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Burkholderia gladioli pv. alliicola, B. cepacia, and B. orbicola are common bacterial pathogens of onion. Onions produce organosulfur thiosulfinate defensive compounds after cellular decompartmentalization. Using whole-genome sequencing and in silico analysis, we identified putative thiosulfinate tolerance gene (TTG) clusters in multiple onion-associated Burkholderia species similar to those characterized in other Allium-associated bacterial endophytes and pathogens. Sequence analysis revealed the presence of three Burkholderia TTG cluster types, with both Type A and Type B being broadly distributed in B. gladioli, B. cepacia, and B. orbicola in both the chromosome and plasmids. Based on isolate natural variation and generation of isogenic strains, we determined the in vitro and in vivo contribution of TTG clusters in B. gladioli, B. cepacia, and B. orbicola. The Burkholderia TTG clusters contributed to enhanced allicin tolerance and improved growth in filtered onion extracts by all three species. TTG clusters also made clear contributions to B. gladioli foliar necrosis symptoms and bacterial populations. Surprisingly, the TTG cluster did not contribute to bacterial populations in onion bulb scales by these three species. Based on our findings, we hypothesize onion-associated Burkholderia may evade or inhibit the production of thiosulfinates in onion bulb tissues. [Graphic: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Background Aberrant inflammatory responses drive the initiation and progression of various diseases, and hyperactivation of NLRP3 inflammasome is a key pathogenetic mechanism. Pharmacological inhibitors of NLRP3 represent a potential therapy for treating these diseases but are not yet clinically available. The natural product butein has excellent anti-inflammatory activity, but its potential mechanisms remain to be investigated. In this study, we aimed to evaluate the ability of butein to block NLRP3 inflammasome activation and the ameliorative effects of butein on NLRP3-driven diseases. Methods Lipopolysaccharide (LPS)-primed bone-marrow-derived macrophages were pretreated with butein and various inflammasome stimuli. Intracellular potassium levels, ASC oligomerization and reactive oxygen species production were also detected to evaluate the regulatory mechanisms of butein. Moreover, mouse models of LPS-induced peritonitis, dextran sodium sulfate-induced colitis, and high-fat diet-induced non-alcoholic steatohepatitis were used to test whether butein has protective effects on these NLRP3-driven diseases. Results Butein blocks NLRP3 inflammasome activation in mouse macrophages by inhibiting ASC oligomerization, suppressing reactive oxygen species production, and upregulating the expression of the antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2). Importantly, in vivo experiments demonstrated that butein administration has a significant protective effect on the mouse models of LPS-induced peritonitis, dextran sodium sulfate-induced colitis, and high-fat diet-induced non-alcoholic steatohepatitis. Conclusion Our study illustrates the connotation of homotherapy for heteropathy, i.e., the application of butein to broaden therapeutic approaches and treat multiple inflammatory diseases driven by NLRP3.

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments. Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood‒tumor barrier (BTB). BTB activates its Wnt signaling to maintain barrier properties, e.g., Mfsd2a-mediated BTB low transcytosis. Here, we reported VCAM-1-targeting nano-wogonin (W@V-NPs) as an adjuvant of nano-orlistat (O@V-NPs) to intensify drug delivery and inhibit lipogenesis of brain metastases. W@V-NPs were proven to be able to inactivate BTB Wnt signaling, downregulate BTB Mfsd2a, accelerate BTB vesicular transport, and enhance tumor accumulation of O@V-NPs. With the ability to specifically kill cancer cells in a lipid-deprived environment with IC50 at 48 ng/mL, W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice. The combination did not induce brain edema, cognitive impairment, and systemic toxicity in healthy mice. Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

Abstract The (re)hemorrhage in patients with sporadic cerebral cavernous malformations (CCM) was the primary aim for CCM management. However, accurately identifying the potential (re)hemorrhage among sporadic CCM patients in advance remains a challenge. This study aims to develop machine learning models to detect potential (re)hemorrhage in sporadic CCM patients. This study was based on a dataset of 731 sporadic CCM patients in open data platform Dryad. Sporadic CCM patients were followed up 5 years from January 2003 to December 2018. Support vector machine (SVM), stacked generalization, and extreme gradient boosting (XGBoost) were used to construct models. The performance of models was evaluated by area under receiver operating characteristic curves (AUROC), area under the precision-recall curve (PR-AUC) and other metrics. A total of 517 patients with sporadic CCM were included (330 female [63.8%], mean [SD] age at diagnosis, 42.1 [15.5] years). 76 (re)hemorrhage (14.7%) occurred during follow-up. Among 3 machine learning models, XGBoost model yielded the highest mean (SD) AUROC (0.87 [0.06]) in cross-validation. The top 4 features of XGBoost model were ranked with SHAP (SHapley Additive exPlanations). All-Elements XGBoost model achieved an AUROCs of 0.84 and PR-AUC of 0.49 in testing set, with a sensitivity of 0.86 and a specificity of 0.76. Importantly, 4-Elements XGBoost model developed using top 4 features got a AUROCs of 0.83 and PR-AUC of 0.40, a sensitivity of 0.79, and a specificity of 0.72 in testing set. Two machine learning-based models achieved accurate performance in identifying potential (re)hemorrhages within 5 years in sporadic CCM patients. These models may provide insights for clinical decision-making.

Abstract Based on the samples from 260 enterprises in Jiangxi Province in 2022, this study examines the enterprises’ employment attitudes towards female employees from the perspective of HR managers. Through factor analysis, one-way analysis of variance, product-moment correlation analysis, and multiple regression analysis, this study investigates the female employment bias and its underlying mechanism across five dimensions: employee change, career development bias, policy impact, job competency and gender bias. The research findings confirm the employment bias against professional women by employers. The study reveals that the implementation of China’s three-child policy has exacerbated employment bias against female employees, especially in male-dominated enterprises. It is therefore recommended to provide more preferential policies for such enterprises. Furthermore, job competency has a significant negative correlation with gender employment bias. Continuing education and skills training are effective measures for professional women of childbearing age, particularly those in low-skilled jobs. With the further implementation of the three-child policy, this study anticipates a more challenging employment or promotion prospects for professional women. This study has also indirectly confirmed the employment dilemma of professional women of childbearing age, indicating potential obstacles in achieving the intended outcomes of the three-child policy.

Abstract Quantitative assessment of retinal microvasculature in optical coherence tomography angiography (OCTA) images is important for studying, diagnosing, monitoring, and guiding the treatment of ocular and systemic diseases. However, the OCTA user community lacks universal and transparent image analysis tools that can be applied to images from a range of OCTA instruments and provide reliable and consistent microvascular metrics from diverse datasets. We present a retinal extension to the OCTA Vascular Analyser (OCTAVA) that addresses the challenges of providing robust, easy-to-use, and transparent analysis of retinal OCTA images. OCTAVA is a user-friendly, open-source toolbox that can analyse retinal OCTA images from various instruments. The toolbox delivers seven microvascular metrics for the whole image or subregions and six metrics characterising the foveal avascular zone. We validate OCTAVA using images collected by four commercial OCTA instruments demonstrating robust performance across datasets from different instruments acquired at different sites from different study cohorts. We show that OCTAVA delivers values for retinal microvascular metrics comparable to the literature and reduces their variation between studies compared to their commercial equivalents. By making OCTAVA publicly available, we aim to expand standardised research and thereby improve the reproducibility of quantitative analysis of retinal microvascular imaging. Such improvements will help to better identify more reliable and sensitive biomarkers of ocular and systemic diseases.

The lack of a suitable rootstock to control scion growth has limited the development of high-density plantations in pear production, which is partly attributed to poor understanding of the dwarfing mechanism. In the present study, the rootstock of the dwarf-type pear (Pyrus betulaefolia) ‘PY-9’ was identified and used as the material for anatomical analysis. ‘PY-9’ grew to half the tree height of the normal cultivar ‘Zhengdu’, along with fewer internodes and shorter length. Significant differences in growth rate between ‘PY-9’ and ‘Zhengdu’ were detected at approximately 30 days after full bloom, which corresponded with the time of the greatest difference in water potential between the dwarf and normal cultivar. ‘PY-9’ showed a higher photosynthetic rate than ‘Zhengdu’. Anatomical analysis showed that ‘PY-9’ had higher area ratios of both phloem and xylem and more developed vascular tissues than ‘Zhengdu’. The three-dimensional reconstructed skeleton of the xylem from X-ray computed tomography scanning revealed greater intervessel connectivity in ‘Zhengdu’ than in ‘PY-9’, which could contribute to the more vigorous growth of ‘Zhengdu’. This study thus provides the first comparison of the microstructural properties of xylem elements between a dwarfing-type and vigorous-type pear rootstock, providing new insights into the dwarfing mechanism in pear and facilitating breeding of dwarf pear rootstocks to increase crop productivity.

