling to regulate intestinal homeostasis and ISC regeneration. : In this article, Zheng and colleagues show that inducible RHOA deletion in mice causes defects in intestine epithelial polarity and deficiencies in intestinal stem cell proliferation, survival, and regeneration. They further demonstrate by genetic rescues that RHOA controls a YAP-EREG axis to mediate canonical Wnt signaling, intestinal stem cell function, and intestinal homeostasis. Keywords: mouse model, intestinal stem cell, regeneration, Rho GTPase, RhoA, Hippo signaling, YAP, Wnt signaling

Aiming at the problem of the poor robustness of existing methods to deal with diverse industrial weld image data, we collected a series of asymmetric laser weld images in the largest laser equipment workshop in Asia, and studied these data based on an industrial image processing algorithm and deep learning algorithm. The median filter was used to remove the noises in weld images. The image enhancement technique was adopted to increase the image contrast in different areas. The deep convolutional neural network (CNN) was employed for feature extraction; the activation function and the adaptive pooling approach were improved. Transfer Learning (TL) was introduced for defect detection and image classification on the dataset. Finally, a deep learning-based model was constructed for weld defect detection and image recognition. Specific instance datasets verified the model’s performance. The results demonstrate that this model can accurately identify weld defects and eliminate the complexity of manually extracting features, reaching a recognition accuracy of 98.75%. Hence, the reliability and automation of detection and recognition are improved significantly. The research results can provide a theoretical and practical reference for the defect detection of sheet metal laser welding and the development of the industrial laser manufacturing industry.

Blood activation and stasis removal from circulation is a central principle for treatment of syndromes related to cerebral and cardiovascular diseases in Chinese herbal medicine. However, blood-activating and stasis-removing patent Chinese herbal medicine (BASR-pCHM) widely used with or without prescription in China and elsewhere are highly variable in composition and manufacture standard, making their safety assessment a challenging task. We proposed that an integrated evaluation of multiple toxicity parameters of BASR-pCHM would provide critical reference and guidelines for their safe clinical application. Examination of standardized extracts from 58 compound BASR-pCHM in vivo in VEGFR2-luc mice and in vitro in cardiac, renal, and hepatic cells identified Naoluotong capsule (NLTC) as a potent organ/cell damage inducer. Composition analysis revealed that NLTC was the one that contained nonherbal ingredients among the BASR-pCHM collection. In vivo and in vitro experiments confirmed that NLTC, as well as its chemical supplement tolperisone hydrochloride, caused organ and cell damage by reducing cell viability, mitochondrial mass/activity, while the NLTC herbal components did not. Taken together, our study showed that safety evaluation of patent herbal medicines already on market is still necessary and urgently needed. In addition, chemical/herbal interactions should be considered as an important contributor of potential toxicity when evaluating the safety of herbal medicine.

Natural killer (NK) cells play an irreplaceable role in the development of colon cancer, in which antitumor function of NK cells was impaired. Astragaloside III is a natural compound from Astragalus that has been shown to have immunomodulatory effects in various systems. However, few studies have evaluated the antitumor effects of Astragaloside III through stimulating systemic immunity and regulating NK cells. In this study, flow cytometry, immunohistochemical analysis, and immunofunctional assays were performed to elucidate the functions of Astragaloside III in restoring antitumor function of NK cells. We demonstrated that Astragaloside III significantly elevated the expression of natural killer group 2D (NKG2D), Fas, and interferon-γ (IFN-γ) production in NK cells, leading to increased tumor-killing ability. Experiments in cell co-culture assays and CT26-bearing mice model further confirmed that Astragaloside III could effectively impede tumor growth by increasing infiltration of NK cells into tumor and upregulating the antitumor response of NK cells. We further revealed that Astragaloside III increased IFN-γ secretion of NK cells by enhancing the expression of transcription factor T-bet. In conclusion, the effective anti-tumor function of Astragaloside III was achieved through up-regulation of the immune response of NK cells and elevation of NKG2D, Fas, and IFN-γ production.

