Search

The imbalance of gut microbiota is an important factor leading to inflammatory bowel disease (IBD). Diffusible signal factor (DSF) is a novel quorum-sensing signal that regulates bacterial growth, metabolism, pathogenicity, and host immune response. This study aimed to explore the therapeutic effect and underlying mechanisms of DSF in a zebrafish colitis model induced by sodium dextran sulfate (DSS). The results showed that intake of DSF can significantly improve intestinal symptoms in the zebrafish colitis model, including ameliorating the shortening of the intestine, reducing the increase in the goblet cell number, and restoring intestinal pathological damage. DSF inhibited the upregulation of inflammation-related genes and promoted the expression of claudin1 and occludin1 to protect the tightness of intestinal tissue. The gut microbiome analysis demonstrated that DSF treatment helped the gut microbiota of the zebrafish colitis model recover to normal at the phylum and genus levels, especially in terms of pathogenic bacteria; DSF treatment downregulated the relative abundance of Aeromonas hydrophila and Staphylococcus aureus, and it was confirmed in microbiological experiments that DSF could effectively inhibit the colonization and infection of these two pathogens in the intestine. This study suggests that DSF can alleviate colitis by inhibiting the proliferation of intestinal pathogens and inflammatory responses in the intestine. Therefore, DSF has the potential to become a dietary supplement that assists in the antibiotic and nutritional treatment of IBD.

Liver disease is a significant global health issue that affects the liver and contributes to approximately 2 million deaths worldwide each year. Although treatment options including surgery and medication are available, effective treatment remains a challenge because of limitations of the traditional drug-delivery methods, such as uneven and nonspecific drug distribution, which lead to negative effects on healthy tissues and a reduction in drug bioavailability. Nanotechnology provides a promising solution for targeted drug delivery to the liver, which has unique anatomical and physiological structures that render it an ideal target for nanomedicine. Several categories of nanomaterials, including inorganic nanomaterials, polymer nanomaterials, and multifunctional nanoparticles (NPs), have been studied as potential agents for targeting this organ in the context of liver diseases. Using surface modification and functionalization, nanomaterials can be selectively targeted to liver tissue or hepatocytes, thus delivering drugs, and enhancing their efficacy while minimizing their side effects. Nanomaterials exhibit numerous benefits; however, their stability and toxicity pose potential risks to living organisms result in adverse effects, such as protein adsorption, and inflammation. Despite the challenges inherent to the development of nanomaterials, ongoing research and development have a great potential for the liver-targeted treatment of liver diseases through the use of nanotechnology. In this review, we first describe the nanomaterials used to target liver diseases, i.e., metallic NPs, ceramic nanomaterials, micelles, polysaccharides, liposomes, dendrimers, carbon nanotubes, and multifunctional NPs. Moreover, the mechanisms for nanomaterials target liver disease are discussed. Finally, this review discusses the current challenges and prospects for future research directions in this field.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

Abstract Background Cancer-associated fibroblasts (CAFs) have significant tumor regulatory functions, and CAFs-derived exosomes (CAFs-Exo) released from CAFs play an important role in the progression of oral squamous cell carcinoma (OSCC). However, a lack of comprehensive molecular biological analysis leaves the regulatory mechanisms of CAFs-Exo in OSCC unclear. Methods We used platelet derived growth factor-BB (PDGF-BB) to induce the transformation of human oral mucosa fibroblast (hOMF) into CAFs, and extracted exosomes from the supernatant of CAFs and hOMF. We validated the effect of CAFs-Exo on tumor progression by exosomes co-culture with Cal-27 and tumor-forming in nude mice. The cellular and exosomal transcriptomes were sequenced, and immune regulatory genes were screened and validated using mRNA-miRNA interaction network analysis in combination with publicly available databases. Results The results showed that CAFs-Exo had a stronger ability to promote OSCC proliferation and was associated with immunosuppression. We discovered that the presence of immune-related genes in CAFs-Exo may regulate the expression of PIGR, CD81, UACA, and PTTG1IP in Cal-27 by analyzing CAFs-Exo sequencing data and publicly available TCGA data. This may account for the ability of CAFs-Exo to exert immunomodulation and promote OSCC proliferation. Conclusions CAFs-Exo was found to be involved in tumor immune regulation through hsa-miR-139-5p, ACTR2 and EIF6, while PIGR, CD81, UACA and PTTG1IP may be potentially effective targets for the treatment of OSCC in the future.