IntroductionGranulocytic myeloid-derived suppressor cells (G-MDSCs) show fast recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) constituting the major part of peripheral blood in the early phase. Although G-MDSCs mediate immune suppression through multiple mechanisms, they may also promote inflammation under specific conditions. MethodsG-MDSCs were isolated from 82 patients following allo-HSCT within 90 days after allo-HSCT, and their interactions with autologous CD3+ T-cells were examined. T-cell proliferation was assessed by flow cytometry following CFSE staining, while differentiation and interferon-γ secretion were characterized using chemokine receptor profiling and ELISpot assays, respectively. NK cell cytotoxicity was evaluated through co-culture with K562 cells. An aGVHD xenogeneic model in humanized mice was employed to study the in vivo effects of human leukocytes. Furthermore, transcriptional alterations in G-MDSCs were analyzed via RNA sequencing to investigate functional transitions.ResultsG-MDSCs promoted inflammation in the early-stage, by facilitating cytokine secretion and proliferation of T cells, as well as their differentiation into pro-inflammatory T helper subsets. At day 28, patients with a higher number of G-MDSCs exhibited an increased risk of developing grades II-IV aGvHD. Besides, adoptive transfer of G-MDSCs from patients at day 28 into humanized mice exacerbated aGvHD. However, at day 90, G-MDSCs led to immunosuppression, characterized by upregulated expression of indoleamine 2,3-dioxygenase gene and interleukin-10 secretion, coupled with the inhibition of T cell proliferation. Furthermore, transcriptional analysis of G-MDSCs at day 28 and day 90 revealed that 1445 genes were differentially expressed. These genes were associated with various pathways, revealing the molecular signatures of early post-transplant differentiation in G-MDSCs. In addition, genes linked to the endoplasmic reticulum stress were upregulated in patients without aGvHD. The acquisition of immunosuppressive function by G-MDSCs may depend on the activation of CXCL2 and DERL1 genes. ConclusionOur findings revealed the alteration in the immune characteristics of G-MDSCs within the first 90 days post-allo-HSCT. Moreover, the quantity of G-MDSCs at day 28 may serve as a predictive indicator for the development of aGvHD.

Abstract Objective To analyze the risk factors associated with intubated critically ill patients in the emergency department (ED) and develop a prediction model by machine learning algorithms. Methods This study was conducted in an academic tertiary hospital in Hangzhou, China. Critically ill patients admitted to the ED were retrospectively analyzed from May 2018 to July 2022. The demographic characteristics, distribution of organ dysfunction, parameters for different organs’ examination, and status of mechanical ventilation were recorded. These patients were assigned to the intubation and non‐intubation groups according to ventilation support. We used the eXtreme Gradient Boosting (XGBoost) algorithm to develop the prediction model and compared it with other algorithms, such as logistic regression, artificial neural network, and random forest. SHapley Additive exPlanations was used to analyze the risk factors of intubated critically ill patients in the ED. Results Of 14,589 critically ill patients, 10,212 comprised the training group and 4377 comprised the test group; 2289 intubated patients were obtained from the electronic medical records. The mean age, mean scores of vital signs, parameters of different organs, and blood oxygen examination results differed significantly between the two groups (p

Abstract Layered two‐dimensional (2D) materials have garnered marvelous attention in diverse fields, including sensors, capacitors, nanocomposites and transistors, owing to their distinctive structural morphologies and superior physicochemical properties. Recently, layered quasi‐2D materials, especially layered bismuth oxyselenide (Bi2O2Se), are of particular interest, because of their different interlayer interactions from other layered 2D materials. On this basis, this material offers richer and more intriguing physics, including high electron mobility, sizeable bandgap, and remarkable thermal and chemical durability, rendering it an utterly prospective contender for use in advanced electronic and optoelectronic applications. Herein, this article reviews the recent advances related with Bi2O2Se. Initially, its structural characterization, band structure, and basic properties are briefly introduced. Further, the synthetic strategies for the preparation of Bi2O2Se are presented. Furthermore, the diverse applications of Bi2O2Se in the field of electronics and optoelectronics, photocatalytic, solar cells and sensing were summarized in detail. Ultimately, the challenges and future perspectives of Bi2O2Se are included.

Abstract Background CRISPR-Cas9 technology has advanced in vivo gene therapy for disorders like hemophilia A, notably through the successful targeted incorporation of the F8 gene into the Alb locus in hepatocytes, effectively curing this disorder in mice. However, thoroughly evaluating the safety and specificity of this therapy is essential. Our study introduces a novel methodology to analyze complex insertion sequences at the on-target edited locus, utilizing barcoded long-range PCR, CRISPR RNP-mediated deletion of unedited alleles, magnetic bead-based long amplicon enrichment, and nanopore sequencing. Results We identified the expected F8 insertions and various fragment combinations resulting from the in vivo linearization of the double-cut plasmid donor. Notably, our research is the first to document insertions exceeding ten kbp. We also found that a small proportion of these insertions were derived from sources other than donor plasmids, including Cas9-sgRNA plasmids, genomic DNA fragments, and LINE-1 elements. Conclusions Our study presents a robust method for analyzing the complexity of on-target editing, particularly for in vivo long insertions, where donor template integration can be challenging. This work offers a new tool for quality control in gene editing outcomes and underscores the importance of detailed characterization of edited genomic sequences. Our findings have significant implications for enhancing the safety and effectiveness of CRISPR-Cas9 gene therapy in treating various disorders, including hemophilia A.

Abstract Background Breast cancer is the most prevalent female tumor, of which triple-negative breast cancer (TNBC) accounts for about 15%. Characterized by its aggressive nature and limited treatment options, TNBC currently stands as a significant clinical challenge. This study aimed to investigate the effects of icariin (ICA) on TNBC and explore the underlying molecular mechanism. Methods Cell viability was assessed using CCK-8 assay, whereas the impact of ICA on cell proliferation was determined using colony formation assay and detection of proliferating cell nuclear antigen protein. Wound healing and transwell assays were used to evaluate the effects of ICA on cell migration and invasion, respectively. Flow cytometry was used to analyze cell cycle distribution and apoptosis. Transmission electron microscopy and monodansylcaverine staining were performed to detect the induction of autophagy, whereas molecular docking was conducted to predict the potential targets associated with autophagy. The in vivo anti-tumor effects of ICA were evaluated using a TNBC 4T1 xenograft mouse model. Protein expression levels were examined using immunoblotting and immunohistochemistry. Results In vitro, ICA effectively suppressed the viability, proliferation, migration, and invasion of TNBC cells and induced G0/G1 phase cell cycle arrest, apoptosis, and autophagy in TNBC cells by regulating the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) signaling pathway. The knockdown of AMPK and inhibition of autophagy with 3-methyladenine reversed the effects of ICA, highlighting the importance of AMPK and autophagy in the anti-cancer mechanism of ICA. In vivo, ICA significantly inhibited TNBC growth, promoted autophagy, and regulated AMPK/mTOR/ULK1 pathway. Conclusions Our findings demonstrated that ICA exerts anti-cancer effects against TNBC and the associated molecular mechanisms. This study will help to facilitate further preclinical and clinical investigations for the treatment of TNBC.

Abstract Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.

