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This work aims to explore whether students' learning outcomes in the virtual museum (VM) 's "Life and Science course" are influenced by the type of knowledge and the different levels of interaction within the museum. The study was conducted using an eye-movement experimental method, based on cognitive load theory, knowledge visualisation and connectionist theory, to construct a virtual museum interaction hierarchy index to identify high and low levels of interaction in the experimental material. A randomised two-factor experiment was organised to obtain eye-movement related indicators and to analyse statistical data in conjunction with retention test scores and transfer test scores, taking into account the influence of the perceived difficulty of the learning material and the level of mental effort of the students on the experiment. This study will provide effective suggestions for museum learning design and resource development, ultimately offer insights in exploring the most suitable learning rules and learning material selection for VM learners.

Abstract Data factors have become an essential factor of production in today’s digital era, and provided renewed energy for China’s green and high-quality development. This study analyses the impact of data factor-driven industries on green total factor productivity (GTFP) and the underlying mechanisms using panel data of 277 Chinese cities from 2008 to 2020. The results show that: First, the urban data factor-driven industry can enhance GTFP. Second, the data factor-driven industry can increase the input–output ratio and enhance GTFP by promoting AI technological innovation and AI technological entrepreneurship. Third, the heterogeneity analysis show that in regions with high levels of digital technological innovation, the market size of data factor-driven industries is larger and the effect of data factor-driven industries in enhancing GTFP is more significant. And in regions with low levels of savings, the data factor-driven industry has limited capital availability and is more efficient in using capital, which has a stronger effect on GTFP enhancement. This study provides valuable empirical evidence on the relationship between data factor-driven industries and urban GTFP, and important policy implications for fully leveraging the green economic effects of data factors, and promoting green and high-quality urban development.

To investigate the differences in volatile components during the processing of Fuling Zhacai, or pickled mustard tuber, with three stacked layers of mustard tuber and salt, gas chromatography-tandem mass spectrometry (GC-MS/MS)-based non-targeted metabolomics combined with multivariate statistical analysis was used to analyze the changes in volatile metabolites and significantly differential metabolic pathways during the spontaneous fermentation of Zhacai. The results showed that a total of 627 volatile compounds were identified from Zhacai samples at different pickling stages, including terpenoids, esters, heterocyclic compounds, terpenoids, aldehydes, ketones, alcohols, phenols, amines, sulfur compounds, acids, halogenated hydrocarbons, and nitrogen compounds. A significant difference was observed in volatile components among pickling stages. A total 157 unique differential metabolites in the 1st pickling stage vs. the control group, 28 in the 2nd vs. the 1st pickling stage, and one in the 3rd vs. 2nd pickling stage were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the differential metabolites were significantly enriched in metabolic pathways including secondary metabolite biosynthesis, diterpenoid biosynthesis, monoterpenoid biosynthesis, caffeine metabolism, and fatty acid biosynthesis. This study provides a theoretical basis for the standardized production of Fuling Zhacai.

Abstract This paper introduces a novel application of spatial-temporal graph neural networks (ST-GNNs) to predict groundwater levels. Groundwater level prediction is inherently complex, influenced by various hydrological, meteorological, and anthropogenic factors. Traditional prediction models often struggle with the nonlinearity and non-stationary characteristics of groundwater data. Our study leverages the capabilities of ST-GNNs to address these challenges in the Overbetuwe area, Netherlands. We utilize a comprehensive dataset encompassing 395 groundwater level time series and auxiliary data such as precipitation, evaporation, river stages, and pumping well data. The graph-based framework of our ST-GNN model facilitates the integration of spatial interconnectivity and temporal dynamics, capturing the complex interactions within the groundwater system. Our modified Multivariate Time Graph Neural Network model shows significant improvements over traditional methods, particularly in handling missing data and forecasting future groundwater levels with minimal bias. The model’s performance is rigorously evaluated when trained and applied with both synthetic and measured data, demonstrating superior accuracy and robustness in comparison to traditional numerical models in long-term forecasting. The study’s findings highlight the potential of ST-GNNs in environmental modeling, offering a significant step forward in predictive modeling of groundwater levels.

Abstract Lake is an important water resources in Mongolia, which has undergone a large variation in past decades. However, it is still challenging to monitor long-term changes in lake water storage (LWS) due to the lack of lake level monitoring and long-term satellite altimetry data for Mongolian lakes. According to the Advanced Land Observing Satellite Digital Elevation Model (ALOS DEM) and the Joint Research Centre (JRC) dataset, we estimated the LWS changes of 55 Mongolian lakes (> 10 km2) from 1991 to 2020. The results showed that the LWS increased by 40.24 km3 from 1991 to 1997, especially for northwestern Mongolia with 31.47 km3. However, the LWS decreased by 32.44 km3 from 1998 to 2010, and the lakes in the northwestern and southern decreased by 20.24 km3 (62%) and 7.38 km3 (23%), respectively, and then the LWS continued to decrease by 10.22 km3 from 2011 to 2020. The precipitation was the primary cause of lake change, which could explain 45.13% of LWS change based on Generalized Linear Model, followed by temperature (26.33%) and irrigated area (16.72%). Analyzing the changing characteristic and driving mechanisms of LWS can provide a scientific basis for local water resources management and planning.

