Acarbose enhances the efficacy of immunotherapy against solid tumours by modulating the gut microbiota.

The crucial role of gut microbiota in shaping immunotherapy outcomes has prompted investigations into potential modulators. Here we show that oral administration of acarbose significantly increases the anti-tumour response to anti-PD-1 therapy in female tumour-bearing mice. Acarbose modulates the gut microbiota composition and tryptophan metabolism, thereby contributing to changes in chemokine expression and increased T cell infiltration within tumours. We identify CD8+ T cells as pivotal components determining the efficacy of the combined therapy. Further experiments reveal that acarbose promotes CD8+ T cell recruitment through the CXCL10-CXCR3 pathway. Faecal microbiota transplantation and gut microbiota depletion assays indicate that the effects of acarbose are dependent on the gut microbiota. Specifically, acarbose enhances the efficacy of anti-PD-1 therapy via the tryptophan catabolite indoleacetate, which promotes CXCL10 expression and thus facilitates CD8+ T cell recruitment, sensitizing tumours to anti-PD-1 therapy. The bacterial species Bifidobacterium infantis, which is enriched by acarbose, also improves response to anti-PD-1 therapy. Together, our study endorses the potential combination of acarbose and anti-PD-1 for cancer immunotherapy.

Effectiveness of foot skin protection technology in elderly patients with diabetic peripheral neuropathy.

Objective: The aim of this study is to assess the effectiveness of foot skin protection technology in elderly patients with diabetic peripheral neuropathy. Methods: The foot skin protection technology was developed based on a comprehensive literature review and preliminary research conducted by our research team. Subsequently, 88 elderly patients with diabetic peripheral neuropathy and experiencing foot skin problems were recruited from two community health service centers in Shanghai. Using a random number table, the participants were randomly assigned to either the control group or the experimental group. Patients in the experimental group received foot skin protection technology interventions, while those in the control group received standard community nursing guidance for a duration of 3 months. The incidence, severity, and discomfort associated with foot skin problems were evaluated before and after the intervention period in both groups. Results: The incidence, severity, and discomfort of foot skin problems notably reduced in the experimental group (all P< 0.05). Conclusion: The foot skin protection technology demonstrates significant potential in enhancing foot skin condition.

Molecular mechanisms of Buqing granule for the treatment of diabetic retinopathy: Network pharmacology analysis and experimental validation.

BACKGROUND: Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. Its blindness rate is high; therefore, finding a reasonable and safe treatment plan to prevent and control DR is crucial. Currently, there are abundant and diverse research results on the treatment of DR by Chinese medicine Traditional Chinese medicine compounds are potentially advantageous for DR prevention and treatment because of its safe and effective therapeutic effects. AIM: To investigate the effects of Buqing granule (BQKL) on DR and its mechanism from a systemic perspective and at the molecular level by combining network pharmacology and in vivo experiments. METHODS: This study collected information on the drug targets of BQKL and the therapeutic targets of DR for intersecting target gene analysis and protein-protein interactions (PPI), identified various biological pathways related to DR treatment by BQKL through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and preliminarily validated the screened core targets by molecular docking. Furthermore, we constructed a diabetic rat model with a high-fat and high-sugar diet and intraperitoneal streptozotocin injection, and administered the appropriate drugs for 12 weeks after the model was successfully induced. Body mass and fasting blood glucose and lipid levels were measured, and pathological changes in retinal tissue were detected by hematoxylin and eosin staining. ELISA was used to detect the oxidative stress index expression in serum and retinal tissue, and immunohistochemistry, real-time quantitative reverse transcription PCR, and western blotting were used to verify the changes in the expression of core targets. RESULTS: Six potential therapeutic targets of BQKL for DR treatment, including Caspase-3, c-Jun, TP53, AKT1, MAPK1, and MAPK3, were screened using PPI. Enrichment analysis indicated that the MAPK signaling pathway might be the core target pathway of BQKL in DR treatment. Molecular docking prediction indicated that BQKL stably bound to these core targets. In vivo experiments have shown that compared with those in the Control group, rats in the Model group had statistically significant (P < 0.05) severe retinal histopathological damage; elevated blood glucose, lipid, and malondialdehyde (MDA) levels; increased Caspase-3, c-Jun, and TP53 protein expression; and reduced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, ganglion cell number, AKT1, MAPK1, and MAPK3 protein expression. Compared with the Model group, BQKL group had reduced histopathological retinal damage and the expression of blood glucose and lipids, MDA level, Caspase-3, c-Jun and TP53 proteins were reduced, while the expression of SOD, GSH-Px level, the number of ganglion cells, AKT1, MAPK1, and MAPK3 proteins were elevated. These differences were statistically significant (P < 0.05). CONCLUSION: BQKL can delay DR onset and progression by attenuating oxidative stress and inflammatory responses and regulating Caspase-3, c-Jun, TP53, AKT1, MAPK1, and MAPK3 proteins in the MAPK signaling pathway mediates these alterations.