A series of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 (Cas9) systems have been engineered for genome editing. The most widely used Cas9 is SpCas9 from Streptococcus pyogenes and SaCas9 from Staphylococcus aureus. However, a comparison of their detailed gene editing outcomes is still lacking. By characterizing the editing outcomes of 11 sites in human induced pluripotent stem cells (iPSCs) and K562 cells, we found that SaCas9 could edit the genome with greater efficiencies than SpCas9. We also compared the effects of spacer lengths of single-guide RNAs (sgRNAs; 18–21 nt for SpCas9 and 19–23 nt for SaCas9) and found that the optimal spacer lengths were 20 nt and 21 nt for SpCas9 and SaCas9, respectively. However, the optimal spacer length for a particular sgRNA was 18–21 nt for SpCas9 and 21–22 nt for SaCas9. Furthermore, SpCas9 exhibited a more substantial bias than SaCas9 for nonhomologous end-joining (NHEJ) +1 insertion at the fourth nucleotide upstream of the protospacer adjacent motif (PAM), indicating a characteristic of a staggered cut. Accordingly, editing with SaCas9 led to higher efficiencies of NHEJ-mediated double-stranded oligodeoxynucleotide (dsODN) insertion or homology-directed repair (HDR)-mediated adeno-associated virus serotype 6 (AAV6) donor knock-in. Finally, GUIDE-seq analysis revealed that SaCas9 exhibited significantly reduced off-target effects compared with SpCas9. Our work indicates the superior performance of SaCas9 to SpCas9 in transgene integration-based therapeutic gene editing and the necessity to identify the optimal spacer length to achieve desired editing results.

Genetic and environmental factors play crucial roles in the development of esophageal cancer (EC) and contribute uniquely or cooperatively to human cancer susceptibility. Sichuan is located in the interior of southwestern China, and the northern part of Sichuan is one of the regions with a high occurrence of EC. However, the factors influencing the high incidence rate of EC in the Sichuan Han Chinese population and its corresponding genetic background and origins are still poorly understood. Here, we utilized genome-wide single nucleotide polymorphisms (SNPs) and Y-chromosome short tandem repeats (Y-STRs) to characterize the genetic structure, connection, and origin of cancer groups and general populations. We generated Y-STR-based haplotype data from 214 Sichuan individuals, including the Han Chinese EC population and a control group of Han Chinese individuals. Our results, obtained from Y-STR-based population statistical methods (analysis of molecular variance (AMOVA), principal component analysis (PCA), and phylogenetic analysis), demonstrated that there was a genetic substructure difference between the EC population in the high-incidence area of northern Sichuan Province and the control population. Additionally, there was a strong genetic relationship between the EC population in the northern Sichuan high-incidence area and those at high risk in both the Fujian and Chaoshan areas. In addition, we obtained high-density SNP data from saliva samples of 60 healthy Han Chinese individuals from three high-prevalence areas of EC in China: Sichuan Nanchong, Fujian Quanzhou, and Henan Xinxiang. As inferred from the allele frequency of SNPs and sharing patterns of haplotype segments, the evolutionary history and admixture events suggested that the Han population from Nanchong in northern Sichuan Province shared a close genetic relationship with the Han populations from Xinxiang in Henan Province and Quanzhou in Fujian Province, both of which are regions with a high prevalence of EC. Our study illuminated the genetic profile and connection of the Northern Sichuan Han population and enriched the genomic resources and features of the Han Chinese populations in China, especially for the Y-STR genetic data of the Han Chinese EC population. Populations living in different regions with high incidences of EC may share similar genetic backgrounds, which offers new insights for further exploring the genetic mechanisms underlying EC.

Abstract Animals living in high‐altitude environments, such as the Tibetan Plateau, must face harsh environmental conditions (e.g., hypoxia, cold, and strong UV radiation). These animals' physiological adaptations (e.g., increased red cell production and turnover rate) might also be associated with the gut microbial response. Bilirubin is a component of red blood cell turnover or destruction and is excreted into the intestine and reduced to urobilinoids and/or urobilinogen by gut bacteria. Here, we found that the feces of macaques living in high‐altitude regions look significantly browner (with a high concentration of stercobilin, a component from urobilinoids) than those living in low‐altitude regions. We also found that gut microbes involved in urobilinogen reduction (e.g., beta‐glucuronidase) were enriched in the high‐altitude mammal population compared to the low‐altitude population. Moreover, the spatial–temporal change in gut microbial function was more profound in the low‐altitude macaques than in the high‐altitude population, which might be attributed to profound changes in food resources in the low‐altitude regions. Therefore, we conclude that a high‐altitude environment's stress influences living animals and their symbiotic microbiota.

Abstract Background Premature ovarian insufficiency (POI) is an important cause of infertility characterized by the functional decline of the ovary. Granulosa cells (GCs) around oocytes are critical for folliculogenesis, and GC dysfunction is one of the important etiologies of POI. The aim of this study was to explore the potential biomarkers of POI by identifying hub genes and analyze the correlation of biomarkers with immune infiltration in POI using RNA profiling and bioinformatics analysis. Methods RNA sequencing was performed on GCs from biochemical POI (bPOI) patients and controls. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to explore the candidate genes. qRT‒PCR was performed to verify the expression of hub genes. Western blot, Cell Counting Kit-8, 5‐ethynyl‐2’‐deoxyuridine (EdU) assays, TUNEL (TdT-mediated dUTP Nick-End Labeling) and flow cytometry analysis were used to validate the possible role of ubiquitin-conjugating enzyme 2C (UBE2C) in POI. CIBERSORT was adopted to explore immune cell infiltration and the correlation between UBE2C and immune cells in bPOI. Results Through analysis of differentially expressed genes (DEGs) and WGCNA, we obtained 143 candidate genes. After construction of the protein‒protein interaction (PPI) network and analysis with Cytoscape, 10 hub genes, including UBE2C, PBK, BUB1, CDC20, NUSAP1, CENPA, CCNB2, TOP2A, AURKB, and FOXM1, were identified and verified by qRT‒PCR. Subsequently, UBE2C was chosen as a possible biomarker of POI because knockdown of UBE2C could inhibit the proliferation and promote the apoptosis of GCs. Immune infiltration analysis indicated that monocytes and M1 macrophages may be associated with the pathogenesis of POI. In addition, UBE2C was negatively correlated with monocytes and M1 macrophages in POI. Conclusions This study identified a hub gene in GCs that might be important in the pathogenesis of POI and revealed the key role of UBE2C in driving POI. Immune infiltration may be highly related with the onset and etiology of POI.

Introduction: Knee osteoarthritis (KOA) is a type of joint disease causing degenerative changes that are challenging to treat. The improved tug-of-war acupuncture (BHZF) can improve joint pain in KOA. However, the associated mechanism has not been validated. Methods: The KOA rabbit model was established. After the surgery, the improved BHZF was provided as an intervention, and the animals were euthanized after 2 weeks. Histopathological changes in the synovium and cartilage were observed on hematoxylin & eosin staining and Safranin O-Fast Green staining. Synovial fluid and serum samples were collected to assess the presence of cytokines using the enzyme-linked immunosorbent assay. The expression of M1 macrophage (CD86) and M2 macrophage (ARG1) markers in the cartilage and synovium was detected via immunohistochemistry and immunofluorescence assays. Results: The improved BHZF could reduce KOA-related pain and inhibit joint swelling. Further, it significantly maintained the morphology of articular chondrocytes in KOA and reduced the decomposition of the cartilage matrix. Then, it significantly reduced the expression of CD86-positive cells (P

Natto has long been considered as a medical-food dual-use product with a hypolipidemic effect. Our study showed that natto was effective in reducing the levels of total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and increasing the level of high-density lipoprotein cholesterol (HDL-C) in the serum of hyperlipidemic mice. Metabolism analysis showed that natto could improve the levels of amino acid metabolites, reduce the contents of acylcarnitines, and reverse the levels of purine alkaloids, mainly involving the tricarboxylic acid (TCA) cycle and metabolism of amino acids. Moreover, natto increased beneficial gut microbiota (e.g., Lactobacillus, Faecalibaculum and Oscillibacter) and reduced pathogenic gut microbiota (e.g., Alistipes and Prevotellaceae-UCG-003). In conclusion, our findings suggest that natto-mediated changes in the gut microbiota and its related metabolites can support the prevention of high-fat diet (HFD)-induced hyperlipidemia, laying the theoretical foundation for the continued development of natto as a functional food.

