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Abstract Background Hypoxia plays an important role in the chemotherapy resistance of nasopharyngeal carcinoma (NPC). Ferroptosis is a newly discovered form of programmed cell death and ferroptosis inducers showed promising therapeutic effects in some cancers. However, the sensibility of NPC cells to ferroptosis under the hypoxic microenvironment is still unclear, and this study was designed to clarify it. Methods NPC cells, treated with erastin, were placed in a normoxia or hypoxic environment (5% CO2, 94% N2 and 1% O2) at 37℃for 24 h. After exposed to hypoxia, ferroptosis-associated phenotypes were detected by CCK8, MDA, GSH, lipid ROS and Fe. The gene expression profiles of head and neck squamous cell carcinoma (HNSCC) tissues were downloaded from the TCGA database to screen construction molecule. BAP1 was screened out and its functions on erastin-induced ferroptosis in NPC cells were detected by knockdown of BAP1. Luciferase reporter assay and co-IP experiment were performed to explore the molecular mechanism. Finally, the tumour xenograft model was applied to further verify these results in vivo. Results CCK8 assay showed that IC50 of NPC cells treated with erastin under hypoxia was significantly lower than that under normoxia. Hypoxia significantly increased the levels of lipid ROS and MDA, and decreased GSH content induced by erastin. A prognostic risk model for HNSCC with six ferroptosis-related genes was constructed and validated based on TCGA database. BAP1 was significantly up-regulated under hypoxia, and luciferase reporter assay showed that HIF-1α was an upstream transcription regulator of BAP1. Knockdown of BAP1 in NPC cells significantly increased the IC50 value of erastin under hypoxia and significantly ameliorated erastin-induced ferroptosis under hypoxia in aspect of lipid ROS, MDA content and GSH. Co-IP results showed that BAP1 mediated deubiquitination of H2A and decreased SLC7A11 expression. Finally, knockdown of BAP1 reduced sensitivity to erastin-induced ferroptosis in a tumour xenograft model. And the level of H2A was significantly decreased in xenograft tumors of BAP1 knockdown cells. Conclusion Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in NPC by stabilizing H2A. Ferroptosis inducers targeting BAP1 may be an effective way to improve chemotherapy resistance in NPC, especially in the hypoxic microenvironment. Graphical Abstract

Abstract Aluminum (Al) is usually added to solid propellants to improve the combustion performance, however the condensed combustion products (CCPs) especially the large agglomerates generated from aluminum combustion can reduce the specific impulse of the engine, and result in two-phase loss, residue accumulation and throat liner ablation. Al and ammonium perchlorate (AP), as important components of NEPE propellants, can affect the formation process of the CCPs of aluminized NEPE propellants. To clarify the effect of Al and AP particle sizes on the properties of the CCPs of aluminized NEPE propellants, a constant-pressure quench vessel was adopted to collect the combustion products of four different formulations of NEPE propellants. It was found that the condensed combustion products are mainly divided into aluminum agglomerates and oxide particles, the diameter of the aluminum agglomerates of these four different formulations of NEPE propellants at 7 MPa was smaller than that in 3 MPa, and the shells of the aluminum agglomerates were smoother and the spherical shape was more perfect. X-ray diffraction analysis of the CCPs of the four NEPE propellants under 3 MPa revealed the presence of both Al and Al2O3. With the increase of the particle size of Al and AP, the oxidation degree of aluminum particles decreases. The particle size of the CCPs of the four different formulations of NEPE propellants under 1 and 3 MPa was analyzed by using a laser particle size analyzer, it is found that the increase of AP particle size is helpful to reduce the size of condensate combustion products. Based on the classical pocket theory, establishing a new agglomeration size prediction model, which can be used to predict the agglomeration size on the burning surface. Compared with the empirical model, the new agglomeration size prediction model is in good agreement with the experimental results.

Abstract This work revisits the notion of complex step derivative approximation (CSDA) and presents its use in constitutive model of a class of nonlinear viscoelastic materials. The effectiveness of a CSDA is evaluated by putting it through a series of straightforward examples. After that, the idea of the CSDA is put to use in order to carry out a numerical evaluation of the algorithmic tangent moduli of a viscoelastic constitutive model. The performance of the constitutive models is evaluated through the use of three different numerical tests, and the results are compared to those that were achieved by the application of an analytical method. In comparison to other numerical differentiation techniques, It has been found that the CSDA scheme is the most computationally efficient and robust method of numerical differentiation, regardless of the size of the finite difference interval.

Abstract Background The 2-phenylethanol (2-PE) tolerance phenotype is crucial to the production of 2-PE, and Pdr1p mutation can significantly increase the tolerance of 2-PE in Saccharomyces cerevisiae. However, its underlying molecular mechanisms are still unclear, hindering the rational design of superior 2-PE tolerance performance. Results Here, the physiology and biochemistry of the PDR1_862 and 5D strains were analyzed. At 3.5 g/L 2-PE, the ethanol concentration of PDR1_862 decreased by 21%, and the 2-PE production of PDR1_862 increased by 16% than those of 5D strain. Transcriptome analysis showed that at 2-PE stress, Pdr1p mutation increased the expression of genes involved in the Ehrlich pathway. In addition, Pdr1p mutation attenuated sulfur metabolism and enhanced the one-carbon pool by folate to resist 2-PE stress. These metabolic pathways were closely associated with amino acids metabolism. Furthermore, at 3.5 g/L 2-PE, the free amino acids content of PDR1_862 decreased by 31% than that of 5D strain, among the free amino acids, cysteine was key amino acid for the enhancement of 2-PE stress tolerance conferred by Pdr1p mutation. Conclusions The above results indicated that Pdr1p mutation enhanced the Ehrlich pathway to improve 2-PE production of S. cerevisiae, and Pdr1p mutation altered the intracellular amino acids contents, in which cysteine might be a biomarker in response to Pdr1p mutation under 2-PE stress. The findings help to elucidate the molecular mechanisms for 2-PE stress tolerance by Pdr1p mutation in S. cerevisiae, identify key metabolic pathway responsible for 2-PE stress tolerance.

Abstract Introduction and objectives In diseases characterized by fibrosis, hepatic stellate cells (HSCs) are mesenchymal cells that play an important role in liver fibrosis. circRNAs are involved in regulating hydatid exocyst formation through miRNA sponge adsorption. The mechanisms of hepatic cystic hydatid outer cyst formation, HSC, and liver fibrosis are unclear. Materials and methods Based on our sequencing data, we validated the mechanism by which circRNA-049637 regulated hepatic cystic hydatid growth and promoted outer fibrocystic wall formation. Results Our results revealed that circRNA_049637 silencing promoted the proliferation of LX-2 human HSCs, affected the cell cycle, and increased the mRNA and protein expression levels of liver fibrosis-related indicators such as α-SMA, COL1A1, COL3A1, and TGFβRII. Conclusions CircRNA_049637 may induce the formation of hepatic hydatid cysts by promoting hepatic fibrosis via HSC activation.

Abstract Background Long coronavirus disease (COVID) after COVID-19 infection is continuously threatening the health of people all over the world. Early prediction of the risk of Long COVID in hospitalized patients will help clinical management of COVID-19, but there is still no reliable and effective prediction model. Methods A total of 1905 hospitalized patients with COVID-19 infection were included in this study, and their Long COVID status was followed up 4–8 weeks after discharge. Univariable and multivariable logistic regression analysis were used to determine the risk factors for Long COVID. Patients were randomly divided into a training cohort (70%) and a validation cohort (30%), and factors for constructing the model were screened using Lasso regression in the training cohort. Visualize the Long COVID risk prediction model using nomogram. Evaluate the performance of the model in the training and validation cohort using the area under the curve (AUC), calibration curve, and decision curve analysis (DCA). Results A total of 657 patients (34.5%) reported that they had symptoms of long COVID. The most common symptoms were fatigue or muscle weakness (16.8%), followed by sleep difficulties (11.1%) and cough (9.5%). The risk prediction nomogram of age, diabetes, chronic kidney disease, vaccination status, procalcitonin, leukocytes, lymphocytes, interleukin-6 and D-dimer were included for early identification of high-risk patients with Long COVID. AUCs of the model in the training cohort and validation cohort are 0.762 and 0.713, respectively, demonstrating relatively high discrimination of the model. The calibration curve further substantiated the proximity of the nomogram’s predicted outcomes to the ideal curve, the consistency between the predicted outcomes and the actual outcomes, and the potential benefits for all patients as indicated by DCA. This observation was further validated in the validation cohort. Conclusions We established a nomogram model to predict the long COVID risk of hospitalized patients with COVID-19, and proved its relatively good predictive performance. This model is helpful for the clinical management of long COVID.

