Objective To explore the activity and mechanism of polymyxin B combined with novel β-lactam/β-lac-tamase inhibitor combinations on biofilm of polymyxin B-resistant Pseudomonas aeruginosa and Klebsiella pneumo-niae.Methods The minimum inhibitory concentration(MIC),minimum biofilm inhibitory concentration(MBIC),and minimum biofilm eradication concentration(MBEC)of all antimicrobial agents were determined by micro-broth dilution method and MBECTM assay.The crystal violet staining method was adopted to evaluate the effect of poly-myxin B combined with cefepime/avibactam,ceftazidime/avibactam,meropenem/avibactam,aztreonam/avibactam,meropenem/vaborbactam,and imipenem/relebactam at sub-MIC doses on inhibition of biofilm formation and eradi-cation of mature biofilm.The best combination scheme for anti-biofilm activity was screened out,and anti-biofilm mechanism of this combination scheme was preliminarily explored with phenol-sulfuric acid method,bacterial motili-ty test,and quorum sensing inhibition test.Results The MBIC and MBEC of all antimicrobial agents were higher than MIC.The combination regimen based on polymyxin B could inhibit the formation of biofilms and eradicate ma-ture biofilm in Pseudomonas aeruginosa and Klebsiella pneumoniae.The combination of polymyxin B with cefepime/avibactam had the highest inhibition and eradication rates,ranging 67.99％-90.16％and 58.26％-63.86％,respectively.The combination of polymyxin B and cefepime/avibactam could inhibit the extracellular poly-saccharides of Klebsiella pneumoniae,with inhibition rates of 34.04％-61.10％,this combination could also re-duce the swimming and twitching motility diameters of bacteria.Cefepime/avibactam monotherapy on quorum sen-sing signaling molecules presented concentration dependent inhibitory effect,and when combined with polymyxin B,the inhibitory effect was consistent with that of monotherapy.Conclusion Polymyxin B and cefepime/avibactam may be potential scheme for clinical treatment for severe biofilm-associated infection caused by polymyxin B-resistant strains,and their mechanisms may be related to the inhibition of bacterial extracellular polysaccharides and motility.

Diabetic retinopathy (DR) is a common complication of diabetes that can lead to visual impairment or even blindness. Current treatments mainly rely on invasive methods, which carry the risk of complications, making early intervention crucial. In recent years, research has revealed that the mechanical microenvironment of the retina plays a key role in the development and progression of DR, involving cell migration, functional disorders, and changes in the extracellular matrix. Mechanobiological mechanisms, such as mechanical signal transduction and the Hippo/Yes-associated protein pathway, are gradually being uncovered. Mechanical diagnostic and therapeutic strategies, including optical coherence elastography, tissue engineering, and intelligent diagnostic systems, offer new directions for DR management. In the future, further integration of biomechanics and mechanobiology research is needed to build multi-scale mechanical models and explore the synergistic regulation mechanisms between mechanical and biochemical factors, aiming to achieve precise and personalized diagnosis and treatment of DR and ultimately improve patients' visual outcomes.

Alternative splicing (AS) serves as a fundamental regulatory mechanism in gene expression, contributing to proteomic diversity by generating an array of mRNA isoforms from precursor mRNA via distinct splice site combinations. In light of the limited therapeutic options currently available, the exploration of AS as a target for drug development is of paramount importance. This review offers an exhaustive analysis of the biological functions and underlying molecular mechanisms associated with various AS-induced splice variants, RNA-binding proteins, and cis-elements, highlighting their significance as clinical biomarkers. We place particular emphasis on the current therapeutic applications of AS in an array of lung diseases, including but not limited to lung cancer, cystic fibrosis, silicosis, acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive pulmonary diseases, pulmonary arterial hypertension, and idiopathic pulmonary fibrosis. The review delves into the role of AS events in the diagnosis and treatment of lung diseases, focusing on the regulatory influence of splicing factors and RNA-binding proteins, while also enumerating the mutated components implicated in AS misregulation. Consequently, a comprehensive understanding of the intricate mechanisms governing these splicing events could potentially offer novel avenues for the development of splicing-targeted therapeutics and diagnostic tools for the prevention and treatment of lung diseases.