Cold stress is an important factor that limits apple production. In this study, we examined the tissue-cultured plantlets of apple rootstocks ‘M9T337’ and ‘60-160’, which are resistant and sensitive to cold stress, respectively. The enriched pathways of differentially expressed genes (DEGs) and physiological changes in ‘M9T337’ and ‘60-160’ plantlets were clearly different after cold stress (1°C) treatment for 48 h, suggesting that they have differential responses to cold stress. The differential expression of WRKY transcription factors in the two plantlets showed that MdWRKY40is and MdWRKY48 are potential regulators of cold tolerance. When we overexpressed MdWRKY40is and MdWRKY48 in apple calli, the overexpression of MdWRKY48 had no significant effect on the callus, while MdWRKY40is overexpression promoted anthocyanin accumulation, increased callus cold tolerance, and promoted the expression of anthocyanin structural gene MdDFR and cold-signaling core gene MdCBF2. Yeast one-hybrid screening and electrophoretic mobility shift assays showed that MdWRKY40is could only bind to the MdDFR promoter. Yeast two-hybrid screening and bimolecular fluorescence complementation showed that MdWRKY40is interacts with the CBF2 inhibitor MdMYB15L through the leucine zipper (LZ). When the LZ of MdWRMY40is was knocked out, MdWRKY40is overexpression in the callus did not affect MdCBF2 expression or callus cold tolerance, indicating that MdWRKY40is acts in the cold signaling pathway by interacting with MdMYB15L. In summary, MdWRKY40is can directly bind to the MdDFR promoter in order to promote anthocyanin accumulation, and it can also interact with MdMYB15L to interfere with its inhibitory effect on MdCBF2, indirectly promoting MdCBF2 expression, and thereby improving cold tolerance. These results provide a new perspective for the cold-resistance mechanism of apple rootstocks and a molecular basis for the screening of cold-resistant rootstocks.

Abstract Background Enhancing health intervention for floating populations has become an essential aspect of public health around the world. China launched a policy reform aimed at implementing immediate reimbursement for trans-provincial inpatient treatments. The objective of this study was to investigate the effects of this policy change on socioeconomic inequality in health among the floating population. Methods This study used two waves of individual-level data from the China Migrants Dynamic Survey (CMDS) collected in 2017 and 2018 as well as administrative hospital data at the city level. The sample included 122061 individuals and 262 cities. Under a quasi-experimental research design, we built up the framework to employ the generalized and multi-period difference-in-differences estimation strategy. We used the number of qualified hospitals that could provide immediate reimbursement to represent the degree and intensity of the implementation of this policy change. We also calculated the Wagstaff Index (WI) to measure socioeconomic inequality in health. Results This policy change and income level had a negative joint impact on the health status of floating population (odds ratio = 0.955, P

Abstract Background/aims Diabetes mellitus (DM) is highly susceptible to diabetic hind limb ischemia (DHI). MicroRNA (MiR)-17-5p is downregulated in DM and plays a key role in vascular protection. Endothelial progenitor cell (EPC)-released exosomes (EPC-EXs) contribute to vascular protection and ischemic tissue repair by transferring their contained miRs to target cells. Here, we investigated whether miR-17-5p-enriched EPC-EXs (EPC-EXsmiR-17-5p) had conspicuous effects on protecting vascular and skeletal muscle in DHI in vitro and in vivo. Methods EPCs transfected with scrambled control or miR-17-5p mimics were used to generate EPC-EXs and EPC-EXsmiR-17-5p. Db/db mice were subjected to hind limb ischemia. After the surgery, EPC-EXs and EPC-EXsmiR-17-5p were injected into the gastrocnemius muscle of the hind limb once every 7 days for 3 weeks. Blood flow, microvessel density, capillary angiogenesis, gastrocnemius muscle weight, structure integrity, and apoptosis in the hind limb were assessed. Vascular endothelial cells (ECs) and myoblast cells (C2C12 cells) were subjected to hypoxia plus high glucose (HG) and cocultured with EPC-EXs and EPC-EXsmiR-17-5p. A bioinformatics assay was used to analyze the potential target gene of miR-17-5p, the levels of SPRED1, PI3K, phosphorylated Akt, cleaved caspase-9 and cleaved caspase-3 were measured, and a PI3K inhibitor (LY294002) was used for pathway analysis. Results In the DHI mouse model, miR-17-5p was markedly decreased in hind limb vessels and muscle tissues, and infusion of EPC-EXsmiR-17-5p was more effective than EPC-EXs in increasing miR-17-5p levels, blood flow, microvessel density, and capillary angiogenesis, as well as in promoting muscle weight, force production and structural integrity while reducing apoptosis in gastrocnemius muscle. In Hypoxia plus HG-injured ECs and C2C12 cells, we found that EPC-EXsmiR-17-5p could deliver their carried miR-17-5p into target ECs and C2C12 cells and subsequently downregulate the target protein SPRED1 while increasing the levels of PI3K and phosphorylated Akt. EPC-EXsmiR-17-5p were more effective than EPC-EXs in decreasing apoptosis and necrosis while increasing viability, migration, and tube formation in Hypoxia plus HG-injured ECs and in decreasing apoptosis while increasing viability and myotube formation in C2C12 cells. These effects of EPC-EXsmiR-17-5p could be abolished by a PI3K inhibitor (LY294002). Conclusion Our results suggest that miR-17-5p promotes the beneficial effects of EPC-EXs on DHI by protecting vascular ECs and muscle cell functions.