The cost of building a lunar outpost can be greatly reduced by adopting melting of lunar regolith using concentrated solar energy beam based on in-situ additive manufacturing, there are still considerable obstacles to boosting the compactness and mechanical strength of the fabricated samples. The exploration of optimizing process parameters to address the above challenges are severely limited by solar time and space on Earth. Herein, a system for millimeter-scale energy beam melting of the lunar regolith simulant was set up to investigate the effects of process parameters, including laser power, scanning speed, hatching space (track overlapping ratio), and powder layer thickness (layer overlapping ratio) on the processes of single-track, multi-track, and multi-layer forming. The best range of single-track forming quality is the regular type with linear energy density of 27.5–100 J/mm. The surface is smooth and devoid of apparent fissures when the track overlapping rate is between 20% and 45% during the multi-track scanning procedure. For multi-layer sample forming, Samples with high density and few defects appear in the range of 45%–73% layer overlapping rate. The process parameters window for sample forming is determined by the combination of linear energy density, track overlapping rate, and layer overlapping rate. The relative density of single-track, multi-track, and multi-layer increases sequentially under the action of remelting, reaching 62.9%, 70%, and 86%, respectively. The average compressive strength of the test specimen is 5.6 MPa satisfies the specifications for the load-bearing structures on the moon. These results would provide essential data for the development of in-situ additive manufacturing.

Abstract Simulated moving bed (SMB) technology is considered one of the most successful techniques in chromatographic separation. However, due to the nonlinearity caused by discrete events and sensitivity to numerous separation performance parameters, purity control in SMB systems has been a challenging issue. Fuzzy controllers are increasingly popular in industrial environments due to their simplicity and effectiveness in handling nonlinearity. However, traditional fuzzy controllers used in industry often overlook considerations of error acceleration, resulting in slight deviations from target values under steady-state conditions and oscillatory behavior when system parameters change. This study proposes an advanced fuzzy controller, where in a series of experiments, the purity control targets for component B are set at 94% and 96%, and for component A are set at 96% and 96%, respectively. Experimental results indicate that the advanced fuzzy controller achieves higher precision, with an average deviation of around 0.1%, for both components B and A. Importantly, under variations in adsorbent parameter(from 0.01 to 0.03), feed concentration(from 4.5 to 5.2), and switching time(from 178 to 182), the experimental results demonstrate smoother control with the advanced controller, particularly when oscillations occur with conventional fuzzy controllers due to switching time variations, indicating robust control with the advanced fuzzy controller.

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

PurposeTo explore whether tumor-associated lymphatic vessel density (LVD) could be a biomarker for the prognosis of patients with esophageal cancer after radical resection.MethodsA systematic literature search was performed through PubMed, EMBASE, Wanfang Data, and Cochrane Library from the inception of databases until March 19, 2024. The selected studies investigated overall survival (OS) and/or recurrence-free survival (RFS) of patients with esophageal cancer with different levels of LVD after radical resection. The OS and RFS data were pooled as hazard ratios (HR) and 95% confidential interval (CI). Furthermore, the standardized mean differences (SMDs) and 95% CI were aggregated to evaluate the correlation between LVD and clinicopathological features.ResultsA total of 10 retrospective studies of 1,201 patients were finally included for the meta-analysis. Patients with esophageal cancer with a high level of LVD exhibited worse OS (HR 1.65, 95% CI 1.18 to 2.31) and RFS (HR 1.57, 95% CI 1.09 to 2.26) than those with a low level of LVD. Subgroup analysis of different pathological subtypes revealed that patients with esophageal adenocarcinoma with a high level of LVD had significantly worse RFS (HR 2.84, 95% CI 1.61 to 5.02) than those with a low level of LVD; while patients with esophageal squamous cell carcinoma with a high level of LVD had similar OS (HR 1.52, 95% CI 0.93 to 2.47) and RFS (HR 1.03, 95% CI 0.72 to 1.48) to those with a low level of LVD. Furthermore, tumors with lymph node metastasis had significantly higher levels of LVD than those without lymph node metastasis (SMD = 1.11, 95% CI 0.54 to 1.67). Tumors at the stages III-IV had significantly higher levels of LVD than those at the stages I-II (SMD = 1.62, 95% CI 0.90 to 2.34).ConclusionA high level of LVD in tumor was associated with worse survival of patients with esophageal cancer after radical resection, especially in patients with esophageal adenocarcinoma. Tumor-associated LVD is a new parameter that should be measured in postoperative pathology for predicting the prognosis of patients with esophageal cancer.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/ PROSPERO, identifier CRD42024553766.

Environmental heavy metals pollution have seriously threatened the health of human beings. An increasing number of researches have demonstrated that environmental heavy metals can influence the telomere length of Peripheral Blood Mononuclear Cells (PBMCs), which implicate biological aging as well as predicts diseases. Our previous study has shown that methylmercury (MeHg)-induced telomere shortening in rat brain tissue was associated with urinary melatonin metabolite 6-sulfatoxymelatonin (aMT6s) levels. Here, we aimed to further elucidate the impact of 4 typical heavy metals (As, Hg, Cd and Pb) on telomere length of PBMCs and their association with urinary aMT6s in rats. In this study, eighty-eight male Sprague-Dawley rats were randomized grouped into eleven groups. Among them, forty 3-month-old (young) and forty 12-month-old (middle-aged) rats were divided into young or middle-aged control groups as well as typical heavy metals exposed groups, respectively. Eight 24-month-old rats (old) was divided into aging control group. The results showed that MeHg exposure in young rats while sodium arsenite (iAs), MeHg, cadmium chloride (CdCl2), lead acetate (PbAc) exposure in middle-aged rats for 3 months significantly reduced the levels of and urinary aMT6s, as well as telomere length of PBMCs. In addition, they also induced abnormalities in serum oxidative stress (SOD, MDA and GPx) and inflammatory (IL-1β, IL-6 and TNF-α) indicators. Notably, there was a significant positive correlation between declined level of urinary aMT6s and the shortening of telomere length in PBMCs in rats exposed to 4 typical heavy metals. These results suggested that 4 typical heavy metals exposure could accelerate the reduction of telomere length of PBMCs partially by inducing oxidative stress and inflammatory in rats, while ageing may be an important synergistic factor. Urinary aMT6s detection may be a alternative method to reflect telomere toxic effects induced by heavy metal exposure.

Summary: Exo70, a key exocyst complex component, is crucial for cell motility and extracellular matrix (ECM) remodeling in cancer metastasis. Despite its potential as a drug target, Exo70’s post-translational modifications (PTMs) are poorly characterized. Here, we report that Exo70 is transamidated on Gln5 with Lys56 of cystatin A by transglutaminases TGM1 and TGM3, promoting tumor metastasis. This modification enhances Exo70’s association with other exocyst subunits, essential for secreting matrix metalloproteinases, forming invadopodia, and delivering integrins to the leading edge. Tumor suppressor liver kinase B1 (LKB1), whose inactivation accelerates metastasis, phosphorylates TGM1 and TGM3 at Thr386 and Thr282, respectively, to inhibit their interaction with Exo70 and the following transamidation. Cantharidin, a US Food and Drug Administration (FDA)-approved drug, inhibits Exo70 transamidation to restrain tumor cell migration and invasion. Together, our findings highlight Exo70 transamidation as a key molecular mechanism and target and propose cantharidin as a therapeutic strategy with direct clinical translational value for metastatic cancers, especially those with LKB1 loss.