Objective To explore the activity and mechanism of polymyxin B combined with novel β-lactam/β-lac-tamase inhibitor combinations on biofilm of polymyxin B-resistant Pseudomonas aeruginosa and Klebsiella pneumo-niae.Methods The minimum inhibitory concentration(MIC),minimum biofilm inhibitory concentration(MBIC),and minimum biofilm eradication concentration(MBEC)of all antimicrobial agents were determined by micro-broth dilution method and MBECTM assay.The crystal violet staining method was adopted to evaluate the effect of poly-myxin B combined with cefepime/avibactam,ceftazidime/avibactam,meropenem/avibactam,aztreonam/avibactam,meropenem/vaborbactam,and imipenem/relebactam at sub-MIC doses on inhibition of biofilm formation and eradi-cation of mature biofilm.The best combination scheme for anti-biofilm activity was screened out,and anti-biofilm mechanism of this combination scheme was preliminarily explored with phenol-sulfuric acid method,bacterial motili-ty test,and quorum sensing inhibition test.Results The MBIC and MBEC of all antimicrobial agents were higher than MIC.The combination regimen based on polymyxin B could inhibit the formation of biofilms and eradicate ma-ture biofilm in Pseudomonas aeruginosa and Klebsiella pneumoniae.The combination of polymyxin B with cefepime/avibactam had the highest inhibition and eradication rates,ranging 67.99％-90.16％and 58.26％-63.86％,respectively.The combination of polymyxin B and cefepime/avibactam could inhibit the extracellular poly-saccharides of Klebsiella pneumoniae,with inhibition rates of 34.04％-61.10％,this combination could also re-duce the swimming and twitching motility diameters of bacteria.Cefepime/avibactam monotherapy on quorum sen-sing signaling molecules presented concentration dependent inhibitory effect,and when combined with polymyxin B,the inhibitory effect was consistent with that of monotherapy.Conclusion Polymyxin B and cefepime/avibactam may be potential scheme for clinical treatment for severe biofilm-associated infection caused by polymyxin B-resistant strains,and their mechanisms may be related to the inhibition of bacterial extracellular polysaccharides and motility.

Diabetic retinopathy (DR) is a common complication of diabetes that can lead to visual impairment or even blindness. Current treatments mainly rely on invasive methods, which carry the risk of complications, making early intervention crucial. In recent years, research has revealed that the mechanical microenvironment of the retina plays a key role in the development and progression of DR, involving cell migration, functional disorders, and changes in the extracellular matrix. Mechanobiological mechanisms, such as mechanical signal transduction and the Hippo/Yes-associated protein pathway, are gradually being uncovered. Mechanical diagnostic and therapeutic strategies, including optical coherence elastography, tissue engineering, and intelligent diagnostic systems, offer new directions for DR management. In the future, further integration of biomechanics and mechanobiology research is needed to build multi-scale mechanical models and explore the synergistic regulation mechanisms between mechanical and biochemical factors, aiming to achieve precise and personalized diagnosis and treatment of DR and ultimately improve patients' visual outcomes.

Objective:To investigate the role and mechanism of long non-coding RNA (lncRNA) gastric cancer associated transcript 3 (GACAT3) in glioma radioresistance.Methods:Real-time reverse transcription PCR (RT-qPCR) was used to detect the expression of lncRNA GACAT3 and miR-497 in human astrocyte NHA cells and glioma cells U251. NC-siRNA and GACAT3-siRNA were transfected into U251 cells, and the cells were treated with X-ray irradiation. Colony formation assay was used to detect the survival fraction of U251 cells. The apoptosis of U251 cells was detected by flow cytometry. Western blot was used to detect the expression of cysteine containing aspartate specific protease 3 (Caspase-3) in U251 cells. Bioinformatics software and dual luciferase reporter gene assay were used to predict and verify the targeting relationship between lncRNA GACAT3 and miR-497, and between miR-497 and Yes-associated protein 1 (YAP1), respectively. NC mimic, miR-497 mimic, GACAT3-siRNA and NC inhibitor, GACAT3-siRNA and miR-497 inhibitor were co-transfected into U251 cells. Colony formation assay, flow cytometry and Western blot were adopted to evaluate the effect of miR-497 overexpression and lncRNA GACAT3 on the radiosensitivity of U251 cells by regulating miR-497.Results:Compared with NHA cells, the expression of lncRNA GACAT3 in U251 cells was significantly up-regulated, and the expression of miR-497 in U251 cells was significantly down-regulated (both P<0.05). After knockdown of GACAT3, the survival fraction of irradiated U251 cells was significantly decreased, while the apoptosis rate and Caspase-3 protein expression were significantly increased (all P<0.05). lncRNA GACAT3 targeted and negatively regulated the expression of miR-497. Overexpression of miR-497 significantly reduced the survival fraction of U251 cells after irradiation, and increased the apoptosis rate and Caspase-3 protein expression. Inhibition of miR-497 significantly reversed the promoting effect of lncRNA GACAT3 knockdown on the radiosensitivity of U251 cells. miR-497 targeted and negatively regulated the expression of YAP1. Conclusion:Knockdown of lncRNA GACAT3 can enhance the radiosensitivity of glioma cells by regulating the miR-497/YAP1 axis.