Lapses in the graft-vs.-host disease (GVHD) prophylaxis and side effects of current standard care following allogeneic hematopoietic stem cell transplantation (allo-HSCT) call for novel regimens. Traditional approaches targeting T cells showed limited success in preventing acute GVHD (aGVHD). System medicine showed promising results treating complex diseases such as sepsis and multi-organ dysfunction syndrome (MODS). Adapting established network pharmacology analysis methods, we aimed to develop novel integrative regimens to prevent aGVHD. Our network pharmacology analysis predicted that Xuebijing injection (XBJ) targets a series of key node proteins in aGVHD network. It also unveiled that Salviae miltiorrhizae (Danshen), an herb in Xuebijing formula, which prevented aGVHD in rats, shares five out of six key GVHD node proteins targeted by XBJ. Interestingly, network pharmacology analysis indicated Xuebijing may share multiple aGVHD targets with Cyclosporin A (CsA), a first-line drug for preventing aGVHD in the clinic. Based on current information, we hypothesized that combination of XBJ and CsA may yield superior results in aGVHD prevention than either drug alone. We performed in vitro and in vivo assays to validate the predictions by the network pharmacology analysis. In vitro assays revealed XBJ prevented platelet aggregation and NF-κB nuclear translocation in macrophages. XBJ also promoted angiogenesis in tube-formation assay. Importantly, the combination of CsA and XBJ was effective in rescuing mice subjected to lethal GVHD. XBJ contributed to the rescue through preventing NF-κB nuclear translocation, attenuating inflammation and maintaining viability of macrophages. Overall, network pharmacology is a powerful tool to develop novel integrative regimens. Combination of XBJ and CsA may shed light on preventing aGVHD.

In this paper, a fixed-point iterative filter developed from the classical extended Kalman filter (EKF) was proposed for general nonlinear systems. As a nonlinear filter developed from EKF, the state estimate was obtained by applying the Kalman filter to the linearized system by discarding the higher-order Taylor series items of the original nonlinear system. In order to reduce the influence of the discarded higher-order Taylor series items and improve the filtering accuracy of the obtained state estimate of the steady-state EKF, a fixed-point function was solved though a nested iterative method, which resulted in a fixed-point iterative filter. The convergence of the fixed-point function is also discussed, which provided the existing conditions of the fixed-point iterative filter. Then, Steffensen’s iterative method is presented to accelerate the solution of the fixed-point function. The final simulation is provided to illustrate the feasibility and the effectiveness of the proposed nonlinear filtering method.

Estrogen receptor alpha (ERα), a ligand-dependent transcription factor, mediates the expression of its target genes by interacting with corepressors and coactivators. Since the first cloning of SRC1, more than 280 nuclear receptor cofactors have been identified, which orchestrate target gene transcription. Aberrant activity of ER or its accessory proteins results in a number of diseases including breast cancer. Here we identified SFR1, a protein involved in DNA homologous recombination, as a novel binding partner of ERα. Initially isolated in a yeast two-hybrid screen, the interaction of SFR1 and ERα was confirmed in vivo by immunoprecipitation and mammalian one-hybrid assays. SFR1 co-localized with ERα in the nucleus, potentiated ER's ligand-dependent and ligand-independent transcriptional activity, and occupied the ER binding sites of its target gene promoters. Knockdown of SFR1 diminished ER's transcriptional activity. Manipulating SFR1 expression by knockdown and overexpression revealed a role for SFR1 in ER-dependent and -independent cancer cell proliferation. SFR1 differs from SRC1 by the lack of an intrinsic activation function. Taken together, we propose that SFR1 is a novel transcriptional modulator for ERα and a potential target in breast cancer therapy.

The revisit intention of tourists has long been a focal point of academic inquiry. However, there is still insufficient research on the antecedents of revisit intention from the perspectives of historical storytelling, destination image and perceived value. Taking the Mogao Grottoes in Dunhuang, a UNESCO World Heritage Site, as a case study, this paper, based on stimulus–organism–response (SOR) theory, examines the impact of historical storytelling on the destination image, perceived value, and revisit intention. Additionally, it further explores the mediating role of destination image and perceived value, as well as the moderating effect of place attachment in this chain. The research findings indicate that: (1) Historical storytelling significantly enhances tourists' perception of the tourism experience and revisit intention; (2) The study supports the mediating effect of destination image and perceived value; (3) Place attachment has a significant positive moderating effect between historical storytelling and revisit intention. Effective historical storytelling can significantly enhance destination image and perceived value, improve tourists' participation and satisfaction in tourism, stimulate revisit intention, and promote the sustainable development of tourist destinations. These findings enrich the research content of cultural heritage tourism, providing valuable suggestions for improving the management level of cultural heritage tourism attractions and increasing visitors' revisit intention. [ABSTRACT FROM AUTHOR]