To investigate clinical nurses’ perception of adverse event risk and to analyze its influencing factors. A proportional stratified random sampling method was applied to recruit nurses from a hospital in Shiyan City, Hubei Province, China. The Nursing Adverse Event Risk Perception Scale, Organizational Support Questionnaire, Nurse Manager Leadership Behavior Questionnaire, Nursing Safety Behavior Questionnaire, and Burnout scale was used to investigate 1084 nurses. Univariate analysis, Pearson correlation analysis, and multiple linear regression analysis were used to analyze the influencing factors. The scores of the Nurses’ Risk Perception of Adverse Nursing Event Scale, Organizational Support Questionnaire, Nurse Manager Leadership Behavior Questionnaire, Nursing Safety Behavior Questionnaire, and Burnout Scale were 14.98 ± 5.39, 52.57 ± 10.00, 88.98 ± 21.08, 56.42 ± 5.03, 30.90 ± 21.49, respectively. According to the correlation analysis, nurses’ perception of adverse nursing events was positively correlated with the sense of organizational support (r = .457, P

Introduction: Cigar wrapper leaves (CWLs) plays a crucial role in reflecting cigar overall quality. Originating from the Qinba region of China, Fangxian Huangjiu (FHJ) is distinctive from other varieties of Huangjiu.Methods: To investigate the effects of FHJ on enhancing the aroma and quality of CWLs, as well as the consequent alterations in microbial communities, Gas Chromatography-Mass Spectrometry (GC-MS) coupled with Odor Active Value (OAV) analysis was utilized to evaluate the volatile aroma components of CWLs.Results and Discussion: The results indicated that the total amount of aroma compounds in CWLs reached 3,086.88 ug/g, increasing of 270.50% and 166.31% compared to the unfermented and naturally fermented groups, respectively. Among them, β-ionone and 4,7,9-megastigmatrien-3-one from the FHJ fermentation group significantly influenced the sensory characteristics of CWLs. Metagenomic results demonstrated that FHJ fermentation enriched the abundance of both shared and unique microbial species in CWLs, while also increased the diversity of differential microbial species. Addition of FHJ effectively altered the microbial community structure of CWLs from a dominance of Staphylococcus to a prevalence of Staphylococcus, Aspergillus, Pseudomonas, and Acinetobacter. The interactions among these diverse microorganisms collectively contribute to the enhancement of the intrinsic quality of CWLs. This paper provides a theoretical basis for improving the quality of CWLs by FHJ and exploring the changes of microbial community structure and interaction between CWLs and FHJ.

IntroductionMicrobial succession and metabolic adjustment during cigar tobacco leaf (CTL) fermentation are key factors to improve the quality and flavor of CTLs. However, the interactions in the above processes remain to be further elucidated.MethodsBacillus altitudinis inoculants were added to the CTLs, and metagenomics and metabolomics were used to analyze the effects of the inoculants on regulating microbial succession, metabolic shift, and aroma production during fermentation.Results and discussionThe addition of the inoculants reinforced the CTL macromolecule transformation and facilitated the aroma production efficiently, and the total aroma production was increased by 43% compared with natural fermentation. The omics analysis showed that Staphylococcus was a main contributor to fatty acid degradation, inositol phosphate metabolism, energy supply (oxidative phosphorylation), nutrient transport (ABC transporter and phosphotransferase system [PTS]), and aroma production (terpenoid backbone biosynthesis, phenylalanine metabolism, and degradation of aromatic compounds). Furthermore, Staphylococcus was positively correlated with TCA cycle intermediates (citric acid, fumaric acid, and aconitic acid), cell wall components, peptidoglycan intermediates (GlcNAc-1-P and UDP-GlcNAc), and phytic acid degradation products (inositol). The characteristics collectively showed Staphylococcus to be the most dominant in the microbial community at the genus level during microflora succession. The addition of the inoculants supplemented the nutritional components of the CTLs, enhanced the metabolic activity and diversity of bacteria such as Corynebacterium, improved their competitive advantages in the microflora succession, and facilitated the richness of microbial communities. Additionally, a metabolic shift in nicotine degradation and NAD + anabolism from Staphylococcus to Corynebacterium in fermentation with inoculants was first observed. Meanwhile, the significantly correlative differential metabolites with Staphylococcus and Corynebacterium were a metabolic complement, thus forming a completely dynamic fermentation ecosystem. The results provided evidence for CTL fermentation optimization.

Abstract Adaptive metabolic responses and innate metabolites hold promising therapeutic potential for stroke, while targeted interventions require a thorough understanding of underlying mechanisms. Adiposity is a noted modifiable metabolic risk factor for stroke, and recent research suggests that it benefits neurological rehabilitation. During the early phase of experimental stroke, the lipidomic results showed that fat depots underwent pronounced lipolysis and released fatty acids (FAs) that feed into consequent hepatic FA oxidation and ketogenesis. Systemic supplementation with the predominant ketone beta‐hydroxybutyrate (BHB) is found to exert discernible effects on preserving blood‐brain barrier (BBB) integrity and facilitating neuroinflammation resolution. Meanwhile, blocking FAO‐ketogenesis processes by administration of CPT1α antagonist or shRNA targeting HMGCS2 exacerbated endothelial damage and aggravated stroke severity, whereas BHB supplementation blunted these injuries. Mechanistically, it is unveiled that BHB infusion is taken up by monocarboxylic acid transporter 1 (MCT1) specifically expressed in cerebral endothelium and upregulated the expression of tight junction protein ZO‐1 by enhancing local β‐hydroxybutyrylation of H3K9 at the promoter of TJP1 gene. Conclusively, an adaptive metabolic mechanism is elucidated by which acute lipolysis stimulates FAO‐ketogenesis processes to restore BBB integrity after stroke. Ketogenesis functions as an early metabolic responder to restrain stroke progression, providing novel prospectives for clinical translation.

Abstract Objective To explore the changes and potential mechanisms of microbiome in different parts of the upper airway in the development of pediatric OSA and observe the impact of surgical intervention on oral microbiome for pediatric OSA. Methods Before adeno-tonsillectomy, we collected throat swab samples from different parts of the oropharynx and nasopharynx of 30 OSA patients and 10 non-OSA patients and collected throat swab samples from the oropharynx of the above patients one month after the adeno-tonsillectomy. The 16 S rRNA V3–V4 region was sequenced to identify the microbial communities. The correlation analysis was conducted based on clinical characteristics. Results There was a significant difference of alpha diversity in different parts of the upper airway of pediatric OSA, but this difference was not found in children with non-OSA. Beta diversity was significantly different between non-OSA and pediatric OSA. At the genus level, the composition of flora in different parts is different between non-OSA and pediatric OSA. The correlation analysis revealed that the relative abundance of Neisseria was significantly correlated with obstructive apnea hypopnea index. Furthermore, the functional prediction revealed that pathways related to cell proliferation and material metabolism were significantly different between non-OSA and pediatric OSA. Besides, the adeno-tonsillectomy has minimal impact on oral microbiota composition in short term. Conclusion The changes in upper airway microbiome are highly associated with pediatric OSA. The relative abundance of some bacteria was significantly different between OSA and non-OSA. These bacteria have the potential to become new diagnostic and early warning biomarkers.

Objective: In order to control the herbal quality and select the optimal harvesting period of Rosa cymosa Tratt., the contents of total polysaccharide, total organic acid and ellagic acid in its leaves and stems at different harvesting periods within one year were studied in this paper. Methods: The samples of leaf or stem were collected monthly from February to December in 2021, and dried in the room temperature, then, their total polysaccharides, total organic acids, and ellagic acids were determined through UV spectrophotometry and high performance liquid chromatography (HPLC), respectively. At the same time, the quality of leaves and stems at differenet harvesting periods were comprehensively evaluated by cluster analysis and principal component analysis. Results: The contents of total polysaccharide, total organic acid and ellagic acid in its leaves and stems showed some fluctuations throughout the year. The contents of polysaccharide in leaves reached higher levels in July (22.689 mg·g−1 and August (23.164 mg·g−1). The content of total organic acids were highest in February (111.484 mg·g−1), June (113.342 mg·g−1), and August (102.425 mg·g−1). The highest levels of ellagic acid were found in April (0.074 mg·g−1), June (0.077 mg·g−1) and August (0.074 mg·g−1). The contents of total polysaccharide in the stems were higher in February (15.650 mg·g−1). The content of total organic acids were highest in May (171.123 mg·g−1), September (178.960 mg·g−1), and February (125.393 mg·g−1). The contents of ellagic acid were significantly higher in February (0.037 mg·g−1) and April (0.038 mg·g−1) than those in stems harvested correspondingly in other months. The leaves and stems were divided into 3 categories according to cluster analysis, which was basically consistent with principal component analysis. By principal component analysis, the cumulative contribution rates of leaves and stems reached 77.067% and 82.970%, respectively. The results showed that the comprehensive evaluation of leaves harvested in August and stems harvested in February was the highest. Conclusion: Therefore, the comprehensive analysis determined that the appropriate harvesting period for Rosa cymosa Tratt. was August for leaves and February for stems. The results of this study could provide some references for the quality evaluation and harvest research of Rosa cymosa Tratt.

