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Abstract Background Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. Methods The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. Results APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. Conclusions APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma.

Abstract Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

Rheumatoid arthritis (RA) is an inflammatory disease accompanied by abnormal synovial microenvironment (SM). Sesquiterpene lactones (SLs) are the main anti-inflammatory ingredients of many traditional herbs utilized in RA treatment. α-Methylene-γ-butyrolactone (α-M-γ-B) is a core moiety that widely exists in natural SLs. This study was designed to investigate the anti-arthritic potential of α-M-γ-B as an independent small molecule in vitro and in vivo. α-M-γ-B exhibited stronger electrophilicity and anti-inflammatory effects than the other six analogs. α-M-γ-B inhibited the production of pro-inflammatory mediators via repolarizing M1 macrophages into M2 macrophages. The transcriptome sequencing suggested that α-M-γ-B regulated the immune system pathway. Consistently, α-M-γ-B attenuated collagen type II-induced arthritic (CIA) phenotype, restored the balance of Tregs-macrophages and remodeled SM via repolarizing the synovial-associated macrophages in CIA mice. Mechanistically, although α-M-γ-B did not prevent the trans-nucleus of NF-κB it interfered with the DNA binding activity of NF-κB via direct interaction with the sulfhydryl in cysteine residue of NF-κB p65, which blocked the activation of NF-κB. Inhibition of NF-κB reduced the M1 polarization of macrophage and suppressed the synovial hyperplasia and angiogenesis. α-M-γ-B failed to ameliorate CIA in the presence of N-acetylcysteine or when the mice were subjected to the macrophage-specific deficiency of Rela. In conclusion, α-M-γ-B significantly attenuated the CIA phenotype by directly targeting NF-κB p65 and inhibiting its DNA binding ability. These results suggest that α-M-γ-B has the potential to serve as an alternative candidate for treating RA. The greater electrophilicity of α-M-γ-B, the basis for triggering strong anti-inflammatory activity, accounts for the reason why α-M-γ-B is evolutionarily conserved in the SLs by medical plants.

Drug discovery is a sophisticated process that incorporates scientific innovations and cutting-edge technologies. Compared to traditional bioactivity-based screening methods, encoding and display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments to promising tools for pharmaceutical hit discovery due to their high screening efficiency, throughput, and resource minimization. This review systematically summarizes the development history, typology, and prospective applications of encoding and displayed technologies, including phage display, ribosomal display, mRNA display, yeast cell display, one-bead one-compound, DNA-encoded, peptide nucleic acid-encoded, and new peptide-encoded technologies, and examples of preclinical and clinical translation. We discuss the progress of novel targeted therapeutic agents, covering a spectrum from small-molecule inhibitors and nonpeptidic macrocycles to linear, monocyclic, and bicyclic peptides, in addition to antibodies. We also address the pending challenges and future prospects of drug discovery, including the size of screening libraries, advantages and disadvantages of the technology, clinical translational potential, and market space. This review is intended to establish a comprehensive high-throughput drug discovery strategy for scientific researchers and clinical drug developers.

Abstract In order to obtain the best mass spectrometry identification results for using the most appropriate methods in clinical practice, we explore the optimal pretreatment methods for different species and morphologies of filamentous fungi. 98 fungal strains were treated with formic acid sandwich method, dispersion method, extraction method, and other methods using a medium element mass spectrometer (EXS3000) as a platform. Each strain had three targets, and the identification rates and confidence differences under different pre-treatment methods were compared to evaluate the identification effects of these methods. The mass spectrometry identification rates of 98 filamentous fungi obtained after pre-treatment with formic acid sandwich method, dispersion method, and extraction method were 85.71%, 82.65%, and 75.51%, respectively. The identification rate of the formic acid sandwich method was significantly higher than the other two methods (P

Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by Kelch-like ECH-associated protein 1 (Keap1) alkylation plays a central role in anti-inflammatory therapy. However, activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified. Deoxynyboquinone (DNQ) is a natural small molecule discovered from marine actinomycetes. The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1. DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo. The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α, β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine. DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway. Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation. The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry. DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489 (Cys489) on Keap1-Kelch domain, ultimately enabling the activation of Nrf2. Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α, β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain, suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

IntroductionEnterobacter chengduensis was defined as a novel species in the genus. Enterobacter in 2019, however, antimicrobial resistance, such as carbapenem resistance, has rarely been described in E. chengduensis. This study described the molecular features of four carbapenem-resistant E. chengduensis strains collected from a tertiary health care hospital in Southwest China.MethodsWhole genome sequencing (WGS) was used to determine the genome sequence of four E. chengduensis strains. The precise species of strains were identified by average nucleotide identity (ANI) and in silico DNA-DNA hybridization (isDDH). The clonal relatedness of four E. chengduensis strains and additional 15 ones from NCBI were examined through phylogenetic analysis. The molecular features of E. chengduensis and genetic structure of carbapenemase- encoding plasmids were characterized through genomic annotation and analysis.ResultsThe results revealed the emergence of blaNDM–1-carrying E. chengduensis strains in China. Multilocus sequence typing (MLST) analysis showed that all 19 E. chengduensis belonged to the same sequence type of ST414. Core SNP analysis suggested the potential intrahospital clonal transmission of ST414 E. chengduensis. The carbapenemase-encoding gene blaNDM–1 was harbored by an IncC-type plasmid, which was experimentally confirmed to be able to conjugate.DiscussionThis study reports the first emergence and potential clonal transmission of blaNDM–1-carrying E. chengduensis. Further surveillance should be advocated to monitor the dissemination of carbapenem-resistant E. chengduensis and blaNDM–1-harboring IncC-type plasmids in China.

Cadmium (Cd), which accumulates in tobacco leaves, enters the human body through inhalation of smoke, causing harmful effects on health. Therefore, identifying the pivotal factors that govern the absorption and resistance of Cd in tobacco is crucial for mitigating the harmful impact of Cd. In the present study, four different Cd-sensitive varieties, namely, ZhongChuan208 (ZC) with resistance, ZhongYan100 (ZY), K326 with moderate resistance, and YunYan87 (YY) with sensitivity, were cultivated in hydroponic with different Cd concentrations (20 µM, 40 µM, 60 µM and 80 µM). The results indicated that plant growth was significantly decreased by Cd. Irrespective of the Cd concentration, ZC exhibited the highest biomass, while YY had the lowest biomass; ZY and K326 showed intermediate levels. Enzymatic (APX, CAT, POD) and nonenzymatic antioxidant (Pro, GSH) systems showed notable variations among varieties. The multifactor analysis suggested that the ZC and ZY varieties, with higher levels of Pro and GSH content, contribute to a decrease in the levels of MDA and ROS. Among all the Cd concentrations, ZC exhibited the lowest Cd accumulation, while YY showed the highest. Additionally, there were significant differences observed in Cd distribution and translocation factors among the four different varieties. In terms of Cd distribution, cell wall Cd accounted for the highest proportion of total Cd, and organelles had the lowest proportion. Among the varieties, ZC showed lower Cd levels in the cell wall, soluble fraction, and organelles. Conversely, YY exhibited the highest Cd accumulation in all tissues; K326 and ZY had intermediate levels. Translocation factors (TF) varied among the varieties under Cd stress, with ZC and ZY showing lower TF compared to YY and K326. This phenomenon mainly attributed to regulation of the NtNramp3 and NtNramp5 genes, which are responsible for the absorption and transport of Cd. This study provides a theoretical foundation for the selection and breeding of tobacco varieties that are resistant to or accumulate less Cd.