Abstract DNA cleavage by nanomaterials has the potential to be utilized as an innovative tool for gene editing. Numerous nanomaterials exhibiting DNA cleavage properties have been identified and cataloged. Yet, the exploitation of property data through data-driven machine-learning approaches remains unexplored. A database was developed, compiling thirty distinctive characteristics, encompassing physical and chemical properties, as well as experimental conditions of nanomaterials that have demonstrated DNA cleavage capability such as in articles published over the past two decades. The DNA cleavage effect and efficiency of nanomaterials were predicted using machine learning algorithms such as support vector machines, deep neural networks, and random forest, and a classification accuracy of 0.93 for the cleavage effect was achieved. Moreover, the potential of utilizing larger datasets to enhance the predictive capacity of models was discussed. The findings indicate the feasibility of predicting nanomaterial properties based on experimental data. Evaluating the performance and effectiveness of the machine learning models trained using the existing data can furnish valuable insights for future materials research endeavors, especially for the design of DNA cleavage with specific sites.

Abstract Background Post-translational modification pathway of protein ubiquitination is intricately associated with tumorigenesis. We previously reported elevated ubiquitin-conjugating enzyme 2T (UBE2T) as an independent risk factor in stage I lung adenocarcinoma and promoting cellular proliferation. However, its underlying mechanisms needed further investigation. Methods Immunohistochemistry was used to assess the expression of UBE2T and retinoic acid receptor-related orphan receptor α (RORA) in stage I LUAD. Cell proliferation, migration, and invasion of LUAD cell lines were measured by Cell Counting Kit-8 assay (CCK-8), Colony-forming assay and Transwell assay, respectively. Western blot analysis was performed to determine the expression of epithelial-mesenchymal transition (EMT) markers. A xenograft model was established to evaluate the proliferative capacity of UBE2T and its interaction with RORA in promoting LUAD. Mechanistic insights into the promotion of early-stage LUAD by UBE2T were obtained through luciferase reporter assay, chromatin immunoprecipitation and co-immunoprecipitation. Results UBE2T and RORA expression was significantly up- and down-regulated in early-stage LUAD patients which’s proved to be associated with unfavorable outcomes, strengthened cell proliferation, migration, EMT and invasion through its interaction with RORA both in vivo and in vitro. The growth NSCLC xenografts was reduced by down-expression of UBE2T but was suppressed by RORA knockout. Mechanistically, UBE2T mediated the ubiquitination of the intermediate transcription factor PBX1, which played a transcriptional role in downstream regulation of RORA. Conclusion The oncogenic role of UBE2T and the UBE2T-PBX1-RORA axis in driving malignant progression in Stage I LUAD had been established. UBE2T might be a novel and promising therapeutic target for LUAD treatment.

Abstract The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3−/− (Shn3 −/− ) mice with augmented osteoblast activity, we show Shn3 −/− mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3 −/− mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.

Abstract Human society is facing increasingly serious problems of environmental pollution and energy shortage, and up to now, achieving high NH3-SCR activity at ultra-low temperatures (

Since 2018, Shandong Province has successively issued a series of pollution prevention and control programs for air pollutants from the coking industry, which plays a key role in coke production in China. However, a comprehensive assessment of the effectiveness of these measures is lacking. For a better understanding of this issue, based on the published air pollutant emission inventory for the independent coking industry and related policies formulated in Shandong in 2018, this study developed business-as-usual scenarios (BAU-2018, BAU-2025, and BAU-2035) and emission reduction optimization scenarios (ERO-2025 and ERO-2035). The emission reduction potential of PM10, SO2, NOx, PM2.5, and CO2 and their corresponding contributions to Shandong’s air quality with the air quality model (CALPUFF) were assessed under different scenarios. In terms of scenario settings, the gross domestic product of the secondary industry and the coke output of independent coking enterprises were used for linear regression to predict the coke output in 2025 and 2035. The mesoscale atmospheric data model, Weather Research and Forecasting, provided simulated three-dimensional meteorological field data for this study. Regional terrain data (90 m) were obtained from the United States Geological Survey. The resolution of the land use type data was 30 m, according to our previous research results. We adopted the MESOPUFF II chemical mechanism to simulate SO2, NOx, SO42−, NO3−, HNO3, PM10, and PM2.5 pollutants. To ensure the accuracy of the enterprise location information, we examined the enterprise latitude and longitude information one by one using Google Earth location recognition and manual visual inspection. The results showed that in the BAU-2018 scenario, the annual contribution ratios of SO2, NOx, PM10, and PM2.5 in Shandong Province were 0.06%–0.84%, 0.01%–0.63%, 0.04%–0.19%, and 0.07%–0.21%, respectively. Linyi has the highest contribution of SO2 and NOx concentrations to air quality, whereas Jining has the highest contribution of PM10 and PM2.5 concentrations to air quality. Compared with the current scenario (BAU-2018), the emission and contribution concentration of each pollutant showed an alarming decrease in the ERO-2025 scenario. Under the ERO-2035 scenario, the results showed that SO2, NOx, PM10, PM2.5, and CO2 emissions would be reduced by 60.12%, 78.24%, 75.07%, 74.20%, and 37.47%, respectively, compared with those under the BAU-2018 scenario. In the ERO-2035 scenario, the average contribution concentrations of SO2, NOx, PM10, and PM2.5 decreased by 60.74%, 78.56%, 75.00%, and 74.53%, respectively. Moreover, the results of this study showed that the comprehensive implementation of ultralow emission standards in Shandong Province had a considerable impact on air pollutant reduction in the independent coking industry, and the synergistic reduction of air pollutants and carbon dioxide showed huge potential.