X-linked adrenoleukodystrophy (ALD) is a rare peroxisome disease with phenotypic heterogeneity. There is a lack of suitable in vitro models to study its pathogenesis. We established two strains of iPSCs from skin fibroblasts of patients with childhood cerebral ALD and Addison’s disease, respectively. CytoTune™2.0 Sendai reprogramming kit was used. The iPSC lines showed typical stem cell morphology, normal karyotype, and carrying ABCD1 variation. The iPSC lines express pluripotency markers, and have the capacity to differentiate into three germ layers. iPSCs can be used as an alternative cell source for ALD in vitro model to study its pathogenesis and therapeutic strategies.

The Grain for Green Program (GFGP) is an important policy implemented by the Chinese government to restore degraded forests. However, there is a limited understanding of the eco-economic benefits of GFGP in Sichuan province. In this study, the ecosystem service value (ESV) in Sichuan from 2001 to 2019 was evaluated dynamically based on the improved value equivalent method. Then, the impact of climate and human activities on ESV was explored. Finally, the eco-economic benefit model of afforestation was constructed to calculate its value efficiency in 183 counties and the return rate on afforestation investment in Sichuan. Our results indicated that the forest ESV (R2 = 0.82, P

Chinese cherry is an economically important fruit crop native to China. Flavor quality is greatly influenced by compositions of soluble sugars and organic acids. To better understand the flavor quality of Chinese cherry, we determined sugar and acid components in thirty-eight landrace and cultivar collections, and two wild resources using the HPLC method. Glucose and fructose were the main components, accounting for 85.91% of soluble sugars. Malic acid was the predominant organic acid, with an average proportion of 65.73% of total acids. Correlation and PCA analysis revealed seven key indicators for evaluating fruit flavor. Compared with wild Chinese cherry, the cultivated collections exhibited higher levels of soluble sugars, especially fructose, and lower levels of organic acid, particularly malic acid in fruits. Finally, we have established grading criteria for seven flavor indicators in Chinese cherry. Our study provides valuable references for identifying flavor compounds and improving flavor quality of Chinese cherry.

AbstractBackground Benign breast lesions are often associated with hard nodule formation after microwave ablation (MWA), which persists for a long time and causes problems in patients. The aim of this study was to evaluate the efficacy of decorin in the treatment of hard nodule formation and its potential mechanism of action.Methods Using a Bama miniature pig model of mammary gland hyperplasia, immunohistochemistry, Masson’s trichrome and western blotting were firstly applied to compare the extent of fibrosis and activation of key members of the TGF-β1/SMAD and MAPK signaling pathways of hard nodule in the control and MWA groups, and then the extent of fibrosis and expression of signaling pathways in hard nodule were examined after application of decorin.Results The results showed that the MWA group had increased levels of TGF-β1, p-SMAD2/3, p-ERK1/2, and collagen I proteins and increased fibrosis at 2 weeks, 4 weeks, and 3 months after MWA. After decorin treatment, the expression levels of each protein were significantly downregulated, and the degree of fibrosis was reduced at 2 weeks, 4 weeks, and 3 months after MWA compared with the MWA group.Conclusion In conclusion, these results suggest that activation of TGF-β1 may play an important role in hard nodule formation and that decorin may reduce hard nodule formation after MWA in a model of mammary gland hyperplasia by inhibiting the TGF-β1/SMAD and MAPK signaling pathways.