Purpose: Previous studies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have focused on factors that influence the achievement of negative conversion of viral RNA. This study aimed to investigate the effects of the genetic mutations in different SARS-CoV-2 strains on the negative conversion time (NCT) among imported cases in Hangzhou, Zhejiang Province, China, in order to provide valuable insights for developing targeted epidemic prevention guidelines. Methods: This retrospective study involved 146 imported SARS-CoV-2 cases in Hangzhou from 8 April 2021 to 11 June 2022. We compared the SARS-CoV-2-specific indicators, clinical indexes, and NCT among the wild-type (WT), Delta, and Omicron groups. Spearman correlation analysis was used to identify the correlations of NCT with mutation types/frequencies. Results: The mean age of the imported cases was 35.3 (SD: 12.3) years, with 71.92 % males and 28.08 % females. The mean cycle threshold (Ct) values of open reading frame 1ab (ORF1ab) and nucleocapsid (N) RNA were 25.17 (SD: 6.44) and 23.4 (SD: 6.76), respectively. The mutations of SARS-CoV-2 strains were mainly located in N, membrane (M), spike (S), ORF1a, ORF1b, ORF3a, ORF6, and ORF9b genes among the WT, Delta, and Omicron groups. NCT was significantly prolonged in the WT and Delta groups compared to the Omicron group. T lymphocyte, white blood cell, eosinophil, and basophil counts were dramatically higher in the WT group than the Delta group. White blood cell, red blood cell, and basophil counts were significantly lower in the Delta group than the Omicron group. Spearman correlation analysis revealed a significant correlation between the NCT of viral RNA and mutation types of viral genes of WT and Omicron strains. Additionally, NCT was markedly negatively correlated with the frequencies of five mutations in Omicron strains (ORF1b:P1223L, ORF1b:R1315C, ORF1b:T2163I, ORF3a:T223I, and ORF6:D61L). Conclusions: This study indicates that five mutations in Omicron strains (ORF1b:P1223L/R1315C/T2163I, ORF3a:T223I and ORF6:D61L) shortened NCT in imported SARS-CoV-2 cases.

Severe vibration of the core of ultra-high voltage (UHV) shunt reactors under operating conditions often leads to the occurrence of suspension electrode, and such a suspended discharge defect will destroy the oil-paper insulation. It is necessary to investigate the influence of vibration on suspended discharge when determining the best operating condition of UHV shunt reactors. The vibration frequency of the suspension electrode and the phase difference between the applied voltage and the vibration are studied by simulation and experiment. The simulation results show that the phase difference between the voltage and the vibration parameters will lead to an increase in the surface maximum field strength. The distortion of the field intensity caused by several typical vibration frequencies of reactor vibration is ranked (in ascending order) thus: 100, 300, 50, and 200 Hz. There is a coupling relationship between the phase difference and the vibration frequency on the suspended discharge, which will lead to an inconsistency between the field intensity and each single factor. The partial discharge test results of the collision between the suspension electrode and the high-voltage electrode show that the discharge generated by vibration at 100 Hz is much higher than that at other frequencies, followed by those at 300 and 50 Hz, and the discharge generated by vibration at 200 Hz is very small. When the phase difference of voltage advance vibration is between 0° and 90°, the quantity of local discharge is large. When the phase difference is between 90° and 180°, the local discharge is small.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a rare disease without standardized treatment modalities. Daratumumab is a human IgG monoclonal anti-CD38 antibody that has been demonstrated to be highly effective and safe in the treatment of PGNMID. This article reports a 66-year-old female who suffered from edema in both lower limbs and face for 6 years with mild proteinuria and hypoproteinemia. Renal biopsy displayed eight glomeruli, among which two presented with glomerulosclerosis, and the remaining six exhibited moderate diffuse hyperplasia of glomerular mesangial cells and stroma with endothelial cell proliferation. Immunofluorescence microscopy revealed lumpy and diffuse deposits of C3, C1q, IgG, and κ light chain in the glomerular mesangium, with strongly positive staining for IgG3 and varying degrees of weak to negative staining for IgG1, IgG2, IgG4, and λ light chain. Additionally, ultrastructural analysis unveiled that the glomerular basement membrane was segmentally thickened, accompanied by diffuse pedicle fusion, segmental tethered insertion, subendothelial deposits, and electron-dense material in tethered areas. The patient received a total dose of 800 mg of daratumumab (400 mg daily for two consecutive days), as well as daily prednisone (25 mg) and valsartan (80 mg), for treatment and achieved complete remission after three-month follow-up. This case represents an early attempt to treat PGNMID with low-dose daratumumab but requires long-term follow-up.

Understanding the invasion of moso bamboo (Phyllostachys edulis) into adjacent evergreen broadleaf forest based on functional traits is crucial due to its significant influence on ecosystem processes. However, existing research has primarily focused on above- or below-ground traits in isolation, lacking a comprehensive integration of both. In this study, we conducted a trait-based analysis including 23 leaf traits and 11 root traits in three forest types - bamboo forest, mixed bamboo and broadleaf forest, and evergreen broadleaf forest - to investigate trait differences, phenotypic integration, and above- and below-ground resource strategies in bamboo and broadleaf species. Our findings demonstrated significant differences in leaf and root key traits between bamboo and broadleaf species, strongly supporting the “phenotypic divergence hypothesis”. Bamboo exhibited stronger trait correlations compared to broadleaf species, indicating higher phenotypic integration. Above- and below-ground strategies were characterized by trade-offs rather than coordination, resulting in a multi-dimensional trait syndrome. Specifically, a unidimensional leaf economics spectrum revealed that bamboo with higher leaf N concentrations (LNC), P concentrations (LPC), and specific leaf area (SLA) adopted a “fast acquisitive” above-ground strategy, while broadleaf species with thicker leaves employed a “slow conservative” above-ground strategy. A two-dimensional root trait syndrome indicated a “conservation” gradient with bamboo adopting a “slow conservative” below-ground strategy associated with higher root tissue density (RTD), and broadleaf species exhibiting a “fast acquisitive” below-ground strategy linked to higher root N concentrations (RNC) and P concentrations (RPC), and a “collaboration” gradient probably ranging from broadleaf species with a “do-it-yourself” strategy characterized by high specific root length (SRL), to bamboo adopting an “outsourcing” strategy with thicker roots. In conclusion, key trait divergence from coexisting broadleaf species, higher phenotypic integration, and multi-dimensional opposite above- and below-ground resource strategies confer competitive advantages to moso bamboo, shedding light on the mechanistic understanding of its invasion into subtropical evergreen broadleaf forest and providing theoretical guidance for maintaining the stability of subtropical forest ecosystem.

Nicotiana tabacum L. (tobacco) has extremely high economic value, medicinal value, scientific research value and some other uses. Though it has been widely cultivated throughout the world, classification and change of its suitable habitats is not that clear, especially in the context of global warming. In order to achieve rational cultivation and sustainable development of tobacco, current (average from 1970-2000) and future (2070, average from 2061-2080) potential suitable habitats of Nicotiana tabacum L. were forecasted with MaxEnt model and ArcGIS platform based on 854 occurrence data and 22 environmental factors in this study. The results revealed that mean temperature of warmest quarter (bio10), annual precipitation (bio12), solar radiation in September (Srad9), and clay content (CLAY) were the four decisive environment variables for the distribution of Nicotiana tabacum L. Under current climate conditions, suitable habitats of Nicotiana tabacum L. were mainly distributed in south-central Europe, south-central North America, most parts of South America, central Africa, south and southeast Asia, and southeast coast of Australia, and only 13.7% of these areas were highly suitable. By the year 2070, suitable habitats under SSP1-2.6, SSP3-7.0, and SSP5-8.5 climate scenarios would all increase with the largest increase found under SSP3-7.0 scenario, while suitable habitats would reduce under SSP2-4.5 climate scenario. Globally, the center of mass of suitable habitats would migrate to southeast to varying degrees within Libya under four different climate scenarios. The emergence of new habitats and the disappearance of old habitats would all occur simultaneously under each climate scenario, and the specific changes in each area, combined with the prediction results under current climate conditions, will provide an important reference for the adjustment of agronomic practices and rational cultivation of Nicotiana tabacum L. both currently and in the future.