People with generalized anxiety disorder tend to have sleep problems, and studies have found correlations between metacognition, rumination, and sleep, but it is unclear how metacognition and rumination work in people with a tendency towards generalized anxiety disorder. The goal of this paper is to investigate the correlation between metacognition, rumination, and sleep in university students with a tendency towards generalized anxiety disorder, and the mediating role of rumination in the effect of metacognition on sleep. The Generalized Anxiety Disorder Scale (GAD-7), the Meta-Cognition Questionnaire (MCQ-30), the Ruminative Responses Scale (RRS), and the Insomnia Severity Index (ISI) were used to investigate and psychometrically measure 566 university students in Anyang Normal College. The results of correlation analysis showed significant positive correlations between metacognition and sleep, ruminative thinking and sleep, and metacognition and rumination in university students with a tendency towards generalized anxiety disorder. Mediation analysis showed that rumination partially mediated the effect of metacognition on sleep, with the mediating effect accounting for 51.1% of the total effect. There is a strong correlation between metacognition, rumination, and sleep in university students with a tendency towards generalized anxiety disorder, and both metacognition and rumination can predict sleep, while metacognition can affect sleep through the mediating effect of rumination.

Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can directly or indirectly influence the disposition process of active drugs in vivo, thereby affecting the bioavailability of drugs. In order to reveal the pharmacokinetic effect of PEG400 on baicalin in hepatocytes and its mechanism, the present study first started with the effect of PEG400 on the metabolic disposition of baicalin at the hepatocyte level, and then the effect of PEG400 on the protein expression of baicalin-related transporters (BCRP, MRP2, and MRP3) was investigated by using western blot; the effect of MDCKII-BCRP, MDCKII-BCRP, MRP2, and MRP3 was investigated by using MDCKII-BCRP, MDCKII-MRP2, and MDCKII-MRP3 cell monolayer models, and membrane vesicles overexpressing specific transporter proteins (BCRP, MRP2, and MRP3), combined with the exocytosis of transporter-specific inhibitors, were used to study the effects of PEG400 on the transporters in order to explore the possible mechanisms of its action. The results demonstrated that PEG400 significantly influenced the concentration of baicalin in hepatocytes, and the AUC0–t of baicalin increased from 75.96 ± 2.57 μg·h/mL to 106.94 ± 2.22 μg·h/mL, 111.97 ± 3.98 μg·h/mL, and 130.42 ± 5.26 μg·h/mL (p ˂ 0.05). Furthermore, the efflux rate of baicalin was significantly reduced in the vesicular transport assay and the MDCKII cell model transport assay, which indicated that PEG400 had a significant inhibitory effect on the corresponding transporters. In conclusion, PEG400 can improve the bioavailability of baicalin to some extent by affecting the efflux transporters and thus the metabolic disposition of baicalin in the liver.

L-Arabinose isomerase (L-AI) has been commonly used as an efficient biocatalyst to produce D-tagatose via the isomerization of D-galactose. However, it remains a significant challenge to efficiently synthesize D-tagatose using the native (wild type) L-AI at an industrial scale. Hence, it is extremely urgent to redesign L-AI to improve its catalytic efficiency towards D-galactose, and herein a structure-based molecular modification of Lactobacillus plantarum CY6 L-AI (LpAI) was performed. Among the engineered LpAI, both F118M and F279I mutants showed an increased D-galactose isomerization activity. Particularly, the specific activity of double mutant F118M/F279I towards D-galactose was increased by 210.1% compared to that of the wild type LpAI (WT). Besides the catalytic activity, the substrate preference of F118M/F279I was also largely changed from L-arabinose to D-galactose. In the enzymatic production of D-tagatose, the yield and conversion ratio of F118M/F279I were increased by 81.2% and 79.6%, respectively, compared to that of WT. Furthermore, the D-tagatose production of whole cells expressing F118M/F279I displayed about 2-fold higher than that of WT cell. These results revealed that the designed site-directed mutagenesis is useful for improving the catalytic efficiency of LpAI towards D-galactose.

Two-dimensional transition metal dichalcogenides (2D-TMDs) possess appropriate bandgaps and interact via van der Waals (vdW) forces between layers, effectively overcoming lattice compatibility challenges inherent in traditional heterojunctions. This property facilitates the creation of heterojunctions with customizable bandgap alignments. However, the prevailing method for creating heterojunctions with 2D-TMDs relies on the low-efficiency technique of mechanical exfoliation. Sb2Te3, recognized as a notable p-type semiconductor, emerges as a versatile component for constructing diverse vertical p–n heterostructures with 2D-TMDs. This study presents the successful large-scale deposition of 2D Sb2Te3 onto inert mica substrates, providing valuable insights into the integration of Sb2Te3 with 2D-TMDs to form heterostructures. Building upon this initial advancement, a precise epitaxial growth method for Sb2Te3 on pre-existing WS2 surfaces on SiO2/Si substrates is achieved through a two-step chemical vapor deposition process, resulting in the formation of Sb2Te3/WS2 heterojunctions. Finally, the development of 2D Sb2Te3/WS2 optoelectronic devices is accomplished, showing rapid response times, with a rise/decay time of 305 μs/503 μs, respectively.

Grapevine is one of the most economically important fruit crops cultivated worldwide. However, grapevine is highly susceptible to virus infections and exposed to the most diverse forms of viral diseases compared to other fruit crops, and virus-induced incompatibility affects plant growth to different degrees ranging from decline to death. The influence of virus-induced incompatibility could be mitigated to an acceptable level by using appropriate rootstocks. However, the viral tolerance of various grapevine rootstocks with diverse genetic backgrounds remains unclear, along with the identification of the specific viral tolerance factors. In this study, the viral tolerance of 21 grapevine rootstocks was evaluated in a green grafting system. Cabernet Franc varieties infected with a single virus [grapevine leafroll associated virus-1 (GLRaV-1)], a co-infection of two viruses (GLRaV-1 plus grapevine virus A—GVA), and no infection were used as the scions, respectively. The vegetative growth and photosynthetic function of the grafts were analyzed 4 months after grafting. The results indicated that some rootstocks could alleviate the influence of the virus infection, with vegetative growth and photosynthetic function sustained at a normal level, whereas other rootstocks were susceptible to the virus infection, resulting in a decline in the growth and photosynthetic function of the grafts. Our research provides evidence for the existence and diversity of viral tolerance among grapevine rootstocks, offering important information for appropriate rootstock selection in the establishment of new vineyards and in the breeding of grapevine rootstocks with enhanced viral tolerance.

Acidovorax citrulli populations exhibit genetic and phenotypic variations, particularly in terms of copper tolerance. Group I strains of A. citrulli generally exhibit higher copper tolerance compared to group II strains. This study aims to identify genes involved in copper tolerance to better understand the differences in copper tolerance between group I and group II strains. Representative strains pslb65 (group I) and pslbtw14 (group II) were selected for comparison. Deletion mutants of putative copper-tolerance genes and their corresponding complementary strains were constructed. The copper tolerance of each strain was evaluated using the minimum inhibitory concentration method. The results showed that the copA, copZ, cueR, and cueO genes played major roles in copper tolerance in A. citrulli, while cusC-like, cusA-like, and cusB-like genes had minor effects. The different expression levels of copper-tolerance-related genes in pslb65 and pslbtw14 under copper stress indicated that they had different mechanisms for coping with copper stress. Overall, this study provides insights into the mechanisms of copper tolerance in A. citrulli and highlights the importance of specific genes in copper tolerance.

Abstract The DOHaD theory suggests that adverse environmental factors in early life may lead to the development of metabolic diseases including diabetes and hypertension in adult offspring through epigenetic mechanisms such as DNA methylation. Folic acid (FA) is an important methyl donor in vivo and participates in DNA replication and methylation. The preliminary experimental results of our group demonstrated that lipopolysaccharide (LPS, 50 µg/kg/d) exposure during pregnancy could lead to glucose metabolism disorders in male offspring, but not female offspring; however, the effect of folic acid supplementation on glucose metabolism disorders in male offspring induced by LPS exposure remains unclear. Therefore, in this study, pregnant mice were exposed to LPS on gestational day (GD) 15–17 and were given three doses of FA supplementation (2 mg/kg, 5 mg/kg, or 40 mg/kg) from mating to lactation to explore its effect on glucose metabolism in male offspring and the potential mechanism. This study confirmed that FA supplementation of 5 mg/kg in pregnant mice improved glucose metabolism in LPS-exposed offspring during pregnancy by regulating gene expression.