Introduction: Poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)] stands out as an organic polymer with remarkable piezoelectric properties, coupled with high chemically stability and biocompatibility, rendering it the most promising organic piezoelectric nanomaterial. Therefore, we aim to explore its developmental history, find current research hotspots, and identify emerging trends.Methods: To comprehensively review the pertinent literature on poly(vinylidene fluoride-trifluoroethylene) or P(VDF-TrFE) in English from 1992 to 2022, we utilized the Web of Science Core Collection. Additionally, bibliometric tools such as CiteSpace, VOSviewer, Bibliometrics online analysis platforms (https://bibliometric.com), along with SCImage graphics, were employed to delineate historical features, track the evolution of active topics, and identify emerging trends on the P(VDF-TrFE) field.Results: The annual publication and citation counts for articles on P(VDF-TrFE) have exhibited consistent growth since 1992, with Asia, notably China, contributing the highest number of publications on P(VDF-TrFE) materials. Interestingly, researchers in the United States demonstrated the most robust international collaborations across various countries. Keywords were categorized into nine clusters: 0# vinylidene fluoride, 1# thin-film transient, 2# energy harvesting, 3# dielectric property, 4# thin film, 5# film, 6# mobile modeling, 7# growth, and 8# pyroelectric sensor. The performance of constituent materials in electronic energy-storage applications and current and future research in nanofields, including nanofilms, nanofibers, and nanogenerator, are considered hotspots and developmental trends, respectively. Among the most cited articles, these articles are commonly related to PVDF and P(VDF-TrFE) ferroelectricity.Conclusion: Therefore, we believe that the electromechanical coupling performance of P(VDF-TrFE) and the research in nano fields is research hotspot that will trend into the future.

Both acute cerebral infarction and malignant tumors are prevalent in the elderly. However, acute cerebral infarction is rarely present as the first clinical manifestation of malignant tumors. By searching the Picture Archiving and Communication System from 2010 to 2022 and the medical record database from 2003 to 2022, we found three cases of Trousseau syndrome, one male and two females with an average age of 69.3 ± 3.2 years, presenting with acute cerebral infarction. Two patients denied having hypertension, diabetes, and coronary heart disease. The average value of the D-dimer was 17.83 ± 12.39 mg/L (normal range, 0 to 0.55 mg/L). Magnetic resonance imaging (MRI) of the brain showed scattered and multiple small infarcts in the watershed area. The sites of infarction were not those that are typically caused by vascular atherosclerosis. One of the females was diagnosed with pancreatic cancer (T2N2M1, stage IV), the male was diagnosed with gastric cancer (T4N3M1, stage IV), and the other female was diagnosed with lung adenocarcinoma (rTxN3M1b, stage IV). The patient with pancreatic cancer underwent a comprehensive geriatric assessment, which revealed that she had a disability, dementia, malnutrition, short life expectancy, and high chemotherapy risk. Ultimately, the patient opted for conservative care, and 3 months after being discharged, she passed away from an acute upper gastrointestinal hemorrhage. Elderly patients with unexplained D-dimer elevation, multiple cerebral vascular lesions detected on MRI, and an absence of typical stroke risk factors need to be monitored for Trousseau syndrome. To screen for cancer, tumor markers and related imaging should be performed first. Trousseau syndrome is primarily treated with chemotherapy, radiotherapy and anticoagulant therapy. The risk of bleeding should be assessed carefully when using anticoagulant therapy in the elderly. Comprehensive geriatric assessment can assist in weighing the benefits and side effects of cancer treatment, making correct medical choices, and improving patients’ quality of life.

ABSTRACT The core endophytes of plants are regarded as promising resources in future agroecosystems. How they affect the assembly of rice-related bacterial communities after early inoculation remains unclear. Here, we examined bacterial communities across 148 samples, including bulk and rhizosphere soils, sterilized roots, stems, and seeds at the seedling, tillering, booting, and maturity stages. Tissue cultured rice seedlings were inoculated with Xathomonas sacchari JR3-14, a core endophytic bacterium of rice seeds, before transplanting. The results revealed that α-diversity indices were significantly enhanced in the root and stem endosphere at the seedling stage. β-diversity was altered at most plant developmental stages, except for the root and stem at the booting stage. Network complexity consequently increased in the root and stem across rice growth stages, other than the stem endosphere at the booting stage. Four abundant beneficial bacterial taxa, Bacillus, Azospira, Azospirillum, and Arthrobacter, were co-enriched during the early growth stage. Infer Community Assembly Mechanisms by Phylogenetic-bin-based null model analysis revealed a higher relative contribution of drift and other eco-evolutionary processes mainly in root compartments across all growth stages, but the opposite pattern was observed in stem compartments. IMPORTANCE Endophytic bacteria are regarded as promising environmentally friendly resources to promote plant growth and plant health. Some of microbes from the seed are able to be carried over to next generation, and contribute to the plant’s ability to adapt to new environments. However, the effects of early inoculation with core microbes on the assembly of the plant microbiome are still unclear. In our study, we demonstrate that early inoculation of the rice seed core endophytic bacterium Xanthomonas sacchari could alter community diversity, enhance complexity degree of network structure at most the growth stages, and enrich beneficial bacteria at the seedling stage of rice. We further analyzed the evolutionary processes caused by the early inoculation. Our results highlight the new possibilities for research and application of sustainable agriculture by considering the contribution of seed endophytes in crop production and breeding.