Abstract This study aimed to determine the relationships between prenatal PM2.5 exposure and childhood growth trajectories during the first 6 years of life. A total of 47,625 pairs of mothers and children were recruited from a prospective birth cohort conducted between 2011 and 2013 in Wuhan, China, and followed for 6 years. We used the group-based trajectory models to classify the population into three trajectory groups: slow growth (n = 13,671, 28.7%), normal growth (n = 29,736, 62.4%), and rapid growth (n = 4218, 8.9%). Multinomial logistic regression models were used to determine the associations of prenatal PM2.5 exposure and childhood growth trajectories. Compared to normal growth trajectory, increased PM2.5 exposure in trimester 1, trimester 2 and the entire pregnancy showed significant associations with an increased risk of the slow growth trajectory but reduced the risk for the rapid growth trajectory, significant association of prenatal PM2.5 exposure with rapid growth trajectory was only observed in the trimester 3. Stratified analyses displayed relatively stronger associations among those mothers with maternal age over 35 years, pre-pregnancy BMI ≥ 25 kg/m2, and previous delivery experience. Prenatal exposure to PM2.5, particularly during the midpoint period of pregnancy, was more likely to have a slow growth trajectory and a lower risk of rapid growth trajectory. Maternal age, pre-pregnancy BMI, and previous delivery experience might modify these associations.

Abstract Aquaporin 3 (AQP3), which is mostly expressed in pulmonary epithelial cells, was linked to lung adenocarcinoma (LUAD). However, the underlying functions and mechanisms of AQP3 in the tumor microenvironment (TME) of LUAD have not been elucidated. Single-cell RNA sequencing (scRNA-seq) was used to study the composition, lineage, and functional states of TME-infiltrating immune cells and discover AQP3-expressing subpopulations in five LUAD patients. Then the identifications of its function on TME were examined in vitro and in vivo. AQP3 was associated with TNM stages and lymph node metastasis of LUAD patients. We classified inter- and intra-tumor diversity of LUAD into twelve subpopulations using scRNA-seq analyses. The analysis showed AQP3 was mainly enriched in subpopulations of M2 macrophages. Importantly, mechanistic investigations indicated that AQP3 promoted M2 macrophage polarization by the PPAR-γ/NF-κB axis, which affected tumor growth and migration via modulating IL-6 production. Mixed subcutaneous transplanted tumor mice and Aqp3 knockout mice models were further utilized, and revealed that AQP3 played a critical role in mediating M2 macrophage polarization, modulating glucose metabolism in tumors, and regulating both upstream and downstream pathways. Overall, our study demonstrated that AQP3 could regulate the proliferation, migration, and glycometabolism of tumor cells by modulating M2 macrophages polarization through the PPAR-γ/NF-κB axis and IL-6/IL-6R signaling pathway, providing new insight into the early detection and potential therapeutic target of LUAD.

This study performed rational feeding of fermented feed to channel catfish and determined its effects on growth, the intestinal bacterial community, and metabolomics of channel catfish. There were three groups: continuous feeding (A, continuous addition of fermented feed to the puffed feed), interval feeding involving weekly intervals addition of fermented feed added to the puffed feed (B), and the control group only fed the puffed feed (C). The experiment lasted 6 months. Channel catfish were weighed and the intestinal flora and metabolomics were detected by 16S rRNA sequencing technology and liquid chromatography-based metabolomics technology, respectively after the experiment. The final body weight (FBW) of channel catfish was significantly higher in the interval feeding group than that in the control group and the continuous feeding group (P < 0.05). The richness and microbial diversity of the intestine was the highest in the interval feeding group, while the richness of the continuous feeding group was the lowest (P > 0.05). Firmicutes, Actinobacteriota, Cyanobacteria, Proteobacteria, Fusobacteriota, Chloroflexi, and Deinococcota were the dominant bacterial phyla among the intestinal flora. The dominant intestinal genera included norank_f_norank_o_Chloroplast, Mycobacterium, Cetobacterium, Romboutsia, Exiguobacterium and Clostridium_sensu_stricto_1. Metabolomic analysis showed that the continuous feeding group mainly affected galactose metabolism and the phosphotransferase system of the intestinal flora in channel catfish through the significant upregulation of N-acetyl-D-galactosamine (P < 0.05) that affected the digestion and absorption of carbohydrates by fish. The differential metabolites L-serine and L-phenylalanine were significantly upregulated (P < 0.05) in the interval feeding group. This affected sulfur metabolism and amino acid metabolism of the intestinal flora, and affected energy absorption, anti-inflammation, and immunity of the channel catfish. This study provided a theoretical basis for the exploration of feeding methods using fermentation feed and healthy green breeding of channel catfish.

Abstract Administrative regulation is an essential institutional arrangement for governing innovation in big data technology. Administrative penalties are one of its main methods. It is worth investigating whether administrative penalties can serve as an institutional safeguard to promote technological innovation. This study collects data on digital technology administrative penalty (DTAP) and big data technology innovation (BDTI) from 2008 to 2020 in 281 cities in China and empirically evaluates the impact and mechanism of DTAP on BDTI. The findings suggest that the normative impact of the DTAP system can foster a conducive business ecosystem for big data innovation. The incentive mechanism motivates firms to increase their long-term investment in technological innovation, while the deterrence mechanism ensures the existence of a regulated competitive market. These mechanisms play a crucial role in facilitating BDTI. Mechanism tests show that the DTAP has the potential to promote novel business models in the digital economy and accelerate progress in industrial digitalisation, which in turn promotes innovation in big data technologies. The impact of the DTAP on promoting BDTI is diverse, with a significantly greater impact in the first-tier cities. DTAP plays a more important role in fostering BDTI in places where the digital factor-driven industry is still in its early stages of development.

Summary: The onset of atherosclerosis (AS) is insidious, and early stage patients have atypical clinical symptoms. After being diagnosed in late stage, it is often prone to sudden and fatal cardiovascular events. Therefore, it is highly desirable to develop precise and efficient diagnosis and therapy strategies of AS. Benefiting from high signal-to-noise ratio, low detection limit, high specificity and sensitivity, a series of activatable fluorescent probes based on atherosclerotic microenvironment have emerged for identification and treatment of AS. In this review, we focus on the atherosclerotic microenvironment and briefly summarize the correlation between the structural transformation and fluorescence signal changes of mono-/double-activatable fluorescent probes upon biomarkers stimulation. Moreover, their cutting-edge progress for AS theranostics is described. Finally, the outlook for activatable theranostic probes based on atherosclerotic microenvironment is discussed to aim at promoting innovative research in imaging-guided precise AS therapy.