BackgroundHypertension is the most significant global risk factor for mortality and morbidity, making standardized blood pressure measurement crucial.ObjectivesTo investigate whether the location of blood pressure monitors and the positioning of cuffs yield differing results in blood pressure measurements.MethodsPatients admitted to the Affiliated Hospital of Jiujiang College between 1 January 2022 and 30 June 2023 were enrolled in this study and randomly allocated into four groups. These groups were defined based on the positioning of monitoring equipment as follows: varied placements of cuffs on automatic blood pressure monitors, different heights for mercury column blood pressure monitors, varied heights for automatic blood pressure monitors, and different orientations for the cuff airbag tubes on electrocardiogram monitors. Blood pressure was measured and recorded for each group, followed by an analysis of the variations in readings across the different setups.ResultsIn the first cohort of 763 individuals, mean systolic blood pressure measured at the standard upper arm site was 128.8 ± 10.5 mmHg, compared to 125.3 ± 10.4 mmHg at the elbow fossa. The corresponding diastolic pressures were 79.2 ± 10.7 and 75.0 ± 10.6 mmHg, respectively. The difference in systolic pressure between these positions was significant at 3.48 ± 3.22 mmHg (t₁ = 29.91, p₁

ABSTRACT Pseudomonas aeruginosa is one of the most common nosocomial pathogens worldwide, known for its virulence, drug resistance, and elaborate sensor-response network. The primary challenge encountered by pathogens during the initial stages of infection is the immune clearance arising from the host. The resident macrophages of barrier organs serve as the frontline defense against these pathogens. Central to our understanding is the mechanism by which bacteria modify their behavior to circumvent macrophage-mediated clearance, ensuring their persistence and colonization. To successfully evade macrophage-mediated phagocytosis, bacteria must possess an adaptive response mechanism. Two-component systems provide bacteria the agility to navigate diverse environmental challenges, translating external stimuli into cellular adaptive responses. Here, we report that the well-documented histidine kinase, LadS, coupled to a cognate two-component response regulator, PA0034, governs the expression of a vital adhesin called chaperone-usher pathway pilus cupA. The LadS/PA0034 system is susceptible to interference from the reactive oxygen species likely to be produced by macrophages and further lead to a poor adhesive phenotype with scantily cupA pilus, impairing the phagocytosis efficiency of macrophages during acute infection. This dynamic underscores the intriguing interplay: as macrophages deploy reactive oxygen species to combat bacterial invasion, the bacteria recalibrate their exterior to elude these defenses.IMPORTANCEThe notoriety of Pseudomonas aeruginosa is underscored by its virulence, drug resistance, and elaborate sensor-response network. Yet, the mechanisms by which P. aeruginosa maneuvers to escape phagocytosis during acute infections remain elusive. This study pinpoints a two-component response regulator, PA0034, coupled with the histidine kinase LadS, and responds to macrophage-derived reactive oxygen species. The macrophage-derived reactive oxygen species can impair the LadS/PA0034 system, resulting in reduced expression of cupA pilus in the exterior of P. aeruginosa. Since the cupA pilus is an important adhesin of P. aeruginosa, its deficiency reduces bacterial adhesion and changes their behavior to adopt a planktonic lifestyle, subsequently inhibiting the phagocytosis of macrophages by interfering with bacterial adhesion. Briefly, reactive oxygen species may act as environmental cues for the LadS/PA0034 system. Upon recognition, P. aeruginosa may transition to a poorly adhesive state, efficiently avoiding engulfment by macrophages.

Abstract LIN28A is important in somatic reprogramming and pluripotency regulation. Although previous studies addressed that LIN28A can repress let-7 microRNA maturation in the cytoplasm, few focused on its role within the nucleus. Here, we show that the nucleolus-localized LIN28A protein undergoes liquid-liquid phase separation (LLPS) in mouse embryonic stem cells (mESCs) and in vitro. The RNA binding domains (RBD) and intrinsically disordered regions (IDR) of LIN28A contribute to LIN28A and the other nucleolar proteins’ phase-separated condensate establishment. S120A, S200A and R192G mutations in the IDR result in subcellular mislocalization of LIN28A and abnormal nucleolar phase separation. Moreover, we find that the naive-to-primed pluripotency state conversion and the reprogramming are associated with dynamic nucleolar remodeling, which depends on LIN28A’s phase separation capacity, because the LIN28A IDR point mutations abolish its role in regulating nucleolus and in these cell fate decision processes, and an exogenous IDR rescues it. These findings shed light on the nucleolar function in pluripotent stem cell states and on a non-canonical RNA-independent role of LIN28A in phase separation and cell fate decisions.

The task of detecting surface defects on substation equipment faces several challenges, including a variety of target categories, the scarcity of original defect image data, complex environmental conditions, low accuracy in existing algorithms, as well as notable issues with false alarms and missed detections. Overcoming these obstacles is crucial for the successful implementation of intelligent inspection systems for substations. To address the problem of limited original data, we first employ the method of ADD-GAN to augment the image training set. Furthermore, this paper proposes a target detection model called YOLO-SD to detect various equipment defects in complex real-world scenarios. In order to enhance the network’s feature extraction capabilities in the presence of complex backgrounds and to improve detection accuracy, a novel deep perceptual feature extraction module named C3+ was introduced in this research. Furthermore, we incorporates SimAM into the neck network of YOLO-SD. This integration not only bolsters the network’s learning capacity but also equips it with the capability to autonomously learn and dynamically fine-tune attention weights to suit different input scenarios. To tackle the challenges posed by variations in size and shapes of different substation equipment defects in images, a novel fusion loss function NWD-CIoU is designed. The improvements enhance the accuracy and robustness of YOLO-SD in defect target detection across different scales. The experiment demonstrated that the YOLO-SD model achieved an mAP@0.5 of 90.3% and mAP@0.5:0.95 of 63.9% in detecting defects in substation equipment. The F1 score reached 81.1%, IoU value was 90.5%. This model realized accurate detection of multi-scale substation defect targets, reaching the state-of-the-art level in substation defects detection.

Objective: Qu Du Qiang Fei 1 Hao Fang (QDQF1) is a novel Chinese herbal medicine formula used to treat coronavirus disease 2019 (COVID-19). However, the pharmacological mechanisms of action of QDQF1 remain unclear. The objective of this study was to identify the effective ingredients and biological targets of QDQF1 for COVID-19 treatment. Materials and Methods: The effective ingredients and mechanisms of action of QDQF1 were analyzed by using network pharmacology methods, which included an analysis of the effective ingredients and corresponding targets, COVID-19-related target acquisition, compound-target network analyses, protein-protein interaction network analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses, and molecular docking studies. Results: In total, 288 effective QDQF1 ingredients were identified. We identified 51 core targets from the 148 targets through an overlap between putative QDQF1 targets and COVID-19-related targets. Six key components, including formononetin, kaempferol, luteolin, naringenin, quercetin, and wogonin were identified through component-target network analyses. GO functional enrichment analysis of the core targets revealed 1296 items, while KEGG pathway enrichment analysis identified 148 signaling pathways. Nine central targets (CCL2, CXCL8, IL1B, IL6, MAPK1, MAPK3, MAPK8, STAT3, and TNF) related to the COVID-19 pathway were identified in the KEGG pathway enrichment analysis. Furthermore, molecular docking analysis suggested that the docking scores of the six key components to the nine central targets were better than those to remdesivir. Conclusions: QDQF1 may regulate multiple immune-and inflammation-related targets to inhibit the progression of severe acute respiratory syndrome coronavirus 2, and thus, may be suitable for the treatment of COVID-19.