Imidacloprid (IMC) is a widely used nicotine-based pesticide that can cause severe harm to water resources. To address this issue, a simple binary heterojunction photocatalyst was constructed to degrade IMC under visible light. Furthermore, the catalyst was able to continue degrading approximately 15% of IMC within 5 h under dark. The possible photocatalytic degradation intermediate's structure and low toxicity were verified by mass spectrometry and zebrafish embryo experiments, respectively. The catalyst also exhibited good stability. Therefore, a simple photocatalyst with excellent performance and low toxicity of degradation products was successfully developed for IMC pesticide removal in water.

Silicon (Si) has become the most promising next-generation anode to replace commercial graphite for Li-ion batteries (LIBs) profiting from its large reversible capacity of 4,200 mA h g−1. However, its sluggish reaction kinetics and large volume effect need to be resolved. Herein, we prepare a ternary GaSiP solid solution with a disordered lattice by a facile mechanochemistry method. As anodes of LIBs, the GaSiP provides a reversible capacity of 1,527 mA h g−1 at 100 mA g−1 with an initial Coulombic efficiency (ICE) of 90.8% based on the reversible Li-storage mechanism integrated intercalation and subsequent conversion processes as confirmed by crystallography characterization and electrochemical measurements. Importantly, the GaSiP carbon composite presents a long cycling stability of maintaining 1,362 mA h g−1 after 50 cycles at 0.1 A g−1, and 75% capacity retention rate after 1,200 cycles at 2 A g−1, and a high-rate performance of remaining 440 mA h g−1 at 20 A g−1. Broadly, this work opens the door to develop ternary phosphides with disordered lattice and liquid metallic phase using for electrochemical energy conversion and storage.

Karst wetlands are widely distributed throughout the southwest China, and play an important role in enhancing carbon sequestration and improving water quality in karst areas. The internationally important karst wetland of Huixian is the largest karst wetland in China, but its water quality has continued to deteriorate as a result of human influences in recent years. Remote sensing technology has become an important approach to estimate water quality parameters (WQPs). However, the feasibility of combining multi-sensor remote sensing images with deep learning to estimate different WQPs in karst wetlands has not been demonstrated yet. To resolve this issue, this study constructed multiple retrieval models of WQPs (Chlorophyll-a (Chla), Phycocyanin (PC), Turbidity (Turb), Dissolved Oxygen (DO)) in karst wetlands using deep learning (Transformer and Mixture Density Network (MDN)) and optimized shallow machine learning (Random Forest (RF), XGBoost (XGB) and Gradient Boosting (GB)) based on multi-sensor images from satellite and UAV platforms. The performance of deep learning in the inversion of WQPs demonstrated to compare with shallow machine learning using multispectral and hyperspectral images. We further quantitatively evaluated the retrieval performance of UAV and satellite, multispectral and hyperspectral images, and presented predictive mapping of the gradient distribution of WQPs. Finally, this study adopted the SHapley Additive exPlanations (SHAP) to tackle the local and global interpretability of the input features contribution to the output of retrieval models. The results showed that (1) Transformer model presented a good prediction of PC and DO (R2 = 0.649 ∼ 0.844), XGB and GB models achieved the highest accuracy estimation of Chla and Turb (R2 = 0.75). (2) The estimation results of WQPs based on UAV platform (R2 = 0.419 ∼ 0.695) was higher than that of satellite-based images. The estimation accuracy of multispectral images (R2 = 0.338 ∼ 0.718) was slightly higher than that of Zhuhai-1 Orbita hyperspectral (OHS) images. The average accuracy of Turb estimated by UAV images (R2 = 0.565 ∼ 0.752) was higher than that of satellite-based images. OHS hyperspectral images had the best DO estimation (R2 = 0.314 ∼ 0.649). (3) This study found 32.66% and 23.01% of water area with the Chla and Turb concentrations exceeding 60 μg/L and 60 NTU, respectively, which revealed that the Huixian karst wetland has suffered serious water pollution. (4) The SHAP analysis reveals that near infra-red and red band are sensitive to predict Chla and DO, red and red-edge bands are sensitive to predict PC and Turb in the karst wetland.