BackgroundThe relationship between the albumin-to-globulin ratio (AGR) and depression is not well understood. This analysis aims to investigate the relationship between AGR in conjunction with depression in U.S. adults.MethodsThis study analyzed information from 31,363 individuals collected by NHANES during the years 2005 to 2018. The PHQ-9 scale was employed to gauge depression, where a score of 10 or above signified depression. Weighted multivariable logistic modeling along with smooth curve fitting were applied to explore the AGR-depression connection. To confirm our findings, we carried out sensitivity analyses, subgroup analyses, and interaction tests.ResultsAfter adjusting for confounding variables, a higher AGR is associated with a lower risk of depression (OR = 0.61, 95% CI: 0.47–0.79). Dividing AGR into quartiles revealed that participants in the highest quartile (Q4) of AGR had a markedly lower risk of depression than those in the lowest quartile (Q1) (OR = 0.64, 95% CI: 0.53–0.77). Using smooth curve fitting, we suggested a possible linear inverse association connecting AGR with depression. Further subgroup and sensitivity analyses supported these findings, although factors such as diabetes and hypertension might influence the relationship.ConclusionOur findings indicate that elevated AGR levels correlate with a lower risk of depression. The findings suggest AGR as a potential biomarker for depression screening and prevention. Further studies are required to determine causality and clarify the mechanisms between AGR and depression.

This study investigated the impact of particle size variation in un-silanized bioactive glass 45S5 (BAG) on the viscosity, stickiness and packability of experimental resin composites, while altering the ratio of 45S5 to inert glass. A series of 25 groups experimental resin composites with a constant total filler loading (65 vol%) were formulated. Filler system contains silanized barium borosilicate (BB, D50 [µm]: 0.7) and un-silanized BAG (45S5). Different ratios of BB and 45S5 were achieved by substituting 65 vol% BB with 0, 5, 10, 15, 20, 25 or 30 vol% of 45S5 (D50 [µm]: 7.0, 10.6, 17.4 and 43.6). The morphology of filler particles and formulated experimental resin composites was examined using a scanning electron microscope (SEM). Viscosity measurements were conducted on both experimental and commercial resin composites measured using an AR-G2 rheometer. A texture analyser instrument was used to measure the stickiness and packability of resin composites. Two commercial resin composites served as control groups for comparison. Statistical analysis, including one-way ANOVA tests, Tukey post-hoc tests (p < 0.05), and Kruskal-Wallis Tests (p < 0.05) for homogeneity of variables, was performed using SPSS software. Results indicated that filler loading and particle size of 45S5 significantly influenced the viscosity, stickiness, and packability of resin composites. Resin composites containing smaller 45S5 particles at lower ratios exhibited characteristics akin to packable resin composites, whereas those with larger 45S5 particles tended to resemble commercial flowable resin composites, contingent upon the particle size and ratio of 45S5.

Business credit supply entails a firm providing credit to its customers as a means to gain a competitive edge. The advent of the digital economy has brought about profound changes in business practices. In this context, it becomes crucial to examine how the digital economy impacts the business credit supply of enterprises. This study employs a theoretical framework to derive insights and carries out an empirical analysis using the City Digital Economy Development Index spanning from 2008 to 2021, along with data from A-share listed companies in Shanghai and Shenzhen. The objective is to explore the influence of the digital economy on corporate business credit supply and its underlying mechanisms. The findings reveal that the digital economy can enhance corporate business credit supply by reducing the incidence of bad debt, thus enabling companies to extend more credit to their customers. This research contributes empirical evidence for understanding the microeconomic impact of the digital economy, while also providing theoretical insights to advance the development of the digital economy and optimize the allocation of financial resources, thereby alleviating corporate financing constraints.

The cure rate for patients with osteosarcoma (OS) has stagnated over the past few decades. Penfluridol, a first-generation antipsychotic, has demonstrated to prevent lung and esophageal malignancies from proliferation and metastasis. However, the effect of penfluridol on OS and its underlying molecular mechanism remains unclear. This study revealed that penfluridol effectively inhibited cell proliferation and migration, and induced G2/M phase arrest in OS cells. In addition, penfluridol treatment was found to increased reactive oxygen species (ROS) levels in OS cells. Combined with the RNA-Seq results, the anti-OS effect of penfluridol was hypothesized to be attributed to the induction of ferroptosis. Western blot results showed that penfluridol promoted intracellular Fe2+ concentration, membrane lipid peroxidation, and decreased intracellular GSH level to induce ferroptosis. Further studies showed that p62/Keap1/Nrf2 signaling pathway was implicated in penfluridol-induced ferroptosis in OS cells. Overexpression of p62 effectively reversed penfluridol-induced ferroptosis. In vivo, penfluridol effectively inhibited proliferation and prolonged survival in xenograft tumor model. Therefore, penfluridol is a promising drug targeting OS in the future.