The heat of hydration is fundamental in understanding the hydration mechanism of cementitious materials, and temperature can significantly affect the heat of hydration. A recent study has shown that coal-derived char can be used as a green additive for improving the engineering properties of conventional cement grout. However, the impact of temperature on heat of hydration of char-cement grout is currently unknown. In this study, the heat of hydration (with degree of hydration) of cement and char-cement grouts at 5, 23, and 35 °C are investigated. This study reveals that incorporating char into the cement grout enhances its degree of hydration at temperatures ranging from 5 to 35 °C, highlighting the potential advantages of using coal char in grouting applications, especially at low temperature.

Compensatory Health Beliefs (CHBs), the notion that healthy behaviors can offset the negative effects of unhealthy actions, have been widely explored in Western contexts. Yet, their relevance within the Chinese cultural milieu remains underexplored. The primary objective of this research was to develop and validate a Chinese version of the CHBs scale (CHBs-C), addressing the gap in the literature regarding the applicability of CHBs within the Chinese cultural context. A multi-stage translation (from English to Chinese) was first completed, and exploratory factor analysis was conducted (n = 476), yielding the 14-item scale (CHBs-C scale). Confirmatory factor analysis was conducted to assess the validity, and the 2-week test–retest reliability, internal consistency and convergent validity of the scale were also assessed (n = 308). Predict validity was verified through testing the relationships between CHBs and health behaviors and habits (n = 274). Factor analysis showed a different factor structure in Chinese context, with only one factor identical to the original version. The fitness index of the new factor structure was good. However, while the scale exhibited acceptable internal consistency and high test–retest reliability, its convergent validity and predictive validity was found to be limited on a general level. Despite this, significant correlations at the subscale level were identified, highlighting nuanced interactions between CHBs and specific health behaviors within the Chinese population. This study not only establishes the CHBs-C scale as a valid and reliable instrument for assessing compensatory health beliefs in China but also lays the groundwork for further exploration of its applications and the potential cultural adaptability of CHBs.

Summary: Enhancer-derived RNAs (eRNAs) play critical roles in diverse biological processes by facilitating their target gene expression. However, the abundance and function of eRNAs in early embryos are not clear. Here, we present a comprehensive eRNA atlas by systematically integrating publicly available datasets of mouse early embryos. We characterize the transcriptional and regulatory network of eRNAs and show that different embryo developmental stages have distinct eRNA expression and regulatory profiles. Paternal eRNAs are activated asymmetrically during zygotic genome activation (ZGA). Moreover, we identify an eRNA, MZGAe1, which plays an important function in regulating mouse ZGA and early embryo development. MZGAe1 knockdown leads to a developmental block from 2-cell embryo to blastocyst. We create an online data portal, M2ED2, to query and visualize eRNA expression and regulation. Our study thus provides a systematic landscape of eRNA and reveals the important role of eRNAs in regulating mouse early embryo development.

Background Elevated platelet count (PLTc) is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis. However, the impact of antipsychotic medications on PLTc and its association with symptom improvement remain unclear.Aims We aimed to investigate changes in PLTc levels following antipsychotic treatment and assess whether PLTc can predict antipsychotic responses and metabolic changes after accounting for other related variables.Methods A total of 2985 patients with schizophrenia were randomised into seven groups. Each group received one of seven antipsychotic treatments and was assessed at 2, 4 and 6 weeks. Clinical symptoms were evaluated using the positive and negative syndrome scale (PANSS). Additionally, we measured blood cell counts and metabolic parameters, such as blood lipids. Repeated measures analysis of variance was used to examine the effect of antipsychotics on PLTc changes, while structural equation modelling was used to assess the predictive value of PLTc on PANSS changes.Results PLTc significantly increased in patients treated with aripiprazole (F=6.00, p=0.003), ziprasidone (F=7.10, p

Background Ovarian cancer is the most lethal gynecological malignancy, with limited treatment options after failure of standard therapies. Despite the potential of poly(ADP-ribose) polymerase inhibitors in treating DNA damage response (DDR)-deficient ovarian cancer, the development of resistance and immunosuppression limit their efficacy, necessitating alternative therapeutic strategies. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) represent a novel class of inhibitors that are currently being assessed in preclinical and clinical studies for cancer treatment.Methods By using a PARG small-molecule inhibitor, COH34, and a cell-penetrating antibody targeting the PARG’s catalytic domain, we investigated the effects of PARG inhibition on signal transducer and activator of transcription 3 (STAT3) in OVCAR8, PEO1, and Brca1-null ID8 ovarian cancer cell lines, as well as in immune cells. We examined PARG inhibition-induced effects on STAT3 phosphorylation, nuclear localization, target gene expression, and antitumor immune responses in vitro, in patient-derived tumor organoids, and in an immunocompetent Brca1-null ID8 ovarian mouse tumor model that mirrors DDR-deficient human high-grade serous ovarian cancer. We also tested the effects of overexpressing a constitutively activated STAT3 mutant on COH34-induced tumor cell growth inhibition.Results Our findings show that PARG inhibition downregulates STAT3 activity through dephosphorylation in ovarian cancer cells. Importantly, overexpression of a constitutively activated STAT3 mutant in tumor cells attenuates PARG inhibitor-induced growth inhibition. Additionally, PARG inhibition reduces STAT3 phosphorylation in immune cells, leading to the activation of antitumor immune responses, shown in immune cells cocultured with ovarian cancer patient tumor-derived organoids and in immune-competent mice-bearing mouse ovarian tumors.Conclusions We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.

Abstract Schizophrenia has been linked to polymorphism in genes encoding components of the complement system, and hyperactive complement activity has been linked to immune dysfunction in schizophrenia patients. Whether and how specific complement components influence brain structure and cognition in the disease is unclear. Here we compared 52 drug-naïve patients with first-episode schizophrenia and 52 healthy controls in terms of levels of peripheral complement factors, cortical thickness (CT), logical memory and psychotic symptoms. We also explored the relationship between complement factors with CT, cognition and psychotic symptoms. Patients showed significantly higher levels of C1q, C4, factor B, factor H, and properdin in plasma. Among patients, higher levels of C3 in plasma were associated with worse memory recall, while higher levels of C4, factor B and factor H were associated with thinner sensory cortex. These findings link dysregulation of specific complement components to abnormal brain structure and cognition in schizophrenia.

Abstract Many Chinese universities are implementing an educational reform to transform their general English courses into academic English courses. Accordingly, how to assess students’ English ability should also be reformed. In this test review, we introduce a school-based general academic English summative test developed by English instructors. An argument-based approach was adopted to analyze the test validity by obtaining students’ test data and their reflective responses to the test. This review can provide a practical reference for the development of a valid general academic English summative test by including practices of course instructors and voices of students, two important test stakeholders, in test design.

The determination of ductile-to-brittle transition temperatures (DBTT) in intermetallic compounds is crucial for assessing their practical applications. In this study, we investigate the intrinsic factors influencing the DBTT of Fe–Al intermetallic compounds through feature engineering. We developed and evaluated two machine learning strategies for this task. Comparing the strategy that incorporates all features, including alloy compositions and atomic features, with the strategy utilizing selected features, it is found that the latter demonstrates superior computational efficiency and reduces overfitting. Specifically, surrogate models based on two selected features, namely cohesive energy and ionization energy, enable accurate prediction of the DBTT of Fe–Al intermetallics, achieving an accuracy of 95%. Additionally, through symbolic regression, we derived a functional expression that captures the relationship between variations in the DBTT and the selected features of intermetallic compounds. These findings have the potential to serve as a valuable guide for optimizing intermetallic compounds.