Introduction Orthodontic treatment using face mask protraction combined with an alternate rapid maxillary expansion and constriction/protraction face mask (Alt-RAMEC/PFM) protocol is effective in the early treatment of patients with class III malocclusion, but the stability of treatment outcomes represents a major concern. Previous studies have suggested that tonsillar hypertrophy can be a risk factor for class III malocclusion and tonsillectomy may prompt the normalisation of dentofacial growth. However, these studies had a low-to-moderate level of evidence. This study was designed to identify the impact of tonsillectomy before orthodontic treatment on the efficacy and stability of Alt-RAMEC/PFM protocols and the sleep quality and oral health in children with anterior crossbite and tonsillar hypertrophy.Methods and analysis This is a two-arm, parallel-group, superiority cluster randomised controlled trial, with four clinics randomly assigned to the surgery-first arm and the orthodontic-first arm in a 1:1 ratio. The Alt-RAMEC protocol involves alternate activation and deactivation of the expander’s jet screw over 6 weeks to stimulate maxillary suture distraction. Patients will be instructed to wear the PFM for a minimum of 14 hours per day. The primary outcomes are changes in Wits appraisal and the degree of maxillary advancement from baseline to the end of orthodontic treatment. Lateral cephalometric radiographs, polysomnography, Obstructive Sleep Apnoea-18 questionnaire and Oral Health Impact Profile-14 questionnaire will be traced, collected and measured. We will recruit 96 patients intofor the study. To assess differences, repeated multilevel linear mixed modelling analyses will be used.Ethics and dissemination This study has been granted ethical approval by the Ethics Committee of the School & Hospital of Stomatology, Wuhan University (approval No. 2023-D10). Written informed consent will be obtained from the participants and their guardians. The results of the trial will be disseminated through academic conferences and journal publications.Trial registration number ChiCTR2300078833.

Summary: The development of targeted drugs for the early prevention and management of chronic kidney disease (CKD) is of great importance. However, the success rates and cost-effectiveness of traditional drug development approaches are extremely low. Utilizing large sample genome-wide association study data for drug repurposing has shown promise in many diseases but has not yet been explored in CKD. Herein, we investigated actionable druggable targets to improve renal function using large-scale Mendelian randomization and colocalization analyses. We combined two population-scale independent genetic datasets and validated findings with cell-type-dependent eQTL data of kidney tubular and glomerular samples. We ultimately prioritized two drug targets, opioid receptor-like 1 and F12, with potential genetic support for restoring renal function and subsequent treatment of CKD. Our findings explore the potential pathological mechanisms of CKD, bridge the gap between the molecular mechanisms of pathogenesis and clinical intervention, and provide new strategies in future clinical trials of CKD.

Arsenic is an environmentally ubiquitous toxic metalloid. Chronic exposure to arsenic may lead to arsenicosis, while no specific therapeutic strategies are available for the arsenism patients. And Ginkgo biloba extract (GBE) exhibited protective effect in our previous study. However, the mechanisms by which GBE protects the arsenism patients remain poorly understood. A liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics analysis was used to study metabolic response in arsenism patients upon GBE intervention. In total, 39 coal-burning type of arsenism patients and 50 healthy residents were enrolled from Guizhou province of China. The intervention group (n = 39) were arsenism patients orally administered with GBE (three times per day) for continuous 90 days. Plasma samples from 50 healthy controls (HC) and 39 arsenism patients before and after GBE intervention were collected and analyzed by established LC-MS method. Statistical analysis was performed by MetaboAnalyst 5.0 to identify differential metabolites. Multivariate analysis revealed a separation in arsenism patients between before (BG) and after GBE intervention (AG) group. It was observed that 35 differential metabolites were identified between BG and AG group, and 30 of them were completely or partially reversed by GBE intervention, with 14 differential metabolites significantly up-regulated and 16 differential metabolites considerably down-regulated. These metabolites were involved in promoting immune response and anti-inflammatory functions, and alleviating oxidative stress. Taken together, these findings indicate that the GBE intervention could probably exert its protective effects by reversing disordered metabolites modulating these functions in arsenism patients, and provide insights into further exploration of mechanistic studies.

Abstract Objectives To analyze the diagnostic value of the tonsil–oropharynx (T/O) ratio on lateral cephalograms for evaluating tonsillar hypertrophy (TH). Methods A cross-sectional study was performed on 185 consecutive children (101 males, 84 females; mean age 7.3 ± 1.4 years) seeking orthodontic treatment. The T/O ratios on lateral cephalograms were calculated following Baroni et al.’s method. Tonsil sizes were clinically determined according to the Brodsky grading scale. Spearman correlation coefficients between the T/O ratio and clinical tonsil size were calculated with the total sample and subgroups and then compared between subgroups. Diagnostic value was analyzed using the receiver operating characteristic (ROC) curve, sensitivity, specificity, positive and negative predictive values, and accuracy. Results There was a strong correlation between the T/O ratio and clinical tonsil size in children (ρ = 0.73; P

Abstract Background Neuroblastoma is one common pediatric malignancy notorious for high temporal and spatial heterogeneities. More than half of its patients develop distant metastases involving vascularized organs, especially the bone marrow. It is thus necessary to have an economical, noninvasive method without much radiation for follow‐ups. Radiomics has been used in many cancers to assist accurate diagnosis but not yet in bone marrow metastasis in neuroblastoma. Methods A total of 182 patients with neuroblastoma were retrospectively collected and randomly divided into the training and validation sets. Five‐hundred and seventy‐two radiomics features were extracted from magnetic resonance imaging, among which 41 significant ones were selected via T‐test for model development. We attempted 13 machine‐learning algorithms and eventually chose three best‐performed models. The integrative performance evaluations are based on the area under the curves (AUCs), calibration curves, risk deciles plots, and other indexes. Results Extreme gradient boosting, random forest (RF), and adaptive boosting were the top three to predict bone marrow metastases in neuroblastoma while RF was the most accurate one. Its AUC was 0.90 (0.86–0.93), F1 score was 0.82, sensitivity was 0.76, and negative predictive value was 0.79 in the training set. The values were 0.82 (0.71–0.93), 0.80, 0.75, and 0.92 in the validation set, respectively. Conclusions Radiomics models are likely to contribute more to metastatic diagnoses and the formulation of personalized healthcare strategies in clinics. It has great potential of being a revolutionary method to replace traditional interventions in the future.

Abstract Developing efficient artificial photocatalysts for the biomimetic photocatalytic production of molecular materials, including medicines and clean energy carriers, remains a fundamentally and technologically essential challenge. Hydrogen peroxide is widely used in chemical synthesis, medical disinfection, and clean energy. However, the current industrial production, predominantly by anthraquinone oxidation, suffers from hefty energy penalties and toxic byproducts. Herein, we report the efficient photocatalytic production of hydrogen peroxide by protonation-induced dispersible porous polymers with good charge-carrier transport properties. Significant photocatalytic hydrogen peroxide generation occurs under ambient conditions at an unprecedented rate of 23.7 mmol g–1 h–1 and an apparent quantum efficiency of 11.3% at 450 nm. Combined simulations and spectroscopies indicate that sub-picosecond ultrafast electron “localization” from both free carriers and exciton states at the catalytic reaction centers underlie the remarkable photocatalytic performance of the dispersible porous polymers.