Achieving high maize yields and efficient phosphorus (P) use with limited environmental impacts is one of the greatest challenges in sustainable maize production. Increasing plant density is considered an effective approach for achieving high maize yields. However, the low mobility of P in soils and the scarcity of natural P resources have hindered the development of methods that can simultaneously optimize P use and mitigate the P-related environmental footprint at high plant densities. In this study, meta-analysis and substance flow analysis were conducted to evaluate the effects of different types of mineral P fertilizer on maize yield at varying plant densities and assess the flow of P from rock phosphate mining to P fertilizer use for maize production in China. A significantly higher yield was obtained at higher plant densities than at lower plant densities. The application of single super-phosphate, triple super-phosphate, and calcium magnesium phosphate at high plant densities resulted in higher yields and a smaller environmental footprint than the application of diammonium phosphate and monoammonium phosphate. Our scenario analyses suggest that combining the optimal P type and application rate with a high plant density could increase maize yield by 22%. Further, the P resource use efficiency throughout the P supply chain increased by 39%, whereas the P-related environmental footprint decreased by 33%. Thus, simultaneously optimizing the P type and application rate at high plant densities achieved multiple objectives during maize production, indicating that combining P management with cropping techniques is a practical approach to sustainable maize production. These findings offer strategic, synergistic options for achieving sustainable agricultural development.

Background: Recently, the osteogenic potential of Adiponectin-labeled adipogenic lineage progenitors (Adipoq-lineage progenitors) in bone marrow has been observed to support bone maintenance and repair. However, little is known about the function of Schnurri-3 (SHN3, also known as HIVEP3) in other mesenchymal lineage cells, apart from its negative regulation of bone formation on osteoblasts. Method: In this study, we used single-cell RNA sequencing (scRNA-seq) profiling to demonstrate that Adipoq-lineage progenitors express higher levels of Shn3 compared to other mesenchymal cell populations in mice and humans. To investigate the role of SHN3 in Adipoq-lineage progenitors, we generated a murine model specifically harboring a Shn3-deficient allele in Adipoq-expressing cells. Information of mice body weight was collected weekly to generate body weight curve. Bone phenotype was analyzed using micro-CT and histomorphometric studies. To eliminate the role of peripheral adipose tissue on bone, we collected adipose wet weight, performed intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests, and conducted a fat-transplantation study. Osteoblast and osteoclast functions were assessed through toluidine blue staining and TRAP staining, respectively. We further investigated the effect of Shn3 depletion on the differentiation of Adipoq-lineage progenitors through immunostaining and in vitro differentiation assays. Finally, we evaluated whether Shn3 deficiency in Adipoq-lineage progenitors affects the fracture healing process by generating bi-cortical femoral fracture models. Results: Depletion of Shn3 in Adipoq-lineage progenitors resulted in a significant increase in trabecular bone mass and bone formation in vivo, without disrupting whole-body energy metabolism and skeletal development. Consistent with these findings, both cell-lineage tracing and functional assays revealed that Shn3 ablation effectively shifted the cell fate of Adipoq-lineage progenitors towards an osteogenic phenotype in the bone marrow. Furthermore, in vivo studies demonstrated that the lack of Shn3 in Adipoq-lineage progenitors also enhanced bone fracture healing under pathological conditions. Conclusion: Overall, our findings provide a novel strategy for targeting the osteoanabolic potential of bone marrow Adipoq-lineage progenitors as a potential treatment for bone loss-related disorders. Translational potential of this article: We have identified a novel gene target that directs the cell fate of a previously identified non-osteogenic cell population under physiological conditions. This study not only expands the therapeutic value of Shn3 ablation in treating osteoporotic or traumatic bone diseases but also provides new insights into the contribution of bone marrow Adipoq-lineage progenitors to osteogenesis. Thus, this article further supports Shn3 silencing as a valuable approach to treat osteopenia and accelerate fracture healing (see graphical abstract)

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells. The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2, resulting in conversion of Bcl-2 from a survival to killer. As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy, targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics. Here, we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway. In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer (TNBC) and MCF-7/LCC2 tamoxifen-resistant breast cancer (TAMR) in a Nur77-dependent manner. Mechanistic studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria, resulting in mitochondria-related apoptosis. Interestingly, XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates. Together, our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

Abstract Background To characterize the current state of emergency medicine (EM) and the requirements for advancing EM clinical practice, education and research in China. Methods An anonymous electronic survey was conducted by Chinese Society of Emergency Medicine during September to October 2021. The survey contained 30 questions divided into 2 sections: the current state of EM development and the requirements for EM growth. Results 722 hospitals were included, of 487 were Level III and 235 were Level II hospitals. We found that after 40 years of development, EM had established a mature disciplinary system and refined sub-specialties including critical care, cardiopulmonary resuscitation, toxicology, disaster and emergency rescue. In Level III hospitals, 70.8% of EDs were standardized training centers for EM residents, but master’s degree program, Doctor Degree program and post-doctoral degree program was approved in only 37.8%, 8.4% and 2.9% of EDs respectively and postgraduate curriculum was available in 1/4 of EDs. Only 8% have national or provincial key laboratories. In addition to advance clinical practice, there was also a high demand to improve teaching and research capacities, mainly focusing on literature review, research design and delivery, paper writing, residency training. Conclusions EM has built a mature discipline system and refined sub-specialties in China. Teaching and research developed parallel with clinical practice. However, there was still a lack of EM master’s and doctoral programs and research capacities need to be improved. More outstanding clinical and academic training should be provided to promote the rapid growth of EM in China.