Abstract Background Neutralizing antibody plays a key role in protecting hosts from invasive pathogens and their virulent components. Current high-throughput assays for antibody screening are based on binding activities. However, those antibodies with high affinity may not have neutralizing activities. Subsequent functionality assays are necessary to identify neutralizing antibodies from binders with high affinity to their target antigens, which is laborious and time-consuming. Therefore, a versatile platform that can rapidly identify antibodies with both high binding affinity and neutralizing activity is desired to curb future pandemics like COVID-19. Results In this proof-of-concept study, we adapted Saccharomyces cerevisiae to either display human antibodies on the yeast surface or secrete soluble antibodies into the cultivation supernatant under a controllable ‘switch’ through different carbon source induced promoters. Initially, an engineered chimeric-bispecific Fab antibody, derived from humanized nanobodies against both Clostridioides difficile toxin A and B (TcdA and TcdB), was successfully expressed either on the yeast cell surface or in the culture medium with intact bioactivity, suggesting the applicability of our system in antibody display and secretion. Next, a combinatorial Fab library was constructed from B cells isolated from a convalescent patient with a high serological neutralizing titer against TcdB. Following three rounds of magnetic bead enrichment and one round of flow cytometry sorting, antibodies against TcdB were enriched efficiently. We then sorted out single binders with high binding affinity and induced them to express soluble antibodies in culture medium. The neutralizing activity of culture supernatant was analyzed using cell-based assay immediately. This way, we rapidly identified two unique neutralizers (out of seven binders) that can neutralize the cytotoxicity of TcdB. Conclusion The antibody screening platform described here simplifies the neutralizing antibody discovery procedure and will be an attractive alternative for screening functional antibodies against infectious diseases.

Two-step sintering to prepare gradient cemented carbides tends to the grain growth of hard phases, which adversely affects the mechanical properties. Spark plasma sintering is a promising pre-sintering process to mitigate grain growth by rapid prototyping and densification. In the present work, gradient cemented carbides with Ni binder instead of traditional Co binder were fabricated by both SPS pre-sintering and vacuum pre-sintering, followed by gradient sintering. The microstructure and elemental distributions of the prepared gradient cemented carbides were thoroughly investigated by XRD, SEM, EDS, EPMA and EBSD, focusing on the gradient layer formation and WC grain growth. The influence of WC grain size on the gradient layer formation was discussed with the aid of the DICTRA simulation. Finer WC grains in the SPS pre-sintered alloy show a smaller tortuosity factor, resulting in a thicker thickness of the gradient surface layer. The variations of hardness from the surface to the interior and the fracture toughness of the bulk for the gradient cemented carbides with different pre-sintering methods were measured through the micro-indentation method. Higher hardness and fracture toughness were obtained by SPS pre-sintered gradient cemented carbide.

The presence of defects in substation equipment is a major factor affecting the safety of power transmission. Therefore, timely and accurate detection of these defects is crucial. As intelligent inspection robots advance, using mainstream object detection models to diagnose surface defects in substation equipment has become a focal point of current research. However, the lack of defect image data is one of the main factors affecting the accuracy of supervised deep learning-based defect detection models. To address the issue of insufficient training data for defect images with complex backgrounds, such as rust and surface oil leakage in substation equipment, which leads to the poor performance of detection models, this paper proposes a novel adversarial deep learning model for substation defect image generation: the Abnormal Defect Detection Generative Adversarial Network (ADD-GAN). Unlike existing generative adversarial networks, this model generates defect images based on effectively segmented local areas of substation equipment images, avoiding image distortion caused by global style changes. Additionally, the model uses a joint discriminator for both overall images and defect images to address the issue of low attention to local defect areas, thereby reducing the loss of image features. This approach enhances the overall quality of generated images as well as locally generated defect images, ultimately improving image realism. Experimental results demonstrate that the YOLOV7 object detection model trained on the dataset generated using the ADD-GAN method achieves a mean average precision (mAP) of 81.5% on the test dataset, and outperforms other image data augmentation and generation methods. This confirms that the ADD-GAN method can generate a high-fidelity image dataset of substation equipment defects.

The increasing discharge of antibiotic wastewater leads to increasing water pollution. Most of these antibiotic wastewaters are persistent, strongly carcinogenic, easy to bioaccumulate, and have other similar characteristics, seriously jeopardizing human health and the ecological environment. As a commonly used wastewater treatment technology, non-homogeneous electro-Fenton technology avoids the hazards of H2O2 storage and transportation as well as the loss of desorption and reabsorption. It also facilitates electron transfer on the electrodes and the reduction of Fe3+ on the catalysts, thereby reducing sludge production. However, the low selectivity and poor activity of electro-synthesized H2O2, along with the low concentration of its products, combined with the insufficient activity of electrically activated H2O2, results in a low ∙OH yield. To address the above problems, composites of layered bimetallic hydroxides and carbon materials were designed and prepared in this paper to enhance the performance of electro-synthesized H2O2 and non-homogeneous electro-Fenton by changing the composite mode of the materials. Three composites, NiFe layered double hydroxides (LDHs)/reduced graphene oxide (rGO), NiMn LDHs/rGO, and NiMnFe LDHs/rGO, were constructed by the electrostatic self-assembly of exfoliated LDHs with few-layer graphene. The LDHs/rGO was loaded on carbon mats to construct the electro-Fenton cathode materials, and the non-homogeneous electro-Fenton oxidative degradation of organic pollutants was realized by the in situ electrocatalytic reduction of O2 to ∙OH. Meanwhile, the effects of solution pH, applied voltage, and initial concentration on the performance of non-homogeneous electro-Fenton were investigated with ceftazidime as the target pollutant, which proved that the cathode materials have an excellent electro-Fenton degradation effect.

Abstract Introduction Tumor‐associated macrophages, a major component of the tumor microenvironment, undergo polarization into M2 macrophages (M2), and thereby exert an immunosuppressive effect to induce cancer metastasis. This study strives to uncover a molecular mechanism underlying this event in hepatocellular carcinoma (HCC). Methods Proteasome subunit alpha 5 (PSMA5) expression in liver hepatocellular carcinoma (LIHC) tissues and its association with LIHC patients were predicted using StarBase. PSMA5 level in human HCC cells was manipulated via transfection. Exosomes were isolated from HCC cells, and internalized into macrophages which were cocultured with HCC cells. Exosome internalization was observed after fluorescence labeling. HCC cell migration and invasion were evaluated by wound healing and Transwell assays. Xenograft assay was performed to investigate the role of PSMA5 in in vitro tumorigenesis. M2 polarization was assessed by enzyme‐linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry. PSMA5 expression in exosomes and Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) activation in macrophages and tumors were detected by Western blot analysis. Results High PSMA5 expression was observed in LIHC tissues and associated with compromised survival of LIHC patients. PSMA5 knockdown inhibited HCC cell migration and invasion. PSMA5 knockdown in HCC cells downregulated PSMA5 level in exosomes from these HCC cells. HCC cell‐isolated exosomes were successfully internalized into macrophages, and facilitated M2 polarization and JAK2/STAT3 pathway activation. HCC cell‐secreted exosomal PSMA5 knockdown inhibited the exosome‐induced effect on macrophages, and attenuated the promotion induced by exosome‐treated macrophages on HCC cell migration/invasion and tumorigenesis along with in vivo M2 polarization and JAK2/STAT3 pathway activation. Conclusion HCC cell‐secreted exosomal PSMA5 knockdown hinders M2 polarization to suppress cancer progression by restraining JAK2/STAT3 signaling.