Abstract Background Previous research has already indicated an elevated risk of breast cancer (BC) among survivors of malignant lymphoma, but the underlying reasons remain unknown. Our objective is to elucidate the causal relationship between malignant lymphoma and BC through Mendelian randomization (MR). Genome-wide association studies (GWAS) data from 181,125 Hodgkin lymphoma (HL) patients and 181,289 non-Hodgkin lymphoma (NHL) patients from the FinnGen Consortium were utilized as exposure. We selected single nucleotide polymorphisms (SNPs) strongly associated with the exposure as instrumental variables to investigate their relationship with BC in a cohort of 107,722 participants. Subsequently, we obtained data from the UK Biobank containing gender-stratified information on HL, NHL, and BC. We validated the findings from our analysis and explored the impact of gender. The Inverse-Variance Weighted (IVW) method served as the primary reference for the two-sample MR, accompanied by tests for heterogeneity and pleiotropy. Results The analysis results from the FinnGen consortium indicate that there is no causal relationship between HL and NHL with BC. HL (OR = 1.01, 95% CI = 0.98–1.04, p = 0.29), NHL (OR = 1.01, 95% CI = 0.96–1.05, p = 0.64). When utilizing GWAS data from the UK Biobank that includes different gender cohorts, the lack of association between HL, NHL, and BC remains consistent. HL (OR = 1.08, 95% CI = 0.74–1.56, p = 0.69), HL-Female (OR = 0.84, 95% CI = 0.59–1.19, p = 0.33), NHL (OR = 0.89, 95% CI = 0.66–1.19, p = 0.44), and NHL-Female (OR = 0.81, 95% CI = 0.58–1.11, p = 0.18). Conclusions The two-sample MR analysis indicates that there is no significant causal relationship between malignant lymphoma (HL and NHL) and BC. The association between malignant lymphoma and breast cancer requires further in-depth research and exploration.

With the aim of improving the processing added value of soybean isolate protein, the single factor and response surface testing method were used to optimize the enzymatic conditions of soybean isolate protein using hydrolysis degree and protein recovery as evaluation indexes. The enzymatic digest of soybean isolate protein fermented by Corynebacterium glutamicum was used to prepare the seasoning, which was evaluated by glutamic acid content and sensory evaluation. The results showed that the optimal enzyme digestion conditions were 2.0 g/100 g of enzyme, pH7.0, 15 g/100 mL of substrate, 54.0 ℃, and 13.0 h. The hydrolysis degree (37.1%) and protein recovery (70.3%) of the optimized enzyme solution were 1.7 times and 0.8 times higher, respectively, than those before the optimization. In the shake flask fermentation conditions, the glutamic acid content of the enzymatic digest fermentation (32.1 g/L) was increased by 32.1% compared to that before optimization. Under the batch replenishment condition of 20 L tank, the glutamic acid yield was (83.6 g/L) 10.0% higher than before optimization. The results of sensory evaluation of the seasonings prepared by fermentation with batch replenishment showed that the freshness of the fermented seasonings was significantly improved (P

This study focused on improving the flavor quality of seasonings, and enzymatic hydrolysis of soybean protein isolate (SPI) seasoning via traditional technology may lead to undesirable flavors. Herein, we aimed to develop a new type of SPI seasoning through microbial fermentation to improve its flavor quality. The effect of Corynebacterium glutamicum fermentation on the flavoring compounds of seasonings in SPI enzymatic hydrolysate was examined. Sensory evaluation showed that the SPI seasoning had mainly aromatic and roasted flavor, and the response signals of S18 (aromatic compounds), S24 (alcohols and aldehydes), and S25 (esters and ketones) sensors of the electronic nose differed significantly. Overall, 91 volatile compounds were identified via gas chromatography–mass spectrometry. SPI seasonings contained a higher number of alcohols, ketones, aromatics, and heterocyclic compounds than traditional seasonings, which had stronger cheese, fatty, and roasted aromas. According to the relative odor activity value (ROAV) analysis, n-pentylpyrzine, 2,6-dimethylpyrazine, and tetramethylpyrazine are the key flavoring compounds (ROAV ≥ 1) of SPI seasoning, which may impart a unique roasted and meaty aroma. Therefore, the fermentation of SPI enzymatic hydrolysate with C. glutamicum may improve the flavor quality of its products, providing a new method for the development and production of new seasoning products.

Background: The relationship between brominated flame retardants (BFRs) exposure and the human liver was still not well understood. Methods: A total of 3108 participants (age > 12) from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2005 to 2016 were included as the study population, with nine BFRs exhibiting a detection rate of over 70% serving as the exposure factor. The singular effects and combined effects of BFRs exposure on liver injury, non-alcoholic fatty liver disease (NAFLD), and advanced hepatic fibrosis (AHF) were evaluated separately. Finally, COX regression was employed to explore the hazard ratios associated with individual BFRs. Results: In our analysis of individual exposures, we found significant positive association of PBB153 with alanine aminotransferase (ALT), PBB153 with aspartate aminotransferase (AST), PBDE47, PBDE85, PBDE99, PBDE100, and PBDE154 with alkaline phosphatase (ALP), PBDE28 and PBB153 with gamma-glutamyl transaminase (GGT), PBB153 with the risk of NAFLD and AHF; and significant negative association of PBB153 with ALP, PBDE28, PBDE47, PBDE99, PBDE100, PBDE85, PBDE209, and PBDE154 with albumin (ALB), PBB153 with AST/ALT. The nonlinear analysis results from Restricted Cubic Spline (RCS) further validated these associations (all P0, P0, P1, P=0.007). Conversely, BFRs exhibited significant negative correlations with ALP (β

Organic UV filters, which are often found in the environment, have been the focus of much public health concern. 2-ethylhexyl-4-methoxycinnamate (EHMC) is one of the most common organic UV filters present in the environment. However, few studies have investigated its developmental neurotoxic (DNT) effects and the underlying molecular mechanisms. In the present study, zebrafish embryos were exposed to low concentration of EHMC (0, 0.01, 0.1, 1 mg/L) in static water starting from 6 h post-fertilization (hpf). Results showed that EHMC exposure caused a reduction in somite count at 13 hpf, a diminishment in head-trunk angle at 30 hpf, a delay in hatching at 48 hpf, and a decrease in head depth and head length at both 30 and 48 hpf. Additionally, EHMC led to abnormal motor behaviors at various developmental stages including altered spontaneous movement at both 23 and 24 hpf, and decreased touch response at 30 hpf. Consistent with these morphological changes and motor behavior deficits, EHMC inhibited axonal growth of primary motor neurons at 30 and 48 hpf, and yielded subtle changes in muscle fiber length at 48 hpf, suggesting the functional relevance of structural changes. Moreover, EHMC exposure induced excessive cell apoptosis in the head and spinal cord regions, increased the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and reduced the level of glutathione (GSH). Defects of lateral line system neuromasts were also observed, but no structural deformity of blood vessels was seen in developing zebrafish. Abnormal expression of axonal growth-related genes (gap43, mbp, shha, and α1-tubulin) and apoptosis-related genes (bax/bcl-2 and caspase-3) revealed potential molecular mechanisms regarding the defective motor behaviors and aberrant phenotype. In summary, our findings indicate that EHMC induced developmental neurotoxicity in zebrafish, making it essential to assess its risks and provide warnings regarding EHMC exposure.

Abstract Oxidative stress is an important mechanism of aging, and in turn, aging can also aggravate oxidative stress, which leads to a vicious cycle. In the process of the brain converting light into visual signals, the eye is stimulated by harmful blue‐light radiation directly. Thus, the eye is especially vulnerable to oxidative stress and becomes one of the organs most seriously involved during the aging process. Cataracts, age‐related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), and dry eye are inextricably linked to the aging process and oxidative stress. Chlorogenic acid (CGA) has been demonstrated to have antioxidant and anti‐inflammatory activities, and its validity has been established experimentally in numerous fields, including cardiovascular disease, metabolic disorders, cancers, and other chronic diseases. There has previously been evidence of CGA's therapeutic effect in the field of ophthalmopathy. Considering that many ophthalmic drugs lead to systemic side effects, CGA may act as a natural exogenous antioxidant for patients to take regularly, controlling their condition while minimizing side effects. In this paper, in vitro and in vivo studies of CGA in the treatment of age‐related eye diseases are reviewed, and the prospects of CGA's antioxidant application for the eye are discussed. The aim of this review is to summarize the relevant knowledge and provide theoretical support for future research.