AIM: To establish a method for quantitation of cefepime and avibactam in M-H broth, and applicated in the in vitro dynamic PK/PD model. METHODS: The cefepime was also determined using the high-performance liquid chromatography method (HPLC), the avibactam was also determined using the liquid chromatography-mass spectrometry (LC-MS/MS), an in vitro dynamic PK/PD model was established to study the PK/PD relationship of cefepime/avibactam against carbapenem resistant Klebsiella pneumoniae (CRKP). RESULTS: The linear ranges of cefepime and avibactam were good at (0.5-20) and (0.1-25) μg/mL (r=0.999), and the lower limit concentrations were 0.5 and 0.1 μg/mL. The extraction recoveries of cefepime and avibactam in M-H broth were 88.0%-101.7% and 90.9%-95.2%, the relative standard deviation of intra-day precision and inter-day precision were less than 5.2%. The concentration-time curves were well simulated by the PK/PD model. All observed concentrations in each experiment were in the range of 20% of the targeted values. For the CRKP of MIC=8 μg/mL and MIC=16 μg/mL, the colony decreased to 2.783Log10 CFU/mL and 1.325Log10 CFU/mL at the cefepime/avibactam 2.5 g q8 h administration after 24 h. CONCLUSION: The determination method of cefepime and avibactam in broth established in this study has high sensitivity and good stability. For the CRKP with MIC≤8 μg/mL,cefepime/avibactam showed that good anti-CRKP activity under routine administration in vitro dynamic PK/PD model.

【Objective】 To establish a three-in-one smart hospital characterized with smart service, smart medical care and smart management to improve the hospital’s ability to prevent and control and respond to coronavirus disease 2019 (COVID-19). 【Methods】 Combined with the core needs of normalized prevention and control of the epidemic, the overall structure of the smart hospital was established. Emerging technologies were used as the means to strengthen system integration and security as the basis, and the interconnection and electronic medical record project were the starting point to carry out 31 projects of information system construction and integration. 【Results】 Through the construction of smart service, a service mechanism that integrates online and offline services and covers the whole process of diagnosis and treatment has been realized. Through the construction of integrated physician workstations, smart nursing, medical quality control and other platforms with electronic medical records as the core, the clinical diagnosis and treatment capabilities have been improved. Through the improvement and optimization of the information system, the capacity of the hospital's emergency management of the epidemic has been effectively improved. 【Conclusion】 The construction of smart hospitals can provide a solid guarantee for the prevention and control of COVID-19, but it also faces many problems. The construction of smart service needs the strong support of the competent government departments, the integration of smart medical care needs to be further strengthened, and smart management needs to be further strengthened.

OBJECTIVE: To investigate the role of NDUFA13 inactivation in the pathogenesis of spontaneous hepatitis in mice and explore the possible mechanisms. METHODS: Hepatocyte-specific NDUFA13 knockout (NDUFA13 RESULTS: Liver-specific NDUFA13 heterozygous knockout mice were successfully constructed as verified by PCR results. HE staining revealed severe liver damage in both 4- week-old and 2-year-old NDUFA13 CONCLUSIONS Hepatocytes-specific NDUFA13 ablation can trigger spontaneous hepatitis in mice possibly mediated by the activation of ROS/NF-κB/NLRP3 signaling.
Animals ; Hepatitis ; Inflammasomes ; Mice ; NF-kappa B/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Signal Transduction

OBJECTIVE： To systematically evaluate the efficacy and safety of octreotide combined with conventional therapy in alleviating malignant bowel obstruction （MBO）， and provide evidence-based reference for clinical medication. METHODS： Retrieved from Cochrane Library， PubMed， Embase， CNKI， Wanfang database and Google academic， RCTs about octreotide combined with conventional therapy （trial group） vs. conventional therapy （control group） for relieving MBO were collected. After literature screening， data extraction and quality evaluation with Cochrane system evaluator manual 5.0 risk evaluation tool， Meta-analysis was conducted by using Rev Man 5.3 statistical software. RESULTS： A total of 13 items of RCT were included， with a total of 850 patients. Meta-analysis results showed that total response rate of trial group was significantly higher than control group [OR＝5.30，95％CI（3.47，8.10），P＜0.000 01]. Results of subgroup analysis showed that total response rate of single administration patients [OR＝6.88，95％CI（3.22，4.68），P＜0.000 01] and continuous administration patients [OR＝4.60， 95％CI（2.76，7.68）， P＜0.000 01] in trial group were significantly higher than control group. The abdominal distension relief time [MD＝－3.92， 95％CI（－4.15， －3.70）， P＜0.000 01]， abdominal pain relief time [MD＝－3.37， 95％CI（－3.61，－3.14）， P＜0.000 01]， nausea and vomiting relief time [MD＝－2.46， 95％CI（－2.81，－2.21）， P＜0.000 01] and exhaust relief time [MD＝－2.88， 95％CI（－3.31， －2.46）， P＜0.000 01] in trial group were significantly shorter than control group. Subgroup analysis of exhaust relief time showed that exhaust relief time of single administration patients [MD＝－2.90，95％CI（－3.48，－2.32），P＜0.000 01] and continuous administration patients [MD＝－2.71， 95％CI（－3.14，－2.29）， P＜0.000 01] in trial group were significantly shorter than control group. After treatment， the gastrointestinal decompression volume （P＜0.05） and the incidence of ADR [OR＝0.28，95％CI（0.13，0.62），P＝0.001] in trial group were significantly lower than in control group. CONCLUSIONS： Octreotide combined with conventional treatment is safe and effective in alleviating MBO.