ABSTRACT Carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKP) strains are increasingly reported, posing a significant threat to public health. Therefore, effective antimicrobial therapy is urgently needed. This study aimed to analyze the in vitro activity of ceftazidime-avibactam (CZA), imipenem-relebactam (IMR), and aztreonam-avibactam (AZA) toward CR-hvKP and carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates. Non-repetitive clinical CRKP and CR-hvKP strains were collected from Sichuan Provincial People’s Hospital between August 2018 and June 2022. CR-hvKP strains were screened using string tests and polymerase chain reaction (PCR). The microbroth dilution method was used to evaluate in vitro antibacterial activity of CZA, IMR, and AZA toward CRKP and CR-hvKP stains. The molecular characteristics of CRKP and CR-hvKP strains were investigated using PCR amplification. The virulence features of CR-hvKP strains were investigated using serum resistance assays and a Galleria mellonella infection model. A total of 114 CRKP and 40 CR-hvKP strains were collected. The susceptibility rates of CRKP and CR-hvKP to tigecycline, colistin, and polymyxin B exceeded 89.5%. The susceptibility rates of CRKP and CR-hvKP to CZA were 64.0% and 77.5%, respectively; the susceptibility rates to IMR were 92.5% and 71.9%, respectively; and the susceptibility rates to AZA were 89.5% and 75.0%, respectively. Multilocus sequence typing and wzi-loci sequencing identified sequence type 11 KL64 as the predominant type in CRKP and CR-hvKP strains. Carbapenemase genes were dominated by blaKPC-2 and blaNDM-1. IMR and AZA may be promising therapeutic agents for the treatment of infections caused by CRKP and CR-hvKP isolates. IMPORTANCE To our knowledge, this is the first study to report the in vitro activity of two novel antimicrobial drugs, including imipenem-relebactam (IMR) and aztreonam-avibactam (AZA), toward carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-hvKP) strains. Our in vitro activity study revealed that only few antibacterial agents (including several novel agents) exhibit high antimicrobial activity toward carbapenem-resistant Klebsiella pneumoniae (CRKP) and CR-hvKP isolates. IMR and AZA may be promising therapeutic agents for the treatment of infections caused by CRKP and CR-hvKP isolates.

Coal char, as a sustainable and eco-friendly material, holds significant potential for use in new construction materials, specifically, coal char-based bricks. This study employed the pre-pressing method to create char bricks containing high char content of 70%. The impact of various curing temperatures (20, 40, 60 °C), humidity levels (15% and 90%), and pressing pressures (3.5, 7, and 10 MPa) on the density, X-ray diffraction, compressive strength, and thermal conductivity of char-based samples were examined. The addition of superplasticizer and the performance of char bricks were assessed by comparing them to traditional clay bricks and corresponding standards. The study discovers that the temperature of 40 °C enhances the early 7-day strength of char brick samples, while the highest 28-day strength is observed in char bricks at a temperature of 20 °C and humidity of 90%. Compared to conventional clay bricks (with density of 1.9 g/cm3, thermal conductivity of 0.39–0.63 W/mK, compressive strength of 10–20 MPa), the proposed char bricks exhibit lower density (∼0.8 g/cm3), lower thermal conductivity (0.26–0.35 W/mK), and good performance in compressive strength (up to 15 MPa). In conclusion, coal char-based bricks with high char content demonstrate significant advantages over traditional clay bricks, making them a sustainable and environmentally friendly building material option.

ABSTRACTEpidemiological characteristics and molecular features of carbapenem-resistant Enterobacter (CR-Ent) species remain unclear in China. In this study, we performed a genomic study on 92 isolates from Enterobacter-caused infections from a multicenter study in China. Whole genome sequencing (WGS) was used to determine the genome sequence of 92 non-duplicated CR-Ent strains collected from multiple tertiary health centres. The precise species of Enterobacter strains were identified by average nucleotide identity (ANI) and in silico DNA–DNA hybridization (isDDH). Molecular features of high-risk CR-Ent sequence type (ST) lineages and carbapenemase-encoding plasmids were determined. The result revealed that the most common human-source CR-Ent species in China was E. xiangfangensis (66/92, 71.93%), and the proportion of carbapenemase-producing Enterobacter (CP-Ent) in CR-Ent was high (72/92, 78.26%) in comparison to other global regions. Furthermore, ST171 and ST116 E. xiangfangensis were the major lineages of CP-Ent strains, and ST171 E. xiangfangensis was more likely to cause infections in older patients. Genomic analysis also highlighted the likelihood of intra-hospital/inter-hospital clonal transmission of ST171 and ST116 E. xiangfangensis. In addition, the blaNDM-harbouring IncX3-type plasmid was identified as the prevalent carbapenemase-encoding plasmid carried by CR-Ent strains, and was experimentally confirmed to be able to self-transfer with high frequency. This study detailed the genomic and clinical characteristics of CR-Ent in China in the form of multicenter for the first time. The high risk of carbapenemase-producing ST171 and ST116 E. xiangfangensis, and the blaNDM-harbouring IncX3-type plasmid were detected and emphasized.

Abstract Background The identification of chemical–target interaction is key to pharmaceutical research and development, but the unclear materials basis and complex mechanisms of traditional medicine (TM) make it difficult, especially for low-content chemicals which are hard to test in experiments. In this research, we aim to apply the node2vec algorithm in the context of drug-herb interactions for expanding potential targets and taking advantage of molecular docking and experiments for verification. Methods Regarding the widely reported risks between cardiovascular drugs and herbs, Salvia miltiorrhiza (Danshen, DS) and Ligusticum chuanxiong (Chuanxiong, CX), which are widely used in the treatment of cardiovascular disease (CVD), and approved drugs for CVD form the new dataset as an example. Three data groups DS-drug, CX-drug, and DS-CX-drug were applied to serve as the context of drug-herb interactions for link prediction. Three types of datasets were set under three groups, containing information from chemical-target connection (CTC), chemical-chemical connection (CCC) and protein–protein interaction (PPI) in increasing steps. Five algorithms, including node2vec, were applied as comparisons. Molecular docking and pharmacological experiments were used for verification. Results Node2vec represented the best performance with average AUROC and AP values of 0.91 on the datasets “CTC, CCC, PPI”. Targets of 32 herbal chemicals were identified within 43 predicted edges of herbal chemicals and drug targets. Among them, 11 potential chemical-drug target interactions showed better binding affinity by molecular docking. Further pharmacological experiments indicated caffeic acid increased the thermal stability of the protein GGT1 and ligustilide and low-content chemical neocryptotanshinone induced mRNA change of FGF2 and MTNR1A, respectively. Conclusions The analytical framework and methods established in the study provide an important reference for researchers in discovering herb–drug interactions, alerting clinical risks, and understanding complex mechanisms of TM.

Background: It has been demonstrated that exosomes derived from HPV-16 E7-over-expressiong non-small cell lung cancer (NSCLC) cells (E7 Exo) trigger increased levels of epidermal growth factor receptor (EGFR) and miR-381-3p. The purpose of this investigation was to examine the role of E7 Exo in NSCLC angiogenesis, and to analyze the contribution of exosomal EGFR and miR-381-3p to it. Methods: The influence of E7 Exo on the proliferation and migration of human umbilical vein endothelial cells (HUVECs) was assessed using colony formation and transwell migration assays. Experiments on both cells and animal models were conducted to evaluate the angiogenic effect of E7 Exo treatment. The involvement of exosomal EGFR and miR-381-3p in NSCLC angiogenesis was further investigated through suppressing exosome release or EGFR activation, or by over-expressing miR-381-3p. Results: Treatment with E7 Exo increased the proliferation, migration, and tube formation capacities of HUVECs, as well as angiogenesis in animal models. The suppression of exosome release or EGFR activation in NSCLC cells decreased the E7-induced enhancements in HUVEC migration and tube formation, and notably reduced vascular endothelial growth factor A (VEGFA) and Ang-1 levels. HUVECs that combined miR-381-3p mimic transfection and E7 Exo treatment exhibited a more significant tube-forming capacity than E7 Exo-treated HUVECs alone, but were reversed by the miR-381-3p inhibitor. Conclusion: The angiogenesis induced by HPV-16 E7 in NSCLC is mediated through exosomal EGFR and miR-381-3p.