Remifentanil vs. dexmedetomidine for cardiac surgery patients with noninvasive ventilation intolerance: a multicenter randomized controlled trial.

BACKGROUND: The optimal sedative regime for noninvasive ventilation (NIV) intolerance remains uncertain. The present study aimed to assess the efficacy and safety of remifentanil (REM) compared to dexmedetomidine (DEX) in cardiac surgery patients with moderate-to-severe intolerance to NIV. METHODS: In this multicenter, prospective, single-blind, randomized controlled study, adult cardiac surgery patients with moderate-to-severe intolerance to NIV were enrolled and randomly assigned to be treated with either REM or DEX for sedation. The status of NIV intolerance was evaluated using a four-point NIV intolerance score at different timepoints within a 72-h period. The primary outcome was the mitigation rate of NIV intolerance following sedation. RESULTS: A total of 179 patients were enrolled, with 89 assigned to the REM group and 90 to the DEX group. Baseline characteristics were comparable between the two groups, including NIV intolerance score [3, interquartile range (IQR) 3-3 vs. 3, IQR 3-4, p = 0.180]. The chi-squared test showed that mitigation rate, defined as the proportion of patients who were relieved from their initial intolerance status, was not significant at most timepoints, except for the 15-min timepoint (42% vs. 20%, p = 0.002). However, after considering the time factor, generalized estimating equations showed that the difference was statistically significant, and REM outperformed DEX (odds ratio = 3.31, 95% confidence interval: 1.35-8.12, p = 0.009). Adverse effects, which were not reported in the REM group, were encountered by nine patients in the DEX group, with three instances of bradycardia and six cases of severe hypotension. Secondary outcomes, including NIV failure (5.6% vs. 7.8%, p = 0.564), tracheostomy (1.12% vs. 0%, p = 0.313), ICU LOS (7.7 days, IQR 5.8-12 days vs. 7.0 days, IQR 5-10.6 days, p = 0.219), and in-hospital mortality (1.12% vs. 2.22%, p = 0.567), demonstrated comparability between the two groups. CONCLUSIONS: In summary, our study demonstrated no significant difference between REM and DEX in the percentage of patients who achieved mitigation among cardiac surgery patients with moderate-to-severe NIV intolerance. However, after considering the time factor, REM was significantly superior to DEX. Trial registration ClinicalTrials.gov (NCT04734418), registered on January 22, 2021. URL of the trial registry record: https://register. CLINICALTRIALS: gov/prs/app/action/SelectProtocol?sid=S000AM4S&selectaction=Edit&uid=U00038YX&ts=3&cx=eqn1z0 .

A pilot study of microRNAs expression profile in plasma of patients with hydatid disease: potential immunomodulation of hydatid disease.