Microplastics (MPs), an emerging group of pollutants, not only have direct toxic effects on aquatic organisms but also cause combined toxicity by absorbing other pollutants. Triphenyltin (TPT), one of the most widely used organotin compounds, has adverse effects on aquatic organisms. However, little is known about the combined toxicity of MPs and TPT to aquatic organisms. To investigate the individual and combined toxicity of MPs and TPT, we selected the common carp (Cyprinus carpio) for a 42-day exposure experiment. Based on the environmental concentrations in a heavily polluted area, the experimental concentrations of MPs and TPT were set at 0.5 mg L−1 and 1 μg L−1, respectively. The effects of MPs combined with TPT on the carp gut–brain axis were evaluated by detecting gut physiology and biochemical parameters, gut microbial 16S rRNA, and brain transcriptome sequencing. Our results suggest that a single TPT caused lipid metabolism disorder and a single MP induced immunosuppression in carp. When MPs were combined with TPT, the involvement of TPT amplified the immunotoxic effect induced by MPs. In this study, we also explored the gut–brain axis relationship of carp immunosuppression, providing new insights for assessing the combined toxicity of MPs and TPT. At the same time, our study provides a theoretical basis for evaluating the coexistence risk of MPs and TPT in the aquatic environment.

Abstract Tirandamycin (TAM B) is a tetramic acid antibiotic discovered to be active on a screen designed to find compounds with neuroprotective activity. The producing strain, SBST2-5T, is an actinobacterium that was isolated from wastewater treatment bio–sludge compost collected from Suphanburi province, Thailand. Taxonomic characterization based on a polyphasic approach indicates that strain SBST2-5T is a member of the genus Streptomyces and shows low average nucleotide identity (ANI) (81.7%), average amino-acid identity (AAI) (78.5%), and digital DNA-DNA hybridization (dDDH) (25.9%) values to its closest relative, Streptomyces thermoviolaceus NBRC 13905T, values that are significantly below the suggested cut-off values for the species delineation, indicating that strain SBST2-5T could be considered to represent a novel species of the genus Streptomyces. The analysis of secondary metabolites biosynthetic gene clusters (smBGCs) in its genome and chemical investigation led to the isolation of TAM B. Interestingly, TAM B at 20 µg/mL displayed a suppressive effect on beta-secretase 1 (BACE1) with 68.69 ± 8.84% inhibition. Molecular docking simulation reveals the interaction mechanism between TAM B and BACE1 that TAM B was buried in the pocket of BACE-1 by interacting with amino acids Thr231, Asp 228, Gln73, Lys 107 via hydrogen bond and Leu30, Tyr71, Phe108, Ile118 via hydrophobic interaction, indicating that TAM B represents a potential active BACE1 inhibitor. Moreover, TAM B can protect the neuron cells significantly (% neuron viability = 83.10 ± 9.83% and 112.72 ± 6.83%) from oxidative stress induced by serum deprivation and Aβ1–42 administration models at 1 ng/mL, respectively, without neurotoxicity on murine P19-derived neuron cells nor cytotoxicity against Vero cells. This study was reportedly the first study to show the neuroprotective and BACE1 inhibitory activities of TAM B.

Abstract Background Chondrocytes are the main cell damage type involved in the occurrence and development of osteoarthritis (OA). Ferroptosis has been confirmed to be related to many degenerative diseases. This research aimed to explore the role of Sp1 and ACSL4 in ferroptosis in the IL-1β-treated human chondrocyte cells line (HCCs). Methods The cell viability was detected with CCK8 assay. The ROS, MDA, GSH, and Fe2+ levels were assessed with corresponding detecting kits. The Col2a1, Acan, Mmp13, Gpx4 and Tfr1 levels were determined by RT-qPCR assay. Western blot was conducted to evaluate the Acsl4 and Sp1 levels. PI staining was carried out to analyze the cell death. The double luciferase report was conducted to verify the interaction between Acsl4 and Sp1. Results The results showed that IL-1β stimulation elevated the LDH release, cell viability, ROS, MDA and Fe2+ levels and declined the GSH levels in the HCCs. Additionally, the mRNA levels of Col2a1, Acan, and Gpx4 were prominently decreased, while Mmp13 and Tfr1 were prominently elevated in the IL-1β stimulated HCCs. Furthermore, Acsl4 protein levels were upregulated in the IL-1β-stimulated HCCs. Both Acsl4 knockdown and ferrostatin-1 treatment neutralized the role of IL-1β in the HCCs. What’s more, Acsl4 was transcriptionally regulated by Specificity protein 1 (Sp1). Sp1 overexpression enhanced the Acsl4 levels and Sp1 knockdown declined it. Conclusion Upregulation of Sp1 activates Ascl4 transcription and thus mediates the occurrence of ferroptosis. Hence, Acsl4 may be a therapeutic target for intervention of OA.