IntroductionFurfural, a main inhibitor produced during pretreatment of lignocellulose, has shown inhibitory effects on S. cerevisiae.MethodIn the present study, new strains named 12–1 with enhanced resistance to furfural were obtained through adaptive laboratory evolution, which exhibited a shortened lag phase by 36 h, and an increased ethanol conversion rate by 6.67% under 4 g/L furfural.Results and DiscussionTo further explore the mechanism of enhanced furfural tolerance, ADR1_1802 mutant was constructed by CRISPR/Cas9 technology, based on whole genome re-sequencing data. The results indicated that the time when ADR1_1802 begin to grow was shortened by 20 h compared with reference strain (S. cerevisiae CEN.PK113-5D) when furfural was 4 g/L. Additionally, the transcription levels of GRE2 and ADH6 in ADR1_ 1802 mutant were increased by 53.69 and 44.95%, respectively, according to real-time fluorescence quantitative PCR analysis. These findings suggest that the enhanced furfural tolerance of mutant is due to accelerated furfural degradation. Importance: Renewable carbon worldwide is vital to achieve “zero carbon” target. Bioethanol obtained from biomass is one of them. To make bioethanol price competitive to fossil fuel, higher ethanol yield is necessary, therefore, monosaccharide produced during biomass pretreatment should be effectively converted to ethanol by Saccharomyces cerevisiae. However, inhibitors formed by glucose or xylose oxidation could make ethanol yield lower. Thus, inhibitor tolerant Saccharomyces cerevisiae is important to this process. As one of the main component of pretreatment hydrolysate, furfural shows obvious impact on growth and ethanol production of Saccharomyces cerevisiae. To get furfural tolerant Saccharomyces cerevisiae and find the underlying mechanism, adaptive laboratory evolution and CRISPR/Cas9 technology were applied in the present study

Aluminum (Al) particles are commonly added to energetic materials including propellants, explosives and pyrotechnics to increase the overall energy density of the composite, but aluminum agglomeration on the combustion surface may lower the combustion efficiency of propellants, resulting in a loss in two-phase flow. Therefore, it is necessary to understand the agglomeration mechanism of aluminum particles on the combustion surface. In this paper, a high-pressure sealed combustion chamber is constructed, and high-speed camera is used to capture the whole process of aluminum accumulation, aggregation and agglomeration on the combustion surface, and the secondary agglomeration process near the combustion surface. The microscopic morphology and chemical composition of the condensed combustion products (CCPs) are then studied by using scanning electron microscopy coupled with energy dispersive (SEM-EDS) method. Results show that there are three main types of condensed combustion products: small smoke oxide particles oxidized by aluminum vapor, usually less than 1 μm; typical agglomerates formed by the combustion of aluminum agglomerates; carbonized agglomerates that are widely distributed, usually formed by irregular movements of aluminum agglomerates. The particle size of condensed combustion products is measured by laser particle size meter. As the pressure increases from 0.5 MPa to 1.0 MPa in nitrogen, the mass average particle size of aluminum agglomerates decreases by 49.7%. As the ambient gas is changed from 0.5 MPa nitrogen to 0.5 MPa air, the mass average particle size of aluminum agglomerates decreases by 67.3%. Results show that as the ambient pressure increases, the higher oxygen content can improve combustion efficiency and reduce the average agglomeration size of aluminum particles.

Abstract Objectives We aimed to use machine learning (ML) algorithms to risk stratify the prognosis of critical pulmonary embolism (PE). Material and methods In total, 1229 patients were obtained from MIMIC-IV database. Main outcomes were set as all-cause mortality within 30 days. Logistic regression (LR) and simplified eXtreme gradient boosting (XGBoost) were applied for model constructions. We chose the final models based on their matching degree with data. To simplify the model and increase its usefulness, finally simplified models were built based on the most important 8 variables. Discrimination and calibration were exploited to evaluate the prediction ability. We stratified the risk groups based on risk estimate deciles. Results The simplified XGB model performed better in model discrimination, which AUC were 0.82 (95% CI: 0.78–0.87) in the validation cohort, compared with the AUC of simplified LR model (0.75 [95% CI: 0.69—0.80]). And XGB performed better than sPESI in the validation cohort. A new risk-classification based on XGB could accurately predict low-risk of mortality, and had high consistency with acknowledged risk scores. Conclusions ML models can accurately predict the 30-day mortality of critical PE patients, which could further be used to reduce the burden of ICU stay, decrease the mortality and improve the quality of life for critical PE patients.

This paper presents a minimally invasive surgical robot system for endoluminal gastrointestinal endoscopy through natural orifices. In minimally invasive gastrointestinal endoscopic surgery (MIGES), surgical instruments need to pass through narrow endoscopic channels to perform highly flexible tasks, imposing strict constraints on the size of the surgical robot while requiring it to possess a certain gripping force and flexibility. Therefore, we propose a novel minimally invasive robot system with advantages such as compact size and high precision. The system consists of an endoscope, two compact flexible continuum mechanical arms with diameters of 3.4 mm and 2.4 mm, respectively, and their driving systems, totaling nine degrees of freedom. The robot’s driving system employs bidirectional ball-screw-driven motion of two ropes simultaneously, converting the choice of opening and closing of the instrument’s end into linear motion, facilitating easier and more precise control of displacement when in position closed-loop control. By means of coordinated operation of the terminal surgical tools, tasks such as grasping and peeling can be accomplished. This paper provides a detailed analysis and introduction of the system. Experimental results validate the robot’s ability to grasp objects of 3 N and test the system’s accuracy and payload by completing basic operations, such as grasping and peeling, thereby preliminarily verifying the flexibility and coordination of the robot’s operation in a master–slave configuration.

Hypopharyngeal squamous cell carcinoma (HSCC) is a kind of malignant tumor with a poor prognosis and low quality of life in the otolaryngology department. It has been found that microRNA (miRNA) plays an important role in the occurrence and development of various tumors. This study found that the expression level of miRNA-107 (miR-107) in HSCC was significantly reduced. Subsequently, we screened out the downstream direct target gene Neuronal Vesicle Trafficking Associated 1 (NSG1) related to miR-107 through bioinformatics analysis and found that the expression of NSG1 was increased in HSCC tissues. Following the overexpression of miR-107 in HSCC cells, it was observed that miR-107 directly suppressed NSG1 expression, leading to increased apoptosis, decreased proliferation, and reduced invasion capabilities of HSCC cells. Subsequent experiments involving the overexpression and knockdown of NSG1 in HSCC cells demonstrated that elevated NSG1 levels enhanced cell proliferation, migration, and invasion, while the opposite effect was observed upon NSG1 knockdown. Further investigations revealed that changes in NSG1 levels in the HSCC cells were accompanied by alterations in ERK signaling pathway proteins, suggesting a potential regulatory role of NSG1 in HSCC cell proliferation, migration, and invasion through the ERK pathway. These findings highlight the significance of miR-107 and NSG1 in hypopharyngeal cancer metastasis, offering promising targets for therapeutic interventions and prognostic evaluations for HSCC.