With the rising incidence of various diseases in China and the constant development of the pharmaceutical industry, there is a growing demand for floxacin-type antibiotics. Due to the large-scale production and high cost of waste treatment, the parent drug and its metabolites constantly enter the water environment through domestic sewage, production wastewater, and other pathways. In recent years, the pollution of the aquatic environment by floxacin has become increasingly serious, making the technology to degrade floxacin in the aquatic environment a research hotspot in the field of environmental science. Metal–organic frameworks (MOFs), as a new type of porous material, have attracted much attention in recent years. In this paper, four photocatalytic materials, MIL-53(Fe), NH2-MIL-53(Fe), MIL-100(Fe), and g-C3N4, were synthesised and applied to the study of the removal of ofloxacin and enrofloxacin. Among them, the MIL-100(Fe) material exhibited the best photocatalytic effect. The degradation efficiency of ofloxacin reached 95.1% after 3 h under visible light, while enrofloxacin was basically completely degraded. The effects of different materials on the visible photocatalytic degradation of the floxacin were investigated. Furthermore, the photocatalytic mechanism of enrofloxacin and ofloxacin was revealed by the use of three trappers (▪O2−, h+, and ▪OH), demonstrating that the role of ▪O2− promoted the degradation effect of the materials under photocatalysis.

With the progress of the power grid system, the coverage area of cables is widening, and the problem of cable faults is gradually coming to affect people’s daily lives. While the vast majority of cable faults are caused by the ablation of the cable buffer layer, polypropylene (PP), as a common cable buffer material, has pyrolysis properties that critically impact cable faults. Studying the semiconductive buffer layer of polypropylene (PP) and its pyrolysis properties allows us to obtain a clearer picture of the pyrolysis products formed during PP ablation. This understanding aids in the accurate diagnosis of cable faults and the identification of ablation events. In this study, the effects of temperature and catalyst (H-Zeolite Standard Oil Corporation Of New York (Socony) Mobil-Five (HZSM-5)) content on the PP thermolysis product distribution were studied by using an online tubular pyrolysis furnace-mass spectrometry (MS) experimental platform. The results showed that PP/40% HZSM-5 presented the highest thermolytic efficiency and relative yield of the main products at 400 °C.

Paving blocks are widely used in engineering construction for durable pavement surfaces characterized by their interlocking capability to enhance structural integrity. This study explores the potential use of char as a byproduct from coal pyrolysis and an alternative raw material to natural aggregates in developing paving blocks, aiming to reduce the associated environmental issues associated with the uncontrolled and excessive mining of natural resources. This study finds the paving blocks made from char to have the required engineering properties as mentioned by ASTM standard C936. Trass and trass-lime are added as supplementary cementitious materials (SCMs) to enhance the performance of char-based paving blocks. The incorporation of SCMs as a cement replacement also aims to reduce the carbon footprint arising from increased cement use. The compressive strength increased from 55.7 MPa to 65.71 MPa at 12.5% cement replacement with trass-lime. The water absorption is reduced to 4.63% from 4.95%. Beneficial effects towards freeze–thaw durability and abrasion resistance are also observed on trass-lime-incorporated paving blocks. This study signifies the remarkable potential use of coal-derived char and SCMs in developing light, high-strength, and durable paving blocks, showcasing their competitive engineering performance. These new char-based paving blocks will contribute towards a more sustainable construction environment and advance the current construction and engineering practices.

To enhance the performance of resistance spot welded joints between aluminum alloy (AA) and mild steel (MS), a specific electrode termed embedded composite electrode was used for welding. The microstructure and properties of the joints obtained under different welding parameters were characterized. The observation results on the cross-section of the joints showed an acetabuliform nugget and ring nugget formed on the AA and MS sides of the joints, respectively, and a reaction layer with bimodal thickness distribution was found at the welding interface. The maximum tensile shear of the joints reached 5.86 kN at the welding current of 26 kA. This study reveals that the resistance spot welding with composite electrodes is a promising approach for restraining the intermetallic compounds growth in the welding central region.

Abstract To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity.

Abstract Mammalian sterile 20-like (Ste20-like) protein kinase 3 (MST3) or serine/threonine-protein kinase 24 (STK24) is a serine/threonine protein kinase that belongs to the mammalian STE20-like protein kinase family. MST3 is a pleiotropic protein that plays a critical role in regulating a variety of events, including apoptosis, immune response, metabolism, hypertension, tumor progression, and development of the central nervous system. The MST3-mediated regulation is intricately related to protein activity, post-translational modification, and subcellular location. Here, we review the recent progress on the regulatory mechanisms against MST3 and its-mediated control of disease progression.

Abstract Nicotiana alata Link et Otto, widely used in landscaping, is not only of great ornamental value but also of high commercial and medical value. The global potential habitat of N. alata and the environmental factors affecting its distribution are not that clear at present. To provide a reference for the reasonable and extensive planting of N. alata now and in the future, the MaxEnt model was used to predict its global suitable habitats under current and future climate conditions, respectively, based on global geographic distribution data of N. alata and the current and future world bioclimatic variables. The results showed that mean temperature of the driest quarter (bio9), precipitation of driest month (bio14), precipitation seasonality (bio15) and max temperature of warmest month (bio5), were the key bioclimatic variables governing the distribution of N. alata. The global suitable habitats of N. alata were mainly distributed in Europe, the United States, southeastern South America, and China under current climate conditions. Compared with current climate conditions, the future climate decreased suitable habitats of N. alata under SSP1-2.6, and SSP2-4.5 scenario and increased suitable habitats of N. alata under SSP3-7.0, and SSP5-8.5 climatic scenarios. The results provided valuable information and theoretical reference for the reasonable planting of N. alata.

To achieve high-precision and high-stability detection of wind speed and direction in complex environments, this research proposes a dual closed-loop control scanning technique for the wind sensor system based on the acoustic resonance principle. This technique has been found to significantly enhance the system’s performance indicators. The acoustic resonance method used on wind sensors allows for the simultaneous modulation of frequency and intensity of signals generated by the transducer, resulting in linear scanning of the ultrasonic transducer. Frequency modulation resolves the issue of a resonance frequency shift caused by environmental factors like pressure and temperature, while intensity modulation addresses transducer performance degradation over time and can significantly improve the signal-to-noise ratio. However, when confronted with issues such as wind shear, the rapid change in the ambient pressure of the wind sensor may lead to the failure of the frequency modulation, followed by the change in the rate of wind shear, resulting in significant errors in wind speed detection. Therefore, the dual closed-loop control method is used to combine the frequency scanning modes—the slow and long scanning and the short and fast scanning. The slow and long scanning is used to solve the resonance frequency shift caused by various slow external changes and achieve frequency following, while the short and fast scanning resolves the resonance frequency shift resulting from rapid changes in wind shear and achieves rapid frequency following. Experimental results demonstrate that the scanning method employing dual closed-loop control can accurately measure wind speed and direction. The wind speed measurement range is 0–50 m/s, with a measurement accuracy of ±0.3 m/s (≤15 m/s)/±4% (>15 m/s), while the wind direction measurement range is 0°–360°, with a measurement accuracy of ±3°. After improvements, the system has high accuracy and stability and strong anti-interference ability and is less affected by environmental changes in complex environments.