Onion center rot is caused by at least four species of genus Pantoea (P. ananatis, P. agglomerans, P. allii, and P. stewartii subsp. indologenes). Critical onion pathogenicity determinants for P. ananatis were recently described, but whether those determinants are common among other onion-pathogenic Pantoea species remains unknown. In this work, we report onion pathogenicity determinants in P. stewartii subsp. indologenes and P. allii. We identified two distinct secondary metabolite biosynthetic gene clusters present separately in different strains of onion-pathogenic P. stewartii subsp. indologenes. One cluster is similar to the previously described HiVir phosphonate biosynthetic cluster identified in P. ananatis and another is a novel putative phosphonate biosynthetic gene cluster, which we named Halophos. The Halophos gene cluster was also identified in P. allii strains. Both clusters are predicted to be phosphonate biosynthetic clusters based on the presence of a characteristic phosphoenolpyruvate phosphomutase (pepM) gene. The deletion of the pepM gene from either HiVir or Halophos clusters in P. stewartii subsp. indologenes caused loss of necrosis on onion leaves and red onion scales and resulted in significantly lower bacterial populations compared with the corresponding wild-type and complemented strains. Seven (halB to halH) of 11 genes (halA to halK) in the Halophos gene cluster are required for onion necrosis phenotypes. The onion nonpathogenic strain PNA15-2 (P. stewartii subsp. indologenes) gained the capacity to cause foliar necrosis on onion via exogenous expression of a minimal seven-gene Halophos cluster (genes halB to halH). Furthermore, cell-free culture filtrates of PNA14-12 expressing the intact Halophos gene cluster caused necrosis on onion leaves consistent with the presence of a secreted toxin. Based on the similarity of proteins to those with experimentally determined functions, we are able to predict most of the steps in Halophos biosynthesis. Together, these observations indicate that production of the toxin phosphonate seems sufficient to account for virulence of a variety of different Pantoea strains, although strains differ in possessing a single but distinct phosphonate biosynthetic cluster. Overall, this is the first report of onion pathogenicity determinants in P. stewartii subsp. indologenes and P. allii. [Graphic: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

BackgroundMany smartphone apps designed to assist individuals in managing their weight are accessible, but the assessment of app quality and features has predominantly taken place in Western countries. Nevertheless, there is a scarcity of research evaluating weight management apps in China, which highlights the need for further investigation in this area. ObjectiveThis study aims to conduct a comprehensive search for the most popular commercial Chinese smartphone apps focused on weight management and assess their quality, behavior change techniques (BCTs), and content-related features using appropriate evaluation scales. Additionally, the study sought to investigate the associations between the quality of various domains within weight management apps and the number of incorporated BCTs and app features. MethodsIn April 2023, data on weight management apps from the iOS and Android app stores were downloaded from the Qimai Data platform. Subsequently, a total of 35 weight management apps were subjected to screening and analysis by 2 researchers. The features and quality of the apps were independently assessed by 6 professionals specializing in nutrition management and health behavioral change using the Mobile Application Rating Scale (MARS). Two registered dietitians, who had experience in app development and coding BCTs, applied the established 26-item BCT taxonomy to verify the presence of BCTs. Mean (SD) scores and their distributions were calculated for each section and item. Spearman correlations were used to assess the relationship between an app’s quality and its technical features, as well as the number of incorporated BCTs. ResultsThe data set included a total of 35 apps, with 8 available in the Android Store, 10 in the Apple Store, and 17 in both. The overall quality, with a mean MARS score of 3.44 (SD 0.44), showed that functionality was the highest scoring domain (mean 4.18, SD 0.37), followed by aesthetics (mean 3.43, SD 0.42), engagement (mean 3.26, SD 0.64), and information (mean 2.91, SD 0.52), which had the lowest score. The mean number of BCTs in the analyzed apps was 9.17 (range 2-18 BCTs/app). The most common BCTs were “prompt review of behavioral goals” and “provide instruction,” present in 31 apps (89%). This was followed by “prompt self-monitoring of behavior” in 30 apps (86%), “prompt specific goal setting” in 29 apps (83%), and “provide feedback on performance” in 27 apps (77%). The most prevalent features in the analyzed apps were the need for web access (35/35, 100%), monitoring/tracking (30/35, 86%), goal setting (29/35, 83%), and sending alerts (28/35, 80%). The study also revealed strong positive correlations among the number of BCTs incorporated, app quality, and app features. This suggests that apps with a higher number of BCTs tend to have better overall quality and more features. ConclusionsThe study found that the overall quality of weight management apps in China is moderate, with a particular weakness in the quality of information provided. The most prevalent BCTs in these apps were reviewing behavioral goals, providing guidance, self-monitoring of behavior, goal setting, and offering performance feedback. The most common features were the need for web access, monitoring and tracking, goal setting, and sending alerts. Notably, higher-quality weight management apps in China tended to incorporate more BCTs and features. These findings can be valuable for developers looking to improve weight management apps and enhance their potential to drive behavioral change in weight management.

Disease outbreaks of bacterial leaf spot and blight of pepper and tomato often occur in both transplant- and field-production systems worldwide. In some cases, the outbreaks are caused by novel bacterial species. Characterization of these novel bacterial species are critical in developing diagnostic assays and identifying management options for pathogen monitoring and sustainable production, respectively. We characterized strains belonging to novel Pseudomonas species that are responsible for outbreaks in pepper and tomato both in transplant-houses and in production fields in Georgia, USA. Phylogenomic analyses and whole genome sequence indices demonstrated that the pepper and tomato strains belonged to P. capsici. The whole-genome comparison revealed that 13 Pseudomonas strains from diverse isolation sources that were curated in NCBI were indeed P. capsici indicating a potential wide-host range for this bacterial species. Our greenhouse-based host-range assay also indicated that P. capsici strains were pathogenic on pepper, tomato, eggplant, cabbage, lettuce, and watermelon corroborating a wide-host-range. A phylogenetic tree inferred from the whole genome sequence data showed that the P. capsici strains from Georgia (pepper and tomato) were genetically diverse, and were closely related to tomato P. capsici strains from Florida. Genomic presence of traditional bacterial virulence factors in P. capsici strains was also determined. Pseudomonascapsici strains encode one set of type I secretion system, two sets of type II secretion systems, one set of type III secretion system, two sets of type V secretion systems, three sets of type VI secretion systems, and various secondary metabolite gene clusters including lipopeptides. In in-vitro assays, it was demonstrated that six out of seven P. capsici strains (pepper and tomato strains from Georgia) were not sensitive to 0.8 mM CuSO4. When the genomes of copper-tolerant strains were compared with the copper-sensitive strains, it was observed that the former strains encode a cluster of genes related to copper tolerance, which were absent in the genomes of copper-sensitive strains. Considering the ability of P. capsici strains to infect a range of vegetable hosts and possession of a wide range of bacterial virulence factors, secondary metabolites, and copper-tolerance genes, we envision that the management of this pathogen might potentially be a challenge.

Acidovorax citrulli is a seed-borne bacterium that causes bacterial fruit blotch of watermelon and other cucurbit plants worldwide. It uses a type III secretion system to inject type III effectors (T3Es) into plant cells, which affect the host immune responses and facilitate pathogen colonization. However, the current understanding of the specific molecular mechanisms and targets of these effectors in A. citrulli is limited. In this study, we characterized a novel T3E called AopU in A. citrulli group II strain Aac5, which shares homology with XopU in Xanthomonas oryzae. The Agrobacterium-mediated gene transient expression system was used to study the effect of AopU on host immunity. The results showed that AopU localized on the cell membrane and nucleus of Nicotiana benthamiana, inhibited reactive oxygen species burst induced by flg22 and the expression of marker genes associated with pathogen-associated molecular pattern-triggered immunity, but activated salicylic acid and jasmonic acid signal pathways. Further investigations revealed that AopU interacts with E3 ubiquitin ligase ClE3R in watermelon, both in vitro and in vivo. Interestingly, the deletion of aopU did not affect the virulence of A. citrulli, suggesting that AopU may have functional redundancy with other effectors in terms of its role in virulence. Collectively, these findings provide new insights into the mechanism of plant immune responses regulated by A. citrulli T3Es.