Lycopene represents one of the central compounds in the carotenoid pathway and it exhibits a potent antioxidant ability with wide potential applications in medicine, food, and cosmetics. The microbial production of lycopene has received increasing concern in recent years. Corynebacterium glutamicum (C. glutamicum) is considered to be a safe and beneficial industrial production platform, naturally endowed with the ability to produce lycopene. However, the scarcity of efficient genetic tools and the challenge of identifying crucial metabolic genes impede further research on C. glutamicum for achieving high-yield lycopene production. To address these challenges, a novel genetic editing toolkit, CRISPR/MAD7 system, was established and developed. By optimizing the promoter, ORI and PAM sequences, the CRISPR/MAD7 system facilitated highly efficient gene deletion and exhibited a broad spectrum of PAM sites. Notably, 25 kb of DNA from the genome was successfully deleted. In addition, the CRISPR/MAD7 system was effectively utilized in the metabolic engineering of C. glutamicum, allowing for the simultaneous knockout of crtEb and crtR genes in one step to enhance the accumulation of lycopene by blocking the branching pathway. Through screening crucial genes such as crtE, crtB, crtI, idsA, idi, and cg0722, an optimal carotenogenic gene combination was obtained. Particularly, cg0722, a membrane protein gene, was found to play a vital role in lycopene production. Therefore, the CBIEbR strain was obtained by overexpressing cg0722, crtB, and crtI while strategically blocking the by-products of the lycopene pathway. As a result, the final engineered strain produced lycopene at 405.02 mg/L (9.52 mg/g dry cell weight, DCW) in fed-batch fermentation, representing the highest reported lycopene yield in C. glutamicum to date. In this study, a powerful and precise genetic tool was used to engineer C. glutamicum for lycopene production. Through the modifications between the host cell and the carotenogenic pathway, the lycopene yield was stepwise improved by 102-fold as compared to the starting strain. This study highlights the usefulness of the CRISPR/MAD7 toolbox, demonstrating its practical applications in the metabolic engineering of industrially robust C. glutamicum.

BackgroundBreast cancer (BC) poses a serious threat to human health. Disulfidptosis is a recently discovered form of cell death associated with cancer prognosis and progression. However, the relationship between BC and disulfidptosis remains unclear.MethodsWe integrated single-cell sequencing and transcriptome sequencing in BC to assess the abundance and mutation status of disulfidptosis-associated genes (DAGs). Subsequently, we clustered the samples based on DAGs and constructed a prognostic model associated with disulfidptosis. Additionally, we performed pathway enrichment, immune response, and drug sensitivity analyses on the model. Finally, we validated the prognostic genes through Immunohistochemistry (IHC).ResultsThe single-cell analysis identified 21 cell clusters and 8 cell types. By evaluating the abundance of DAGs in different cell types, we found specific expression of the disulfidoptosis core gene SLC7A11 in mesenchymal stem cells (MSCs). Through unsupervised clustering of DAGs, we identified two clusters. Utilizing differentially expressed genes from these clusters, we selected 7 genes (AFF4, SLC7A11, IGKC, IL6ST, LIMD2, MAT2B, and SCAND1) through Cox and Lasso regression to construct a prognostic model. External validation demonstrated good prognostic prediction of our model. BC patients were stratified into two groups based on riskscore, with the high-risk group corresponding to a worse prognosis. Immune response analysis revealed higher TMB and lower TIDE scores in the high-risk group, while the low-risk group exhibited higher CTLA4/PD-1 expression. This suggests that both groups may respond to immunotherapy, necessitating further research to elucidate potential mechanisms. Drug sensitivity analysis indicated that dasatinib, docetaxel, lapatinib, methotrexate, paclitaxel, and sunitinib may have better efficacy in the low-risk group. Finally, Immunohistochemistry (IHC) validated the expression of prognostic genes, demonstrating higher levels in tumor tissue compared to normal tissue.ConclusionOur study has developed an effective disulfidptosis-related prognostic prediction tool for BC and provides personalized guidance for the clinical management and immunotherapy selection of BC patients.

Increased proliferation and migration of abnormal airway smooth muscle cells (ASMCs) are significantly associated with asthma. Recently, the function of long non-coding RNAs (lncRNAs) in ASMCs has been identified. Our research attempted to resolve the function of the lncRNA DGCR5 in ASMCs and focus on its in-depth mechanisms of proliferation and migration. Quantitative real-time PCR and western blotting were used to evaluate the expressions of RNA and proteins, respectively. The CCK-8 assay was used to detect cell proliferation. Transwell assays were used to assess migration. Luciferase and RNA pull-down assays were used to verify the targeting between miR-204-5p and lncRNA DGCR5 or SRSF7. LncRNA DGCR5 was upregulated in ASMCs stimulated with PDGF-BB. Knockdown of DGCR5 reversed the effect of platelet-derived growth factor BB (PDGF-BB) on the proliferation and migration of ASMCs. The results of this study showed that lncRNA DGCR5 binds to miR-204-5p, and SRSF7 is the target of miR-204-5p. Rescue experiments verified the interaction between miR-204-5p and DGCR5, as well as that between miR-204-5p and SRSF7. Overall, this study revealed that the lncRNA DGCR5/miR-204-5p/SRSF7 signalling axis has key regulatory effects on the proliferation and migration of ASMCs.

This paper presents a computational fluid dynamics study of morphology and structure dynamics of the flow over a supersonic secant-ogive cylinder boat tail projectile under heavy rain. The discrete phase model is employed to approximate the process of droplet–particle collision with the projectile wall and the formation of a liquid film. The simulation results indicate that at certain angles of attack, rain impact decreases lift coefficient of projectile by as much as 14.9%, as the wall pressure distribution is distinctly reformed. Moreover, the rain condition induces the formation of a liquid film on the front end of the projectile, as the angle of attack increases, the stability of this liquid film gradually improves, while its thickness and coverage rise to the peak values and then decrease. On the projectile’s trailing half, however, the liquid film developed a watery pattern. The collision of liquid droplets causes momentum loss to the projectile, while an unstable liquid film tends to exacerbate aerodynamic performance loss, a stable liquid film would mitigate the performance loss.

Background We aim to investigate the potential value of cuproptosis-related lncRNA signaling in predicting clinical prognosis and immunotherapy and its relationship with drug sensitivity in head and neck squamous cell carcinoma (HNSCC). Methods We first identified the lncRNAs associated with cuproptosis genes in HNSCC and then conducted a series of analytical studies to investigate the expression and prognostic significance of these lncRNAs. Finally, we used RT-qPCR to validate our findings in a laryngeal squamous cell carcinoma cell line and 12 pairs of laryngeal squamous cell carcinoma and adjacent normal tissues. Results We identified 11 differentially expressed lncRNAs that were associated with cuproptosis genes in HNSCC and also served as prognostic markers for this cancer. Enrichment analysis revealed that these lncRNAs were related to immune-related functions that were suppressed in patients with oncogene mutations in the high-risk group. The patients with a high tumor mutation burden exhibited poor overall survival (OS). We used the tumor immune dysfunction and exclusion model to show that the patients in the high-risk group had great potential for immune evasion and less effective immunotherapy. We also identified several drugs that could be effective in treating HNSCC. Experimental validation showed that AC090587.1 and AC012184.3 exhibited differential expression between the TU686 and HBE cell lines, and SNHG16 showed differential expression among the TU686, TU212, and control HBE cells. Among the 12 pairs of cancer and adjacent tissues collected in the clinic, only SNHG16 showed differential expression. Targeted therapy against SNHG16 holds promise as a prospective novel strategy for the clinical management of HNSCC.

Catastrophic geo-hazards have occurred frequently in the karst areas of Southwestern China for these years because of internal, external geologic processes and human engineering activities, which makes it urgently necessary to reveal their triggering mechanisms for their consequences controlling. Detailed site geological investigation, full-scale block distinct-element-code modeling and related engineering geological analysis were conducted to recognize main characteristics, controlling factors and dynamic formation mechanism of a so-called underground mining-induced landslide. Results on the Pusa landslide show its dynamic formation is influenced by micro-landform, rock strata types, rock mass structure, weathering, goaf, heavy rainfall and, especially blasting vibration during underground developing and mining, i.e. controlling factor. Based on the numerical modeling, whole subsidence and clock-wise rotation are obvious characteristics of deformation caused by the goaf and the heavy rainfall during pre-failure of the landslide. What’s more, the whole subsidence which was caused by the goaf is one of the key characteristics of the underground mining-induced landslide. After the landslide behaves its critical failure, following dynamic responses include shattering, scraping off part top of the bed, debris flowing and final depositing. Finally, the dynamic formation mechanism is proposed based on evolution of main forces contributing the Pusa landslide. The forces are actuated by the seepage stress, vertical and horizontal blasting stresses, shear stress, unloading stress and dilation stress caused by the caved rock mass.