Abstract Phyllosphere endophytes play a critical role in a myriad of biological functions, such as maintaining plant health and overall fitness. They play a determinative role in crop yield and quality by regulating vital processes, such as leaf functionality and longevity, seed mass, apical growth, flowering, and fruit development. This study conducted a comprehensive bibliometric analysis aiming to review the prevailing research trajectories in phyllosphere endophytes and harness both primary areas of interest and emerging challenges. A total of 156 research articles on phyllosphere endophytes, published between 2002 and 2022, were retrieved from the Web of Science Core Collection (WoSCC). A systematic analysis was conducted using CiteSpace to visualize the evolution of publication frequency, the collaboration network, the co-citation network, and keywords co-occurrence. The findings indicated that initially, there were few publications on the topic of phyllosphere endophytes. However, from 2011 onwards, there was a notable increase in the number of publications on phyllosphere endophytes, gaining worldwide attention. Among authors, Arnold, A Elizabeth is widely recognized as a leading author in this research area. In terms of countries, the USA and China hold the highest rankings. As for institutional ranking, the University of Arizona is the most prevalent and leading institute in this particular subject. Collaborative efforts among the authors and institutions tend to be confined to small groups, and a large-scale collaborative network needs to be established. This study identified the influential journals, literature, and hot research topics. These findings also highlight the interconnected nature of key themes, e.g., phyllosphere endophyte research revolves around the four pillars: diversity, fungal endophytes, growth, and endophytic fungi. This study provides an in-depth perspective on phyllosphere endophytes studies, revealing the identification of biodiversity and microbial interaction of phyllosphere endophytes as the principal research frontiers. These analytical findings not only elucidate the recent trajectory of phyllosphere endophyte research but also provide invaluable insights for similar studies and their potential applications on a global scale.

Abstract Immune checkpoint inhibitor (ICI) rechallenge in non‐small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD‐1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Introduction Bronchiolitis is one of the most common reasons for hospital admissions in early childhood. As supportive treatment, some treatment guidelines suggest using nasal irrigation with normal saline (NS) to facilitate clearance of mucus from the airways. In addition, most paediatric departments in Denmark use nebulised NS for the same purpose, which can mainly be administered as inpatient care. However, no studies have ever directly tested the effect of saline in children with bronchiolitis.Methods and analysis The study is an investigator-initiated, multicentre, open-label, randomised, controlled non-inferiority trial and will be performed at six paediatric departments in eastern Denmark. We plan to include 300 children aged 0–12 months admitted to hospital with bronchiolitis. Participating children are randomised 1:1:1 to nebulised NS, nasal irrigation with NS or no saline therapy. All other treatment will be given according to standard guidelines.The primary outcome is duration of hospitalisation, analysed according to intention-to-treat analysis using linear regression and Cox regression analysis. By including at least 249 children, we can prove non-inferiority with a limit of 12 hours admission, alpha 2.5% and a power of 80%. Secondary outcomes are need for respiratory support with nasal continuous positive airway pressure or high-flow oxygen therapy and requirement of fluid supplements (either by nasogastric tube or intravenous).Ethics and dissemination This study may inform current practice for supportive treatment of children with bronchiolitis. First, if NS is found to be helpful, it may be implemented into global guidelines. If no effect of NS is found, we can stop spending resources on an ineffective treatment. Second, if NS is effective, but nasal irrigation is non-inferior to nebulisation, it may reduce the workload of nurses, and possible duration of hospitalisation because the treatment can be delivered by the parents at home.Trial registration number NCT05902702.

Summary: Background: Endovascular therapy (EVT) was demonstrated effective in acute large vessel occlusion (LVO) with large infarction. Revealing subgroups of patients who would or would not benefit from EVT will further inform patient selection for EVT. Methods: This post-hoc analysis of the ANGEL-ASPECT trial, a randomised controlled trial of 456 adult patients with acute anterior-circulation LVO and large infarction, defined by ASPECTS 3–5 or infarct core volume 70–100 mL, enrolled from 46 centres across China, between October 2, 2020 and May 18, 2022. Patients were randomly assigned (1:1) to receiving EVT and medical management or medical management alone. One patient withdrew consent, 455 patients were included in this post-hoc analysis and categorised into 4 subgroups by lower or higher NIHSS (< or ≥16) and smaller or larger infarct core (< or ≥70 mL). Those with lower NIHSS & smaller core, and higher NIHSS & larger core were considered clinical-radiological matched subgroups; otherwise clinical-radiological mismatched subgroups. Primary outcome was 90-day modified Rankin Scale (mRS). ANGEL-ASPECT is registered with ClinicalTrials.gov, NCT04551664. Findings: Overall, 139 (30.5%) patients had lower NIHSS & smaller core, 106 (23.3%) higher NIHSS & larger core, 130 (28.6%) higher NIHSS & smaller core, and 80 (17.6%) lower NIHSS & larger core. There was significant ordinal shift in the 90-day mRS toward a better outcome with EVT in clinical-radiological matched subgroups: lower NIHSS & smaller core (generalised OR, 1.76; 95% CI, 1.18–2.62; p = 0.01) and higher NIHSS & larger core (1.64; 1.06–2.54; 0.01); but not in the two clinical-radiological mismatched subgroups. Interpretation: Our findings suggested that in patients with anterior-circulation LVO and large infarction, EVT was associated with improved 90-day functional outcomes in those with matched clinical and radiological severities, but not in those with mismatched clinical and radiological severities. Simultaneous consideration of stroke severity and infarct core volume may inform patient selection for EVT. Funding: Unrestricted grants from industry [Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology].

UV-B radiation and drought majorly restrict plant growth, particularly in summer. ELONGATED HYPOCOTYL 5 (HY5), a bZIP transcription factor (TF), has a beneficial impact on photomorphogenesis. However, the sequence of HY5 from Betula platyphylla (BpHY5) has not been identified and the gene functions remain unclarified. We cloned the sequence of BpHY5, which was targeted to the nucleus. The hypocotyl phenotypes of heterologous expression in Arabidopsis thaliana and reverse mutation showed that BpHY5 is homologous to AtHY5. The expression of BpHY5 was increased in response to UV-B radiation, drought conditions, and the presence of abscisic acid (ABA). The overexpression of BpHY5 resulted in increased tolerance to UV-B radiation and drought and decreased ABA sensitivity with higher germination and greening rate, more developmental root system, stronger reactive oxygen species scavenging ability, and lower damage degree. The lignin content under UV-B condition of BpHY5/Col was higher than that of Col. Furthermore, overexpressing BpHY5 up-regulated the expression of genes related to tolerance (NCED3/9, ABI5, DREB2A, RD20, ERF4, NDB2, and APX2). In brief, the study suggests that BpHY5 from birch serves as a beneficial modulator of plant responses to UV-B radiation and drought stress.