Metabolism-related fatty liver disease (MAFLD) is the most common form of chronic liver disease in the world. Its pathogenesis is influenced by both environmental and genetic factors. With the upgrading of gene screening methods and the development of human genome project, whole genome scanning has been widely used to screen genes related to MAFLD, and more and more genetic variation factors related to MAFLD susceptibility have been discovered. There are genetic variants that are highly correlated with the occurrence and development of MAFLD, and there are genetic variants that are protective of MAFLD. These genetic variants affect the development of MAFLD by influencing lipid metabolism and insulin resistance. Therefore, in-depth analysis of different mechanisms of genetic variation and targeting of specific genetic variation genes may provide a new idea for the early prediction and diagnosis of diseases and individualized precision therapy, which may be a promising strategy for the treatment of MAFLD.

Abstract Background Escherichia fergusonii is a rare opportunistic pathogen in humans and animals, especially with biofilm. Methods In one case, E. fergusonii with biofilm was detected in the bile, and silver staining was used to prove it had biofilm. The clinical characteristics and drug susceptibility of eight cases of E. fergusonii retrieved from the literature were also summarized. Results This is a case of E. fergusonii with biofilm, which has not been reported in China. The 8 cases retrieved from the literature did not specify whether they had biofilm, but we analyzed their clinical characteristics and drug susceptibility. All patients were treated with antimicrobial drugs. 8 cases showed sensitivity to piperacillin/tazobactam and imipenem in 6 cases (75%), but poor sensitivity to levofloxacin and ciprofloxacin. Conclusion The silver staining method proved biofilm in this case, which is the first case of E. fergusonii with biofilm in China.

Adolescence has always been regarded as a period of rapid psychological and behavioral change. Adolescents are subject to more difficult behaviors, and those difficult behaviors have a great impact on co-parenting and parenting burnout. In order to reveal the relationship between these factors, this study investigated the mediating effect of difficult adolescent behaviors on that relationship by constructing a theoretical model and examined the moderating effect of family functioning. In order to provide a scientific basis for preventing and intervening in adolescents’ problematic behaviors and improving parents’ parenting burnout, we conducted a study on the parents of 1638 teenagers in a junior high school in Huanggang City, China in May 2023, with a questionnaire filled out by the parents. The research tools included a parenting burnout questionnaire, Parental collaborative parenting Scale (PPCR), Adolescent Strengths and Difficult Behaviors Questionnaire (Parental Version), Family Function Scale, etc. An independent sample t test and ANOVA test were used to analyze whether there are certain demographic variables in parenting burnout, and SPSS27.0 was used for descriptive statistics, reliability and validity tests, correlation analysis and common method deviation tests. The adjusted mediation model was tested by using the SPSS macro program Process4.0. Results: The variance in the explanatory capacity of the largest factor in this study was 21.955%, which did not exceed the critical value of 40%, so there was no obvious common method deviation in the data of this study. The independent sample t test and ANOVA test showed that there are certain differences in parental rearing burnout dependent on parental gender, the main caregivers, family economic income and demographic variables. The results of the adjusted mediation model test by Process4.0 show the following: (1) Adolescent difficult behavior plays an intermediary role between parental collaborative parenting and parenting burnout; (2) the indirect effect of collaborative parenting on parenting burnout through adolescents’ problematic behaviors is regulated by family functions; (3) the relationship between adolescent difficult behavior and parenting burnout is regulated by family function; (4) the direct influence of collaborative parenting on parenting burnout is also regulated by family function. Conclusion: Adolescents’ difficult behavior partially mediates the influence of parents’ collaborative parenting on parenting burnout. In addition, family function not only mediates the front and back ends of mediation, but also mediates the direct influence of collaborative parenting on parenting burnout. These findings are instructive for improving family parenting problems and promoting adolescent development. The results of this study may be helpful in enhancing parents’ awareness of parenting of adolescents in China, which will provide reference for some teachers in China to understand adolescent behavior. At the same time, the results may provide new enlightenment for mental health professionals and enable them to fully understand the parenting contradictions between parents and adolescents in China.

Vulvovaginal candidiasis (VVC) is a common gynecologic disorder caused by fungal infections of the vaginal mucosa, with the most common pathogen being Candida albicans (C. albicans). Exploring metabolite changes in the disease process facilitates further discovery of targets for disease treatment. However, studies on the metabolic changes caused by C. albicans are still lacking. In this study, we used C. albicans-infected vaginal epithelial cells to construct an in vitro model of VVC, analyzed the metabolites by UHPLC-Q-Exactive MS, and screened the potential metabolites based on metabolomics. The results showed that C. albicans infection resulted in significant up-regulation of D-arabitol, palmitic acid, adenosine, etc.; significant down-regulation of lactic acid, nicotinamide (NAM), nicotinate (NA), etc.; and disruption of amino acid metabolism, and that these significantly altered metabolites might be potential therapeutic targets of VVC. Further experiments showed that C. albicans infection led to a decrease in glycolytic enzymes in damaged cells, inhibiting glycolysis and leading to significant alterations in glycolytic metabolites. The present study explored the potential metabolites of VVC induced by C. albicans infection based on metabolomics and verified the inhibitory effect of C. albicans on vaginal epithelial cell glycolysis, which is valuable for the diagnosis and treatment of VVC.

Glycolate plays an important role as a platform chemical in both polymeric material and cosmetic industries. However, the microbial production of glycolate often encounters challenges associated with unbalanced metabolic flux, leading to a notably low titer. Additionally, the use of expensive inducers, such as IPTG, contributes to an increase in the overall production cost. To address these issues, the key enzymes involved in the glycolate biosynthetic route, including citrate synthase (gltA), isocitrate lyase (aceA), isocitrate dehydrogenase kinase/phosphatase (aceK) and glyoxylate reductase (ycdW), were overexpressed in E. coli under the control of inducible promoters with varying strengths in order to determine the optimal combination. Subsequently, the glycolate pathway was further modulated by replacing inducible promoters with various constitutive synthetic promoters. Through this systematic optimization, the best strain, named Mgly4T1562, produced 3.02 g/L glycolate with 97.32% theoretical yield in shake-flask cultivation. The titer further increased to 15.53 g/L in a fed-batch experiment. Notably, this study marks the first successful utilization of synthetic promoters in tuning the glycolate biosynthetic pathway for glycolate biosynthesis. The strategy presented in this research holds significant promise for facilitating the cost-effective and industrially viable production of glycolate without the need for expensive inducers.

Transit-oriented development (TOD) has become a dominant form of spatial planning and land use in large cities internationally. As the intersections of urban space and rail transportation, metro station areas play a key public service function in the lives of city residents. Based on the “5D” index and Node-Place theory in the metro station area, current research on the built environment in metro station areas focuses on improving the economic and transportation efficiency while neglecting public perception of the construction of station space. Sentiments, as an important part of the individual’s perception, are closely related to the built environment. Therefore, this study takes 187 metro stations within the fifth ring road of Beijing, China, as an example and extracts public sentiment information from social media data using a wide range of natural language processing techniques to quantitatively analyze the distribution of the public’s sentiment characteristics (including intensity, polarity, and category) in the metro station area and deeply explores the spatial correlation with the distribution of the objective built environment elements. The study shows that influenced by the spatial design of the metro station, density, land use functions, etc., the sentiment intensity of the station area within the Fifth Ring Road of Beijing is “strong in the east and weak in the west, strong in the north and weak in the south”, and the sentiment polarity has the characteristic of gradually negative from inside to outside in a circular pattern. Synthesizing the sentiment perception in the metro station area, our study further divided the Beijing metro station area into four major categories and eight specific subtypes.

A transverse flux linear motor is a special type of linear motor with a high thrust force density, and it has broad application prospects in the field of linear direct-drive systems. In the process of oil production, the vibration of the linear motor poses a significant amount of harm to the system due to its special slender structure. This paper focuses on the electromagnetic vibration of a transverse flux permanent magnet linear submersible motor (TFPMLSM). Firstly, the no-load air gap flux density is calculated based on the field modulation principle. Secondly, the radial electromagnetic force (REF) of the TFPMLSM is calculated, and the finite element method (FEM) is used to analyze the time-space and spectral characteristics of the REF. Then, the influence of secondary eccentricity on the frequency spectrum of the REF is further concluded. Finally, the natural frequencies of each vibration mode are calculated using the modal superposition method and the influence of the REF on the motor vibration is obtained through magnetic-structural coupling analysis. The research results found that the motor does not cause resonance at low speeds, and the fundamental frequency of REF has the greatest impact on electromagnetic vibration.