Facing towards the Carbon Neutrality goal by 2060, renewable energy sources are boosted in China in the past decade. Either these renewables or power systems are sensitive and vulnerable to natural disasters, such as wildfire and typhoon. In this paper, a fire spot identification algorithm is proposed for wildfire disaster occurred in transmission line corridors based on Fengyun-3E (FY-3E). It mitigates the effect of large observation of solar zenith angle, as well as changes of satellite views, on the infrared channel detection. And cloud information under complex atmospheric conditions is analyzed to extract the cloud pixel fire spot, which decreases false ratio of fire-spot alerts. According to the analysis of hybrid pixel linear spectrums, the fire-spot detection sensitivity of FY-3E is four times as that of geostationary meteorological satellites. The effectiveness of the proposed algorithm was confirmed by an application in the Shanxi province power grid of State Grid in China. It shows that and the FY-3E has a superiority in wildfire monitoring for power system in terms of fire detection sensitivity, spatial range accuracy, and positioning accuracy. Compared to geostationary meteorological satellites, the fire locating accuracy of FY-3E is increased by more than one-fold. This research can assist the operation and maintenance departments of transmission lines to rapidly detect wildfire, thereby reducing the damage of wildfires on the power grid.

Soft materials such as silver, copper and Babbitt SnSb11Cu6 were deposited on the surface of tin bronze by electro spark alloying (ESA) to form the antifriction coating. The data of the antifriction coating were tested by electronic balance, three-dimensional optical profilometer, scanning electron microscope (SEM), energy dispersive spectrometer (EDS), X-ray diffractometer (XRD), Vickers microhardness tester and tribometer. The mass gain, roughness, thickness, surface morphology and phase composition, cross-section and element distribution, microhardness and tribological properties of the antifriction coating were analyzed. The results show that the grain size of the antifriction coating is fine and the metallurgical bonding between the coating and the substrate is good. The surface of each substrate is composed of three layers of coating. The optimal parameters of electro spark alloying are as follows: the discharge voltages of Ag, Cu and Babbitt alloy coatings are 60 V, 60 V and 30 V respectively, the energy storage capacitance is 150 μF, 150 μF and 90 μF respectively, and the working efficiency is 3 min/cm2, 3 min/cm2 and 4 min/cm2 respectively. Under the optimized parameters, the average mass transfer efficiency is 54.4 mg/cm2, the average surface roughness is 32.3 μm, and the maximum thickness is about 160 μm. The surface friction coefficient of the soft antifriction coating is 55.6 % of that of the tin bronze substrate. The main wear mechanisms of the soft antifriction coating prepared by electro spark alloying technique are plastic deformation accompanied by slight polishing.

Objective: The purpose of this study was to investigate the inhibitory effect of brusatol, a nigakilactone extracted from Brucea javanica, on lung cancer for development of therapeutic drugs. We explored the effects of brusatol on the proliferation, migration, and invasion of lung cancer PC-9 cells in vitro and analyzed the mechanisms involved. Materials and Methods: MTT assay was used to determine the effect of brusatol on the proliferative capacity of PC-9 and H1975 cells in vitro. The half-maximal inhibitory concentrations (IC50) were calculated and used as a reference for subsequent experiments. Variations in the number and size of tumor cell clusters were monitored by the colony formation assay as evidence for the effect of brusatol on cell proliferation. The effect of brusatol on the migration and invasion of PC-9 cells was evaluated using wound healing and transwell assays, respectively. Apoptosis in lung cancer cells was detected using the Annexin V-FITC/propidium iodide assay. The correlated anticancer mechanism was detected using Western blotting. Results: The IC50 values of brusatol acting on PC-9 and H1975 cells were 1.58 ± 0.30 μM and 31.34 ± 2.72 μM, respectively, according to the MTT experiment. In addition, brusatol suppressed PC-9 cell proliferation, migration, and invasion, as well as induced apoptosis, which may be related to the downregulation of epidermal growth factor receptor (EGFR), β-catenin, Akt, and STAT3 expression. Conclusions: Brusatol showed potent anticancer activity against lung cancer PC-9 cells, inhibiting the proliferative capacity and metastatic potential of PC-9 cells. Its anticancer effect may be related to the downregulation of EGFR, β-catenin, Akt, and STAT3.

Our previous studies have demonstrated that human papillomavirus (HPV)-16 E7 oncoprotein promoted epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) cells. Moreover, recent studies have found that exosomes can mediate EMT of NSCLC cells and epidermal growth factor receptor (EGFR) is related to the progression of NSCLC. Here, we further investigated the role of exosomal EGFR in HPV-16 E7-induced EMT of NSCLC cells. Our results showed that the exosomes derived from the stable HPV-16 E7-overexpressing A549 and NCI-H460 NSCLC cells (E7 Exo) significantly increased migration, invasion, and proliferation abilities of NSCLC cells as compared with the exosomes derived from empty vector-infected NSCLC cells (ev Exo). Moreover, both in vitro and in vivo results demonstrated that E7 Exo dramatically enhanced EMT of NSCLC cells and promoted the growth of subcutaneous NSCLC xenografts. Additionally, HPV-16 E7 enhanced the expression of EGFR and p-EGFR in both NSCLC cells and exosomes. Furthermore, the inhibition of EGFR activation or exosome secretion suppressed E7 Exo-induced migration, invasion, and EMT of NSCLC. Moreover, 12 kinds of differentially expressed miRNAs between E7 Exo and ev Exo (fold change≥2, P ≤ .05) were screened out, of which 7 miRNAs were up-regulated while 5 miRNAs were down-regulated in A549 E7 Exo. Taken together, our findings suggest that exosomal EGFR is involved in HPV-16 E7-induced EMT of NSCLC cells, which may play a key role in the progression of HPV-related NSCLC.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate a variety of physiological and pathological functions. miR-26a is one of the many miRNAs that have been identified as regulators of cancer development and as potential anticancer drug targets. However, the specific cellular and molecular mechanisms by which miR-26a attenuates hepatocarcinogenesis are still elusive. Here, we interrogated mouse models with miR-26a cell-specific overexpression in either hepatocytes or myeloid cells to show that miR-26a strongly attenuated the chemical-induced hepatocellular carcinoma (HCC). miR-26a overexpression broadly inhibited the inflammatory response in both hepatocytes and macrophages by decreasing several key oncogenic signaling pathways in HCC promotion. These findings thus reveal new insights into a concerted role of miR-26a in both hepatocytes and Kupffer cells to suppress hepatocarcinogenesis, thereby highlighting the potential use of miR-26a mimetics as potential approaches for the prevention and treatment of HCC.

Portulaca oleracea L. (purslane) is a food and a traditional drug worldwide. It exhibits anti-inflammatory, anti-oxidative, anti-tumor, and anti-diabetic bioactivities; but its activity on diabetic-associated endothelial dysfunction is unknown. This study aimed to investigate the effect of purslane on endothelial function and the underlying mechanisms. Male C57BL/6 mice had 14-week ad libitum access to a high-fat rodent diet containing 60% kcal% fat to induce obesity and diabetes whereas purslane extract (200 mg/kg/day) was administered during the last 4 weeks via intragastric gavage. Primary rat aortic endothelial cells and isolated mouse aortas were cultured with a risk factor, high glucose or tunicamycin, together with purslane extract. By ESI-QTOF-MS/MS, flavonoids and their glycoside products were identified in the purslane extract. Exposure to high glucose or tunicamycin impaired acetylcholine-induced endothelium-dependent relaxations in aortas and induced endoplasmic reticulum (ER) stress and oxidative stress with the downregulation of 5′ AMP-activated protein kinase (AMPK)/ endothelial nitric oxide synthase (eNOS) signaling. Co-incubation with purslane significantly ameliorated these impairments. The effects of purslane were abolished by Compound C (AMPK inhibitor). Four-week purslane treatment ameliorated aortic relaxations, ER stress, and oxidative stress in diabetic obese mice. This study supported that purslane protected endothelial function, and inhibited ER stress and oxidative stress in vasculature through AMPK/eNOS activation, revealing its therapeutic potential against vascular complications in diabetes.