Abstract Gangliosides play vital biological regulatory roles and are associated with neurological system diseases, malignancies, and immune deficiencies. They have received extensive attention in developing targeted drugs and diagnostic markers. However, it is difficult to obtain enough structurally defined gangliosides and analogs especially at an industrial-relevant scale, which prevent exploring structure-activity relationships and identifying drug ingredients. Here, we report a highly modular chemoenzymatic cascade assembly (MOCECA) strategy for customized and large-scale synthesis of ganglioside analogs with various glycan and ceramide epitopes. We typically accessed five gangliosides with therapeutic promising and systematically prepared ten GM1 analogs with diverse ceramides. Through further process amplification, we achieved industrial production of ganglioside GM1 in the form of modular assembly at hectogram scale. Using MOCECA-synthesized GM1 analogs, we found unique ceramide modifications on GM1 could enhance the ability to promote neurite outgrowth. By comparing the structures with synthetic analogs, we further resolved the problem of contradicting descriptions for GM1 components in different pharmaceutical documents by reinterpreting the exact two-component structures of commercialized GM1 drugs. Because of its applicability and stability, the MOCECA strategy can be extended to prepare other glycosphingolipid structures, which may pave the way for developing new glycolipid drugs.

Temperature uniformity and temperature fluctuation are two important parameters of refrigerator and have significant effects on fresh-keeping and cold-storage technology. The influencing factors of temperature distribution attract more attention in refrigerator factory. However, the definitions of temperature uniformity and temperature fluctuation are still ambiguous, and present characterization methods cannot accurately describe the temperature field of refrigerator. This paper proposed a novel dual characterization method to reveal the temperature uniformity and fluctuation (TUF) and presented a new arrangement strategy of temperature measuring elements in refrigerator. Results show the proposed method can simultaneously and visibly characterize the TUF behavior. The slope and area of curves in temperature radar chart reveal the TUF distribution clearly. The first layer of refrigerator shows a greater temperature fluctuation, especially when the compressor is working. Refrigerators with different volume have different TUF phenomena. Adding a cold storage module on the top of refrigerator can notably improve TUF feature and make the internal temperature closer to target temperature. The mechanism of TUF change was discussed from heat transfer and cascaded energy utilization. The proposed dual characterization method can reveal temperature distribution with space and time simultaneously and help improve the temperature field of cold-heat preservation to save energy.

Abstract Immune checkpoint inhibitors (PD‐1/PD‐L1 and CTLA‐4 blockade) have revolutionized the treatment landscape in non‐small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO‐IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Abstract Objective: To investigate the involvement of HOX transcript antisense RNA (HOTAIR) in the injury of renal tubular epithelial cells induced by high glucose. Results: In high glucose‐induced HK‐2 cells, the expression of HOTAIR was upregulated, resulting in suppressed cell proliferation. Meanwhile, HOTAIR upregulates the expression of pro‐apoptotic proteins Bax and cleaved caspase‐3, while downregulating the expression of the anti‐apoptotic protein Bcl‐2. Luciferase reporter assays revealed that HOTAIR could target miR‐126‐5p. Additionally, it was found that the PI3K/Akt signaling pathway serves as a downstream target of miR‐126‐5p. Knockdown of HOTAIR relieved apoptosis, whereas further inhibition of miR‐126‐5p led to apoptosis in HK‐2 cells. Conclusions: HOTAIR plays a regulatory role in mediating high glucose‐induced injuries in HK‐2 cells, specifically affecting apoptosis and cell viability, via the miR‐126‐5p/PI3K/Akt signaling pathway.

Waste copper-containing paint residue (WCPR) represents a typical hazardous waste containing both toxic organic substances and toxic heavy metals, but there are few reports on the recycling of heavy metals. The recovery of Cu from WCPR by H2SO4 leaching–extraction–stripping has the advantages of eco-friendliness, simplicity of operation, and high value-added product. The results show that under the optimal conditions, the leaching rate of Cu in WCPR is 94.31% (18.02 g/L), while the extraction and stripping rates of Cu in the leaching solution are 99.46 and 95.32%, respectively. Due to the high concentration of Cu2+ with fewer impurities in the stripping solution, the stripping solution is heated, evaporated, cooled, and crystallized to successfully produce high-purity dark blue CuSO4 crystal, accomplishing the high-value recycling of Cu in WCPR. In addition, the leach residue of WCPR contains acrylic resin and SiO2, which can be used in cement kilns for incineration, thus realizing the overall recycling and utilization of WCPR. HIGHLIGHTS The process of Cu recovery from waste copper-containing paint residue was first proposed to regenerate CuSO4.; Using leaching–extraction–stripping to recover Cu has the advantages of eco-friendliness and high value-added product.; The stripping solution without impurities can be used directly to regenerate CuSO4.; The resulting residue with no environmental risk can be cement kiln incineration.; The process can eliminate Cu pollution and recover Cu resource.;