IntroductionMany patients who undergo assisted reproductive technology (ART) suffer from recurrent implantation failure (RIF). The addition of hyaluronic acid (HA) to the transfer medium is one of several methods to improve pregnancy outcomes. We investigated whether HA could improve the live birth and clinical pregnancy rates of RIF patients.MethodsThis study included 248 RIF patients, who were divided into two groups: the control (CTL) group (n=137), which received transfer medium without HA, and the HA group (n=111), which received transfer medium with HA. The two groups were compared according to the ART outcome.ResultsThe primary outcomes were the clinical pregnancy and live birth rates. Secondary outcomes include a positive urine pregnancy test, the implantation, ongoing pregnancy, multiple pregnancy, clinical miscarriage, and ectopic pregnancy rates, foetal or congenital defects, obstetric complications, infant birth weight and any related adverse events. Regarding the primary outcomes, the clinical pregnancy rate was significantly higher in the HA group than in the control group, and there was no significant difference in the live birth rate (LBR) between the HA and control groups. Regarding the secondary outcomes, the implantation, multiple pregnancy and ectopic pregnancy rates were similar between the two groups.DiscussionOur findings supported the conclusion that HA can improve the clinical pregnancy rate of patients with RIF undergoing FET cycles, but the live birth rate was not significantly improved with the addition of HA to the traditional transfer medium.

Bile acids (BAs) are synthesized in liver tissue from cholesterol and are an important endocrine regulator and signaling molecule in the liver and intestine. It maintains BAs homeostasis, and the integrity of intestinal barrier function, and regulates enterohepatic circulation in vivo by modulating farnesoid X receptors (FXR) and membrane receptors. Cirrhosis and its associated complications can lead to changes in the composition of intestinal micro-ecosystem, resulting in dysbiosis of the intestinal microbiota. These changes may be related to the altered composition of BAs. The BAs transported to the intestinal cavity through the enterohepatic circulation are hydrolyzed and oxidized by intestinal microorganisms, resulting in changes in their physicochemical properties, which can also lead to dysbiosis of intestinal microbiota and overgrowth of pathogenic bacteria, induction of inflammation, and damage to the intestinal barrier, thus aggravating the progression of cirrhosis. In this paper, we review the discussion of BAs synthesis pathway and signal transduction, the bidirectional regulation of bile acids and intestinal microbiota, and further explore the role of reduced total bile acid concentration and dysregulated intestinal microbiota ratio in the development of cirrhosis, in order to provide a new theoretical basis for the clinical treatment of cirrhosis and its complications.

Jujuboside B (JuB), one of the main active triterpenoid saponins from the traditional Chinese medicine Ziziphus jujuba, possesses a wide range of pharmacological activities. However, it is unknown whether JuB can inhibit tumor angiogenesis, a crucial step in solid tumor growth. In this study, we found that JuB significantly inhibited the proliferation, migration, and tube formation of human umbilical vein endothelial cells in a dose-dependent manner. JuB also suppressed angiogenesis in chick embryo chorioallantoic membranes and Matrigel plugs. Moreover, through angiogenesis inhibition, JuB delayed the growth of human HCT-15 colorectal cancer xenograft in mice. Western blot assay demonstrated that JuB inhibited the phosphorylation of VEGFR2 and its key downstream protein kinases, such as Akt, FAK, Src, and PLCγ1. In conclusion, the antiangiogenic potency and molecular mechanism of JuB are revealed for the first time, indicating that this triterpene saponin may be further explored as a potential drug candidate or lead compound for antiangiogenic cancer therapy.

Abstract Background Patients with recurrent implantation failure (RIF) may have more uterine contractions. Several observational studies suggested that atosiban administration around embryo transfer resulted in higher pregnancy rates in RIF patients. This study aimed to evaluate the effect of atosiban given before fresh embryo transfer on pregnancy outcomes of women with RIF. Methods A prospective, randomized, double-blind controlled clinical trial was performed in IVF center of Shanghai First Maternity and Infant Hospital. According to a computer-generated randomization list, 194 infertile women with RIF received fresh embryo transfer between July 2017 and December 2019 were randomly allocated into the atosiban (n = 97) and the placebo (n = 97) groups. Women in the treatment group received atosiban intravenously about 30 min before embryo transfer with a bolus dose of 6.75 mg over one minute. Those in the placebo group received only normal saline infusion for the same duration. Results There was no significant difference in the live birth rate between the atosiban and placebo groups (42.3% vs 35.1%, P = 0.302, RR = 1.206 (0.844–1.723)). No significant differences were found between the two groups in the positive pregnancy test, clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and implantation rates. Similar results were found when stratified by the number of embryos previously transferred, number of previous failed embryo transfers, frequency of endometrial peristalsis on embryo transfer day (≥ 3 waves/min) or serum estradiol (E2) on the day of hCG above the median level. And, there was no correlation between the serum E2 level on the day of hCG and the frequency of endometrial peristalsis on embryo transfer day. The frequency of endometrial peristalsis on embryo transfer day, total FSH/HMG dosage and duration were the significant factors which independently predicted the likelihood of a live birth. Conclusions These results suggested that atosiban treatment before fresh embryo transfer might not improve the live birth rate in RIF patients. Trial registration The study had been approved by the Institutional Review Board of the hospital (2017 ethics No.43) and was registered under Clinicaltrials.gov with an identifier NCT02893722.

Objective: To compare how hospitals that use single-vendor vs best-of-breed electronic health record (EHR) vendors utilize clinical and organizational evaluation capabilities. Methods: Data from the 2018 (June 1, 2016, to December 31, 2017) American Hospital Association Information Technology Supplement Survey and Medicare Final Rule Standardizing File were used. Multinomial logistic regression analysis of hospitals (n=1902) was conducted to identify hospital characteristics associated with the use of EHRs for (1) clinical care evaluation capabilities and (2) organizational evaluation capabilities. Results: Single-vendor EHR hospitals were more likely (relative risk ratio, 3.37; 95% confidence interval, 1.97-5.76) to use EHRs for clinical care and organizational evaluation capabilities. Not-for-profit hospitals were more likely to use EHRs for all organizational evaluation capabilities than government nonfederal hospitals. For-profit hospitals were less likely to use EHRs for organizational or clinical evaluation capabilities than government nonfederal hospitals. Conclusion: Hospitals using the single-vendor EHR system were more likely to engage in clinical care and organizational evaluation than hospitals using best-of-breed EHR systems.

Cotton is widely grown in many countries around the world due to the huge economic value of the total natural fiber. Verticillium wilt, caused by the soil-borne pathogen Verticillium dahliae, is the most devastating disease that led to extensive yield losses and fiber quality reduction in cotton crops. Developing resistant cotton varieties through genetic engineering is an effective, economical, and durable strategy to control Verticillium wilt. However, there are few resistance gene resources in the currently planted cotton varieties, which has brought great challenges and difficulties for breeding through genetic engineering. Further revealing the molecular mechanism between V. dahliae and cotton interaction is crucial to discovering genes related to disease resistance. In this review, we elaborated on the pathogenic mechanism of V. dahliae and the resistance mechanism of cotton to Verticillium wilt. V. dahliae has evolved complex mechanisms to achieve pathogenicity in cotton, mainly including five aspects: (1) germination and growth of microsclerotia; (2) infection and successful colonization; (3) adaptation to the nutrient-deficient environment and competition of nutrients; (4) suppression and manipulation of cotton immune responses; (5) rapid reproduction and secretion of toxins. Cotton has evolved multiple physiological and biochemical responses to cope with V. dahliae infection, including modification of tissue structures, accumulation of antifungal substances, homeostasis of reactive oxygen species (ROS), induction of Ca2+ signaling, the mitogen-activated protein kinase (MAPK) cascades, hormone signaling, and PAMPs/effectors-triggered immune response (PTI/ETI). This review will provide an important reference for the breeding of new cotton germplasm resistant to Verticillium wilt through genetic engineering.