ABSTRACT Importance Infantile spasm (IS) is a kind of refractory epilepsy. The first‐line treatments for IS are adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin. Objective This study aimed to evaluate the efficacy of magnesium sulfate and ACTH (MgSO4+ACTH) combination therapy in patients with IS who failed first‐line treatments. Methods In this retrospective study, the clinical data of patients with IS who failed first‐line treatments were collected in the Chinese PLA General Hospital. Patients received MgSO4+ACTH combination therapy after first‐line treatments failed. The course of treatments was 2 weeks. The therapeutic dose of ACTH and MgSO4 was 2.5 U·kg−1·d−1 and 0.25 g·kg−1·d−1, respectively. Results A total of 229 patients with IS who failed the first‐line treatments were collected. At the end of the MgSO4+ACTH combination treatment, the seizure‐free rate was 48.5% (111/229), and the resolution of hypsarrhythmia on electroencephalogram (EEG) was 72.1% (165/229). About 21.4% (49/229) of patients showed side effects, including infectious diseases, hypokalemia, and diarrhea. Interpretation For patients with IS who failed first‐line treatments, in terms of the seizure‐free rate and resolution of hypsarrhythmia on EEG, MgSO4+ACTH combination therapy can be considered.

Abstract Stroke is closely associated with carotid plaques. The assessment of carotid plaque is still the key issue of stroke prevention in clinical practice. This prospective cross‐sectional study included patients with carotid plaque evaluated by ultrasonography (US). The intima‐media thickness (IMT), lumen stenosis severity, thickness, and length of carotid plaque were measured by the routine US, and the amplitudes of subharmonics in the upstream shoulder, top, and downstream shoulder of all plaques and corresponding lumens were observed by Subharmonic Aided Pressure Estimation (SHAPE) US examination from the US contrast agent perflubutane microbubbles (Sonazoid), which analyzed the clinical parameters of patients, the subharmonic amplitude characteristics of all plaques and lumens, and the parameter differences between the ischemic stroke (IS) group and control group. From May 2021 to February 2022, 46 carotid plaques of 23 patients were included. For plaques, the subharmonic amplitude in the plaque (−60.52 ± 4.46) was lower than that in the opposing level lumen (−56.82 ± 5.68 dB), the subharmonic gradient across the plaque cap was negatively correlated with plaque thickness (r = −0.51, p

Abstract Background The present study aimed to explore the potentials of lncRNA LINC00313 in osteoarthritis (OA). Methods qRT-PCR was performed to detect the expression of LINC00313 in OA tissues and cells. CCK-8 and EDU were used to detect cell proliferation. The ELISA test kit was conducted to detect the expression of inflammatory factors. Flow cytometry was used to detect the apoptosis rates. Western blot was applied to measure the protein expression. The luciferase reporter gene test was carried out to verify the relationship between miR-525-5p and LINC00313 or GDF5. Results The data showed that the expression of LINC00313 was significantly down-regulated in OA tissues and cells. Functionally, LINC00313 promoted the proliferation of chondrocytes and suppressed the secretion of inflammatory factors and cell apoptosis. Moreover, LINC00313 functioned as a ceRNA to up-regulate the expression of GDF5 via sponging miR-525-5p. Luciferase and RNA pull-down assays further verified the interaction between miR-525-5p and LINC00313 (or GDF5). Moreover, overexpression of miR-525-5p or down-regulated GDF5 degraded the cellular functions of chondrocyte. Rescue experiments showed that the overexpression of miR-525-5p reversed the increase in cell viability and the decrease in pro-inflammatory factors and apoptosis rate mediated by LINC00313. The knockdown of GDF5 reversed the promotion of miR-525-5p knockdown on cell viability and the inhibition of pro-inflammatory factors and apoptosis rate. Conclusions LINC00313 inhibited the development of OA through regulating miR-525-5p/GDF5 axis. LncRNA LINC00313 can be used as a potential target for the treatment of OA.