Echinococcosis is a zoonotic disease, which seriously endangers human health. The immune game between parasite and host is not fully understood. Exosomes are thought to be one of the ways of information communication between parasite and host. In this study, we attempted to explore the communication between Echinococcus granulosus and its host through the medium of exosomes. We collected plasma from E. granulosus patients (CE-EXO) and healthy donors (HD-EXO) and extracted exosomes from the plasma. The expression profile of miRNA in plasma was determined by second generation sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to annotate the function of target genes of differential miRNAs. Meanwhile, we co-cultured plasma exosomes from healthy donors and plasma exosomes from E. granulosus patients with Jurkat T cells with or without phytohaemagglutinin (PHA) stimulation. The expression of CD69 on Jurkat T cells was detected by flow cytometry. The results showed that the miRNA of exosomes between healthy donors and E. granulosus patients was significantly different. GO and KEGG were used to annotate the function of target genes of differential miRNAs. The results indicate that many important pathways are involved in inflammation, metabolism, and immune response after parasite infection, such as p53 signaling pathway, PI3K-Akt signaling pathway, and glycolysis/gluconeogenesis. Flow cytometry showed that CE-EXO reduced the expression of CD69 + on Jurkat T cells. Our present results suggest that these differentially expressed miRNAs may be important regulators of parasite-host interactions. Meanwhile, functional prediction of its target genes provides valuable information for understanding the mechanism of host-parasite interactions. These results provide clues for future studies on E. granulosus escape from host immune attack, which could help control E. granulosus infection.

Transarterial Embolization Enhances Programmed Cell Death Ligand 1 Expression and Influences CD8+T Lymphocytes Cytotoxicity in an Orthotopic Hepatocellular Carcinoma Rat Model.

PURPOSE: To investigate the influence of transarterial embolization (TAE) on programmed cell death-ligand 1(PD-L1) expression and CD8+T tumour infiltrative lymphocyte cytotoxicity in the Sprague-Dawley (SD) rat model of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: An orthotopic HCC model was established in twenty SD rats treated with TAE (lipiodol, n = 10) or sham (normal saline, n = 10) using homologous N1S1 hepatoma cells. Rats were euthanized 1 week after embolization. Flow cytometry was used to assess the proportion of CD4+T, CD8+T and programmed cell death-1+(PD-1+) CD8+T lymphocytes in the spleens and tumours. Distribution of CD8+T, granzyme-B+CD8+T lymphocytes and PD-L1+ cells was assessed by immunohistochemistry (IHC) or multiplex IHC. p value < 0.05 was considered statistically significant. RESULTS: The CD4/CD8 ratio and PD-1+CD8+ T lymphocytes exhibited higher values in TAE-treated tumours compared to sham-treated tumours (p = 0.021 and p = 0.071, respectively). Conversely, the number of CD8+T lymphocytes was decreased in TAE-treated tumours (p = 0.043), especially in the central region (p = 0.045). However, more CD8+T lymphocytes were found infiltrating the marginal region than central region in TAE-treated tumours (p = 0.046). The proportion of granzyme-B+CD8+T lymphocytes and the PD-L1 positive areas was elevated in tumours that treated with TAE (p all < 0.05). There was a negative correlation between PD-L1 expression and the number of infiltration of CD8+ T lymphocytes (p = 0.036). CONCLUSIONS: Immune cells are distributed unevenly in the tumours after TAE. The intrinsic induction state of the tumour after embolization may be insufficient to elicit a maximal response to PD-1/PD-L1 inhibitors.

Binding characterization of odorant-binding protein BhorOBP29 in Batocera horsfieldi (Hope) with host-plant volatiles.

Odorant binding proteins (OBPs) are involved in odorant discrimination and act as the first filter in the peripheral olfactory system. Previous studies have shown that BhorOBP29 is potentially involved in olfactory perception in an important wood-boring pest Batocera horsfieldi (Hope) (Coleoptera: Cerambycidae), however, its function remains unclear. Here, we investigated the ligand-binding profiles of recombinant BhorOBP29 with 22 compounds from its host plant using fluorescence competitive binding assays and fluorescence quenching assays. The results showed that BhorOBP29 could bind to five ligands relying mainly on hydrophobic interactions. Molecular docking analysis indicated that residues Ile48, Leu51, Met52, Trp57, Asn105, and Val119 were extensively involved in the interactions between BhorOBP29 and the five ligands. Furthermore, the site-directed mutagenesis analysis revealed that Leu51 and Met52 residues were indispensable for BhorOBP29-ligands binding. Finally, electroantennogram (EAG) assays confirmed that hexanal, (-)-limonene, and 2-methylbutyraldehyde elicited a concentration-dependent EAG response with a maximum at the concentration of 1/10 v/v. These findings suggest that BhorOBP29 may play a significant role in the perception of host plant volatiles by B. horsfieldi. This study may help to discover novel behavioral regulation and environmentally friendly strategies for controlling B. horsfieldi in the future.