Gastric cancer (GC), a common and high-mortality disease, still occupies an important position in current cancer research, and Helicobacter pylori (H. pylori) infection as its important risk factor has been a hot and challenging research area. Among the numerous pathogenic factors of H. pylori, the virulence protein CagA has been widely studied as the only bacterial-derived oncoprotein. It was found that CagA entering into gastric epithelial cells (GECs) can induce the dysregulation of multiple cellular pathways such as MAPK signaling pathway, PI3K/Akt signaling pathway, NF-κB signaling pathway, Wnt/β-catenin signaling pathway, JAK-STAT signaling pathway, Hippo signaling pathway through phosphorylation and non-phosphorylation. These disordered pathways cause pathological changes in morphology, adhesion, polarity, proliferation, movement, and other processes of GECs, which eventually promotes the occurrence of GC. With the deepening of H. pylori-related research, the research on CagA-induced abnormal signaling pathway has been updated and deepened to some extent, so the key signaling pathways activated by CagA are used as the main stem to sort out the pathogenesis of CagA in this paper, aiming to provide new strategies for the H. pylori infection and treatment of GC in the future.

Polyethylene glycol 400 (PEG400) is a widely used pharmaceutical excipient in the field of medicine. It not only enhances the dispersion stability of the main drug but also facilitates the absorption of multiple drugs. Our previous study found that the long-term application of PEG400 as an adjuvant in traditional Chinese medicine preparations resulted in wasting and weight loss in animals, which aroused our concern. In this study, 16S rRNA high-throughput sequencing technology was used to analyze the diversity of gut microbiota, and LC-MS/MS Q-Exactive Orbtriap metabolomics technology was used to analyze the effect of PEG400 on the metabolome of healthy mice, combined with intestinal pathological analysis, aiming to investigate the effects of PEG400 on healthy mice. These results showed that PEG400 significantly altered the structure of gut microbiota, reduced the richness and diversity of intestinal flora, greatly increased the abundance of Akkermansia muciniphila (A. muciniphila), increased the proportion of Bacteroidetes to Firmicutes, and reduced the abundance of many beneficial bacteria. Moreover, PEG400 changed the characteristics of fecal metabolome in mice and induced disorders in lipid and energy metabolism, thus leading to diarrhea, weight loss, and intestinal inflammation in mice. Collectively, these findings provide new evidence for the potential effect of PEG400 ingestion on a healthy host.

Abstract Due to excessive elongation of the eyeball, myopia-related vascular abnormalities are frequently observed in the central retinal artery (CRA) and its intraretinal branches. In addition to inconsistency in previously reported findings, hemodynamic (reduced flow velocity, increased vascular resistance) and morphological changes (narrower vessel diameter) were usually studied separately. This cross-sectional study evaluated the hemodynamic and morphological characteristics concurrently in a large sample of healthy myopes, by using the color Doppler ultrasound and adaptive optics retinal camera. Results showed that the retrobulbar segment of CRA had a tendency of slightly reduced flow velocity in eyeballs with longer axial length, but the correlation was not significant after adjusting for the multiple correlations. Vascular resistance was not affected by the axial elongation. With respect to the intraretinal branches, no significant changes in longer eyes of total diameter or lumen diameter were observed, while both the wall thickness and the wall cross-sectional area were significantly increased, but only a marginally increase in the wall to lumen ratio was found with increasing axial length. This implies some potential small artery remodeling in the intraretinal CRA branches. Overall, blood supply of the inner retina in healthy young myopes is likely to be maintained. Additionally, morphological parameters of vascular microstructure could be potential biomarkers to monitor myopia progression and understand myopia-related vascular abnormalities in future studies.

Trehalose metabolism is related to the sclerotial development of Rhizoctonia solani AG-1 IA, the causal agent of rice sheath blight (RSB). Here, we further elucidated the functions of three genes Rstre, Rstps1 and Rstpp that encode three key enzymes trehalase (TRE), alpha, alpha-trehalose- phosphate synthase (TPS1) and trehalose 6-phosphate phosphatase (TPP) in the sclerotial development of R. solani AG-1 IA. Due to the lack of a stable genetic transformation system for R. solani, the heterologous expression of these three genes in Pichia pastoris GS115 was performed. The results showed that reactive oxygen species (ROS) contents and enzyme activities in R. solani decreased significantly in the treatments of the fermentation broths of Rstps1 and Rstpp transformants, and that in the treatment of the fermentation broth of Rstre transformant visibly increased. Furthermore, the fermentation broths of the transformants of all the three genes were added to potato dextrose agar (PDA) medium for the cultivation of R. solani, as a result, the dry weight of sclerotia in each PDA plate containing the fermentation broths of Rstps1 and Rstpp transformants significantly increased compared with the control, and that of Rstre transformant obviously decreased. Finally, 178 proteins were found to interact with RSTPS1, and 16 of them were associated with ROS. Taken together, the findings suggest that all these three genes related to trehalose metabolism play important roles in the sclerotial development of R. solani AG-1 IA, and can be used as new targets for the development of novel high-efficiency fungicides for the controlling of RSB.

Autism spectrum disorder (ASD) is a highly inheritable neurodevelopmental disorder that causes diverse deficits in social communication and restricted repetitive sensorimotor behaviors. Here, we studied a human-induced pluripotent cell line from an autistic patient with impaired social function and a normal intelligence quotient (IQ > 70). The cell line was validated by its morphology, gene expression, and potential to differentiate into three germ layers. This model can be used to explore the pathophysiological and molecular mechanisms in patients with ASD, compared those of with patients with normal cognitive abilities.

Background and Aims: Methionine has been proven to inhibit addictive behaviors of cocaine dependence. This study aimed to identify the potential mechanisms of MET relating to its inhibitory effects on cocaine induced cellular and behavioral changes.Methods: MRNA and miRNA high-throughput sequencing of the prefrontal cortex in a mouse model of cocaine conditioned place preference (CPP) combined with L-methionine was performed. Differentially expressed miRNAs (DE-miRNAs) and differentially expressed genes (DEGs) regulated by cocaine and inhibited by L-methionine were identified. DEGs were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then, the identified DEGs were subjected to the DAVID webserver for functional annotation. Finally, miRNA-mRNA regulatory network and miRNA-mRNA-TF regulatory networks were established to screen key DE-miRNAs and coregulation network in Cytoscape.Results: Sequencing data analysis showed that L-methionine reversely regulated genes and miRNAs affected by cocaine. Pathways associated with drug addiction only enriched in CS-down with MC-up genes targeted by DE-miRNAs including GABAergic synapse, Glutamatergic synapse, Circadian entrainment, Axon guidance and Calcium signaling pathway. Drug addiction associated network was formed of 22 DEGs including calcium channel (Cacna1c, Cacna1e, Cacna1g and Cacng8), ephrin receptor genes (Ephb6 and Epha8) and ryanodine receptor genes (Ryr1 and Ryr2). Calcium channel gene network were identified as a core gene network modulated by L-methionine in response to cocaine dependence. Moreover, it was predicted that Grin1 and Fosb presented in TF-miRNA-mRNA coregulation network with a high degree of interaction as hub genes and interacted calcium channels.Conclusion: These identified key genes, miRNA and coregulation network demonstrated the efficacy of L-methionine in counteracting the effects of cocaine CPP. To a certain degree, it may provide some hints to better understand the underlying mechanism on L-methionine in response to cocaine abuse.

Leaves are the main vegetative organs of the aboveground part of plants and play an important role in plant morphogenesis. KNOTTED-LIKE HOMEOBOX (KNOX) plays a crucial role in regulating leaf cell fate and maintaining leaf development. In this study, we analyzed LtKNOX1 from Lilium tsingtauense and illustrated its function in transgenic plants. Tissue-specific expression analysis indicated that LtKNOX1 was highly expressed in stems, young flower buds, and shoot apical meristems (SAMs). Ectopic overexpression of LtKNOX1 in Nicotiana benthamiana suggested that transformants with mild phenotypes were characterized by foliar wrinkles and mildly curled leaves; transformants with intermediate phenotypes showed severely crimped blades and narrow leaf angles, and the most severe phenotypes lacked normal SAMs and leaves. Moreover, the expression levels of genes involved in the regulation of KNOX in transgenic plants were detected, including ASYMMETRIC LEAVES1, PIN-FORMED 1, GA20-oxidase, CUP-SHAPED COTYLEDON 2, CLAVATA 1 and WUSCHEL(WUS), and the expression of other genes were down-regulated except WUS. This study contributes to our understanding of the LtKNOX1 function.