Abstract Background Carotid vulnerable plaque is an important risk factor for stroke occurrence and recurrence. However, the relationship between risk parameters related to carotid vulnerable plaque (plaque size, echogenicity, intraplaque neovascularization, and plaque stiffness) and neurological outcome after ischemic stroke or TIA is unclear. This study investigates the value of multimodal ultrasound-based carotid plaque risk biomarkers to predict poor short-term functional outcome after ischemic stroke or TIA. Methods This study was a single-center, prospective, continuous, cohort study to observe the occurrence of adverse functional outcomes (mRS 2–6/3–6) 90 days after ischemic stroke or TIA in patients, where the exposure factors in this study were carotid plaque ultrasound risk biomarkers and the risk factors were sex, age, disease history, and medication history. Patients with ischemic stroke or TIA (mRS ≤3) whose ipsilateral internal carotid artery stenosis was ≥50% within 30 days were included. All patients underwent multimodal ultrasound at baseline, including conventional ultrasound, superb microvascular imaging (SMI), and shear wave elastography (SWE). Continuous variables were divided into four groups at interquartile spacing for inclusion in univariate and multifactorial analyses. After completion of a baseline ultrasound, all patients were followed up at 90 days after ultrasound, and patient modified neurological function scores (mRSs) were recorded. Multivariate Cox regression and ROC curves were used to assess the risk factors and predictive power for predicting poor neurological function. Results SMI revealed that 20 (30.8%) patients showed extensive neovascularization in the carotid plaque, and 45 (69.2%) patients showed limited neovascularization in the carotid plaque. SWE imaging showed that the mean carotid plaque stiffness was 51.49 ± 18.34 kPa (23.19–111.39 kPa). After a mean follow-up of 90 ± 14 days, a total of 21 (32.3%) patients had a mRS of 2–6, and a total of 10 (15.4%) patients had a mRS of 3–6. Cox regression analysis showed that the level of intraplaque neovascularization and plaque stiffness were independent risk factors for a mRS of 2–6, and the level of intraplaque neovascularization was an independent risk factor for a mRS of 3–6. After correcting for confounders, the HR of intraplaque neovascularization level and plaque stiffness predicting a mRS 2–6 was 3.06 (95% CI 1.05–12.59, P = 0.041) and 0.51 (95% CI 0.31–0.83, P = 0.007), respectively; the HR of intraplaque neovascularization level predicting a mRS 3–6 was 6.11 (95% CI 1.19–31.45, P = 0.031). For ROC curve analysis, the mRSs for intraplaque neovascularization level, plaque stiffness, and combined application to predict 90-day neurological outcome ranged from 2 to 6, with AUCs of 0.73 (95% CI 0.59–0.87), 0.76 (95% CI 0.64–0.89) and 0.85 (95% CI 0.76–0.95), respectively. The mRSs for the intraplaque neovascularization level to predict 90-day neurological outcome ranged from 3 to 6, with AUCs of 0.79 (95% CI 0.63–0.95). Conclusion Intraplaque neovascularization level and plaque stiffness may be associated with an increased risk of poor short-term functional outcome after stroke in patients with recent anterior circulation ischemic stroke due to carotid atherosclerosis. The combined application of multiple parameters has efficacy in predicting poor short-term functional outcome after stroke.

Abstract Background Parkinson’s disease (PD) is a neurodegenerative disease and is clinically characterized by a series of motor symptoms (MS) and nonmotor symptoms (NMS). NMS often appear before MS, while cognitive impairment mostly occurs within a few years after the diagnosis of PD. Therefore, we aimed to predict the risk factors for cognitive impairment (CI) in PD patients based on transcranial sonography, clinical symptoms, and demographic characteristics. Methods Based on the occurrence time of CI, a total of 172 PD patients were divided into non-CI (N-CI, n = 48), CI at the first treatment (F-CI, n = 58), and CI at the last treatment (L-CI, n = 66) groups. Clinical data (including MS and NMS) and ultrasonic data of all patients at the first treatment and the last treatment were collected retrospectively. Independent samples t tests were used to compare continuous data, and chi-square tests were used to compare categorical data. The risk factors for CI and Parkinson’s disease dementia were identified by logistic regression analysis, and an ROC curve was established to explore the diagnostic efficacy. Results 1) The age of onset, first treatment and smoking history of CI patients were significantly different from those of N-CI patients. When age of first treatment ≥61 years was considered the boundary value to diagnose CI, the sensitivity and specificity were 77.40 and 66.70%, respectively. 2) The severity of depression was significantly different between F-CI and N-CI patients at the first treatment, while the cumulative and new or aggravated memory deficit was significantly different between the L-CI and N-CI patients at the last treatment. 3) There was a significant difference in TCS grading between the first and last treatment in L-CI patients. 4) Depression, sexual dysfunction, and olfactory dysfunction in NMS were independent risk factors for CI during the last treatment. 5) The sensitivity and specificity of predicting CI in PD patients were 81.80 and 64.60%, respectively. Conclusions PD patients with CI were older, and most of them had a history of smoking. Furthermore, there was good diagnostic efficiency for predicting CI in PD via TCS combined with clinical characteristics (especially NMS).