BackgroundMethylmercury (MeHg) is a neurotoxin, and melatonin (MT) has a protective effect on the nervous system, but whether it can antagonize MeHg-induced nerve cell damage and the associated mechanism remain unknown.ObjectiveHuman neuroblastoma cells (SH-SY5Y cells) were used as research objects. A MeHg-induced SH-SY5Y cell senescence model was established to observe autophagy related protein, lysosomal number, and function changes, as well as potential intervention role and associated mechanism of MT.Methods(1) After SH-SY5Y cells were treated with different doses of MeHg (0, 0.125, 0.25, 0.5, 1, 2, and 4 μmol·L−1) for 48 h, the cell viability was detected using a cell viability detection kit (CCK-8 method) and the viability rate was calculated. Senescent cells were detected by an acidic senescence-associated-β-galactosidase (SA-β-gal) staining. (2) A MeHg dose of 0.5 μmol·L−1 that significantly induced senescence of SH-SY5Y cells was screened, and a half and a quarter of the dose (0.25 and 0.125 μmol·L−1) were used for the middle and low dose groups, respectively. (3) In the MT intervention experiments, SH-SY5Y cells were divided into four groups, including control group (0.1% DMSO), MeHg group (0.5 μmol·L−1 MeHg), MT group (1 mmol·L−1 MT), and MT intervention group (1 mmol·L−1 MT+0.5 μmol·L−1 MeHg). In the MT intervention group, cells were exposed to 0.5 μmol·L−1 MeHg for 48 h after 24 h of 1 mmol·L−1 MT pretreatment. (4) SA-β-gal staining was conducted to observe cell senescence; Western blotting for the expression levels of senescence-associated protein p16, autophagy-associated protein p62, LC3Ⅱ, and lysosomal-associated proteins LAMP1, LAMP2, and TFEB; Lyso-Tracker Red for the quantity of lysosomes; LysoSensor Green DND-189 for lysosomal pH changes; electron microscope for the morphological changes of lysosomes.ResultsThe results of CCK-8 indicated that the viability rate of cells decreased with the increase of MeHg exposure concentration. Compared with the control group, the SA-β-gal positive cell ratio in the 0.5 μmol·L−1 MeHg group increased by 48% (P

Interaction between microbial plays an important role in Baijiu brewing. Cyberlindnera fabianii and Clavispora lusitaniae are common non-Saccharomyces yeast in Baijiu brewing, but their interaction with mold is not clear. This study focused on sensory evaluation, content of volatile flavor substances, yeast biomass, enzyme activity and metabolites, and discussed the interaction between C. fabianii HY-11, C. lusitaniae HY-21 and Aspergillus oryzae M-08 in the brewing process. Results showed that, when two non-Saccharomyces yeasts were co-cultured with A. oryzae M-08, respectively, the biomass of C. fabianii HY-11 and C. lusitaniae HY-21 were 4.96 and 0.97-fold higher and alpha-amylases increased by 70.31 and 107.73-fold than that of pure fermentation using single yeast. These results indicated that the two yeasts were dependent on A. oryzae M-08. Compared with C. lusitaniae HY-21, the mixed fermentation of C. fabianii HY-11 and A. oryzae M-08 showed better flavor. After 6 days of fermentation, strong cantaloupe, wine and ester aroma were obtained. The total amount of volatile flavor substances was up to 1408.97 μg/g, which was 381.87-fold higher than that under single yeast fermentation condition. A. oryzae M-08 interacted well with C. fabianii HY-11 and C. lusitaniae HY-21. Compared with the single yeast fermentation system, the level of free amino acids in the mixed fermentation system increased by 105.02 and 3837.29 μg/g, and the esterase activity increased by 27.67 and 387.82 U/g, respectively. Therefore, the metabolism of volatile flavor substances was promoted. This study elucidates the relationship between two non-Saccharomyces yeasts and A. oryzae M-08 and their flavor characteristics, providing a theoretical basis for their rational application.

Abstract The development of a nonlinear viscoelastic constitutive model of composite solid propellant (CSP) coupled with effects of strain rate and confining pressure is essential to assess the reliability of solid propellant grains during ignition operation process. In the present work, a nonlinear viscoelastic constitutive model with novel energy-based damage initiation criterion and evolution model was firstly proposed to describe the coupled effects of confining pressure and strain rate on mechanical responses of CSP. In the developed damage initiation criterion and evolution model, the linear viscoelastic strain energy density was introduced as the damage driving force, and the coupled effects of strain rate, damage history and confining pressure on damage growth were taken into account. Then, uniaxial tensile tests from low strain rates to medium strain rates and various confining pressures, and stress relaxation tests were conducted using a self-made active confining pressure device. Finally, the identification procedures of model parameters and validation results of the constitutive model were presented. Moreover, the master curve of damage initiation parameter was constructed through the time-pressure superposition principle (TPSP). The results show that the developed nonlinear constitutive model is capable of predicting the stress–strain responses of CSP under different strain rates and confining pressures.

The effects of citric acid addition coupled with pH on cell growth, metabolism, and spore yield of B. licheniformis were studied in a 30 L bioreactor, and the gene expression differences related to energy metabolism, oxidative stress effect, and amino acid transport at the log-phase were examined by qPCR. Results showed that: Citric acid supplement coupled with pH7.5 during 19.5~28 h was conducted, reaching a final content of 78 μmol/L in the medium. The feeding strategy prolonged the periods of cell growth and spore formation, and the peak cells (36 h) reached 4.2×1010 CFU/mL that was 42.9% higher than the control (without citric acid supplement). Meanwhile, spore yield (36 h) reached 4.1×1010 CFU/mL, increased by 215.4% compared with the control (24 h, 1.3×1010 CFU/mL). The qPCR assays showed that the expression levels of icd, zwf and cydA was 2.6, 4.1 and 1.9 times higher than that of the control, respectively. Meanwhile, brnQ, vpr, yvbW, katA, yqjM, ahpF, sodA and abrB were decreased by 88%, 18%, 65%, 89%, 10%, 90%, 41% and 60% compared with the control, respectively. The data suggested that citric acid supplementation enhanced the efficiencies of TCA cycle, HMP pathway and electron transport, weakened the oxidative stress effects on cells, and improved the phosphorylation level of Spo0A, thus promoting the sporulation efficiency. The results would provide theoretical supports for the industrial production of Bacillus fermentation efficiently.

The salt–tolerant yeast Zygosaccharomyces rouxii is a typical aroma–producing yeast used in food brewing, but its mechanism of high temperature tolerance is still unclear. In this study, the response mechanism of Z. rouxii to glucose under high temperature stress at 40 °C was explored, based on the total synthetic lowest–nutrient medium. The results of the growth curves and scanning electron microscopy showed that high glucose was necessary for Z. rouxii to restore growth under high temperature stress, with the biomass at 300 g/L of glucose (OD600, 120h = 2.44 ± 0.26) being 8.71 times higher than that at 20 g/L (OD600, 120h = 0.28 ± 0.08). The results of the transcriptome analysis, combined with RT–qPCR, showed that the KEGG analysis of differentially expressed genes was enriched in pathways related to glucose metabolism, and high glucose (300 g/L) could effectively stimulate the gene expression of glucose transporters, trehalose synthesis pathways, and xylitol synthesis pathways under a high temperature, especially the expression of the glucose receptor gene RGT2 (up–regulated 193.7 times at 12 h). The corresponding metabolic characteristics showed that the contents of intracellular metabolites, such as glucose (Cmax, 6h = 6.50 ± 0.12 mg/g DCW), trehalose (Cmax, 8h = 369.00 ± 17.82 μg/g DCW), xylitol (Cmax, 8h = 1.79 ± 0.27 mg/g DCW), and glycerol (Cmax, 8h = 268.10 ± 44.49 μg/g DCW), also increased with time. The accumulation of acetic acid, as the main product of overflow metabolism under high temperature stress (intracellular Cmax, 2h = 126.30 ± 10.96 μg/g DCW; extracellular Cmax, 12h = 499.63 ± 27.16 mg/L), indicated that the downstream glycolysis pathway was active. Compared with the normal physiological concentration of glucose, a high glucose concentration can effectively stimulate the gene expression and metabolism of salt–tolerant Z. rouxii under high–temperature conditions to restore growth. This study helps to deepen the current understanding of the thermoadaptive growth mechanism of salt–tolerant Z. rouxii.

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