On optimal charging scheduling for electric vehicles with wind power generation.

We consider the scheduling of battery charging of electric vehicles (EVs) integrated with renewable power generation. The increasing adoption of EVs and the development of renewable energies contribute importance to this research. The optimization of charging scheduling is challenging because of the large action space, the multi-stage decision making, and the high uncertainty. To solve this problem is time-consuming when the scale of the system is large. It is urgent to develop a practical and efficient method to properly schedule the charging of EVs. The contribution of this work is threefold. First, we provide a sufficient condition on which the charging of EVs can be completely self-sustained by distributed generation. An algorithm is proposed to obtain the optimal charging policy when the sufficient condition holds. Second, the scenario when the supply of the renewable power generation is deficient is investigated. We prove that when the renewable generation is deterministic there exists an optimal policy which follows the modified least laxity and longer remaining processing time first (mLLLP) rule. Third, we provide an adaptive rule-based algorithm which obtains a near-optimal charging policy efficiently in general situations. We test the proposed algorithm by numerical experiments. The results show that it performs better than the other existing rule-based methods.

Identification of novel Tet(X6)-Tet(X2) recombinant variant in Elizabethkingia meningoseptica from a bullfrog farm and downstream river in China.

Introduction: The dissemination of strains producing tetracyclines monooxygenase Tet(X) from breeding farms to the natural environment poses a potential threat to public health. Methods: Antimicrobial susceptibility testing and WGS were performed to identify resistance phenotypes and genotypes. Cloning experiments, sequence alignment, and homology modeling were used to characterize the function and formation mechanisms of the recombinant variant. The mobilization potential of Tet(X) was assessed by collinearity analysis, conjugation experiments, and phylogenetic analysis. Results: Three tet(X)-producing Elizabethkingia meningoseptica strains were isolated from bullfrog breeding ponds, the sewage outlet, and downstream river in Zhejiang Province, China. These strains carry a novel Tet(X) variant, differing from Tet(X6) by seven residues, and possess the ability to degrade tetracyclines. Interestingly, the novel Tet(X) is a recombinant variant formed by homologous recombination of Tet(X6) and the C-terminal of Tet(X2). Further analysis revealed that Tet(X6) formed several Tet(X) variants, including Tet(X5), through homologous recombination. The novel tet(X) gene is located on a circularizable integrative and conjugative element (ICEEmeChn3), with ISwz1 participating in the recombination of its multi-drug resistance region, potentially facilitating the mobilization and recombination of tet(X) in early hosts. These three strains were clonally transmitted and shared a close genetic relationship (SNP < 62) with a clinically-sourced strain isolated from the same province. Discussion: To our knowledge, this is the first report of homologous recombination between Tet(X) variants with differing activities. These clonal strains provide evidence of the transmission of tet(X)-positive strains from aquaculture sewage to the natural environment, highlighting the need to strengthen the monitoring and management of this emerging farming model.

Shear Mechanism of a Novel SFCBs-Reinforced Composite Shear Connector: Experimental, Theoretical Investigations and Numerical Model.

Traditional stud and perfobond leiste (PBL) shear connectors are commonly used as load-transferring components in steel-concrete composite structures. Composite shear connectors fully utilize the advantages of traditional stud and PBL shear connectors. In order to maximize the advantages of composite shear connectors, a novel shear connector for complex environments was proposed. The steel-FRP composite bars (SFCBs) with excellent fatigue resistance and corrosion resistance were introduced to replace the steel bars. This study discussed the failure modes, load-slip curves, and load-strain curves of the composite shear connector. In addition, a finite element analysis (FEA) model was developed to analyze the influence of various factors on its shear behavior. Results showed that compared with traditional composite shear connectors, the introduction of SFCB resulted in a promotion of 7.85% in shear stiffness, and it also led to a significant increase of 63.61% in ductility, further enhancing the mechanical performance. Meanwhile, FEA models were well fitted to the test results, and parametric analysis showed variate effects on shear bearing capacity. In the end, an equation was established to calculate the shear capacity of composite shear connectors, which could provide a reference for further research and engineering applications.