Abstract Hypoxic-ischemic brain damage (HIBD) can result in significant global rates of neonatal death or permanent neurological disability. N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism, and m6A dysregulation is implicated in various neurological diseases. However, the biological roles and clinical significance of m6A in HIBD remain unclear. We currently evaluated the effect of HIBD on cerebral m6A methylation in RNAs in neonatal rats. The m6A dot blot assay showed a global augmentation in RNA m6A methylation post-HI. Herein, we also report on demethylase FTO, which is markedly downregulated in the hippocampus and is the main factor involved with aberrant m6A modification following HI. By conducting a comprehensive analysis of RNA-seq data and m6A microarray results, we found that transcripts with m6A modifications were more highly expressed overall than transcripts without m6A modifications. The overexpression of FTO resulted in the promotion of Akt/mTOR pathway hyperactivation, while simultaneously inhibiting autophagic function. This is carried out by the demethylation activity of FTO, which selectively demethylates transcripts of phosphatase and tensin homolog (PTEN), thus promoting its degradation and reduced protein expression after HI. Moreover, the synaptic and neurocognitive disorders induced by HI were effectively reversed through the overexpression of FTO in the hippocampus. Cumulatively, these findings demonstrate the functional importance of FTO-dependent hippocampal m6A methylome in cognitive function and provides novel mechanistic insights into the therapeutic potentials of FTO in neonatal HIBD.

Estimating the proportion of land-use types in different regions is essential to promote the organization of a compact city and reduce energy consumption. However, existing research in this area has a few limitations: (1) lack of consideration of land-use distribution-related factors other than POIs; (2) inability to extract complex relations from heterogeneous information; and (3) overlooking the correlation between land-use types. To overcome these limitations, we propose a knowledge-based approach for estimating land-use distributions. We designed a knowledge graph to display POIs and other related heterogeneous data and then utilized a knowledge embedding model to directly obtain the region embedding vectors by learning the complex and implicit relations present in the knowledge graph. Region embedding vectors were mapped to land-use distributions using a label distribution learning method integrating the correlation between land-use types. To prove the reliability and validity of our approach, we conducted a case study in Jinhua, China. The results indicated that the proposed model outperformed other algorithms in all evaluation indices, thus illustrating the potential of this method to achieve higher accuracy land-use distribution estimates.

Abstract Objective Fucosyltransferases (FUTs) molecules have been identified to be involved in carcinogenesis of malignant tumors. Nevertheless, the biological function of fucosyltransferases-3 (FUT3) in lung adenocarcinoma (LUAD) malignant phenotype remains unclear. Herein, we investigated the association between FUT3 and LUAD pathological process. Methods Immunochemistry, RT-qPCR and western blot assays were conducted to evaluate the expression of FUT3 in LUAD and corresponding adjacent tissues. The prognostic value of FUT3 was assessed via Kaplan‑Meier plotter database. The biological process and potential mechanism of FUT3 in LUAD were conducted via GSEA. Additionally, immunofluorescence and metabolite activity detection were performed to determine the potential role of FUT3 in LUAD glucose metabolism. The active biomarkers associated with NF-κB signaling pathway were detected via western blot. Subcutaneous tumor model was conducted to analyze the effect of FUT3 on tumorigenesis of LUAD. Results FUT3 was remarkably upregulated in LUAD tissues compared with adjacent tissues from individuals. FUT3 overexpression may predict poor prognosis of LUAD patients. Knockdown of FUT3 significantly inhibited tumor proliferation, migration and glucometabolic alteration in LUAD cells. Moreover, GSEA demonstrated that elevated FUT3 was positively related to NF-κB signaling pathway. Additionally, in vitro and in vivo assays also indicated that downregulation of FUT3 resulted in the suppression of oncogenesis and glucose metabolism via inactivation of NF-κB pathway. Conclusion Our findings demonstrated that FUT3 was involved in glucometabolic process and tumorigenesis of LUAD via NF-κB signaling pathway. FUT3 may be an optimal target for diagnosis and treatment of LUAD patients.

Abstract Knowledge graph (KG) fact prediction aims to complete a KG by determining the truthfulness of predicted triples. Reinforcement learning (RL)-based approaches have been widely used for fact prediction. However, the existing approaches largely suffer from unreliable calculations on rule confidences owing to a limited number of obtained reasoning paths, thereby resulting in unreliable decisions on prediction triples. Hence, we propose a new RL-based approach named EvoPath in this study. EvoPath features a new reward mechanism based on entity heterogeneity, facilitating an agent to obtain effective reasoning paths during random walks. EvoPath also incorporates a new postwalking mechanism to leverage easily overlooked but valuable reasoning paths during RL. Both mechanisms provide sufficient reasoning paths to facilitate the reliable calculations of rule confidences, enabling EvoPath to make precise judgments about the truthfulness of prediction triples. Experiments demonstrate that EvoPath can achieve more accurate fact predictions than existing approaches.

Wildfires have short- and long-term impacts on the geoenvironment, including the changes to biogeochemical and mechanical properties of soils, landfill stability, surface- and groundwater, air pollution, and vegetation. Climate change has increased the extent and severity of wildfires across the world. Simultaneously, anthropogenic activities—through the expansion of urban areas into wildlands, abandonment of rural practices, and accidental or intentional fire-inception activities—are also responsible for a majority of fires. This paper provides an overall review and critical appraisal of existing knowledge about processes induced by wildfires and their impact on the geoenvironment. Burning of vegetation leads to loss of root reinforcement and changes in soil hydromechanical properties. Also, depending on the fire temperature, soil can be rendered hydrophobic or hydrophilic and compromise soil nutrition levels, hinder revegetation, and, in turn, increase post-fire erosion and the debris flow susceptibility of hillslopes. In addition to direct hazards, wildfires pollute air and soil with smoke and fire suppression agents releasing toxic, persistent, and relatively mobile contaminants into the geoenvironment. Nevertheless, the mitigation of wildfires’ geoenvironmental impacts does not fit within the scope of this paper. In the end, and in no exhaustive way, some of the areas requiring future research are highlighted.