Establishment of a Mouse Model of Mycoplasma pneumoniae-Induced Plastic Bronchitis.

Plastic bronchitis (PB) constitutes a life-threatening pulmonary disorder, predominantly attributed to Mycoplasma pneumoniae (MP) infection. The pathogenic mechanisms involved remain largely unexplored, leading to the absence of reliable approaches for early diagnosis and clear treatment. Thus, the present investigation aimed to develop an MP-induced mouse model of PB, thereby enhancing our understanding of this complex condition. In the first stage, healthy BALB/c mice were utilized to investigate the optimal methods for establishing PB. This involved the application of nebulization (15-20 min) and intratracheal administration (6-50 µL) with 2-chloroethyl ethyl sulfide (CEES) concentrations ranging from 4.5% to 7.5%. Subsequently, the MP model was induced by administering an MP solution (2 mL/kg/day, 108 CFU/50 µL) via the intranasal route for a duration of five consecutive days. Ultimately, suitable techniques were employed to induce plastic bronchitis in the MP model. Pathological changes in lung tissue were analyzed, and immunohistochemistry was employed to ascertain the expression levels of vascular endothelial growth factor receptor 3 (VEGFR-3) and the PI3K/AKT/mTOR signaling pathway. The administration of 4.5% CEES via a 6 µL trachea was the optimal approach to establishing a PB model. This method primarily induced neutrophilic inflammation and fibrinous exudate. The MP-infected group manifested symptoms indicative of respiratory infection, including erect hair, oral and nasal secretions, and a decrease in body weight. Furthermore, the pathological score of the MP+CEES group surpassed that of the groups treated with MP or CEES independently. Notably, the MP+CEES group demonstrated significant activation of the VEGFR-3 and PI3K/AKT/mTOR signaling pathways, implying a substantial involvement of lymphatic vessel impairment in this pathology. This study successfully established a mouse model of PB induced by MP using a two-step method. Lymphatic vessel impairment is a pivotal element in the pathogenetic mechanisms underlying this disease entity. This accomplishment will aid in further research into treatment methods for patients with PB caused by MP.

Bioorthogonal Cu Single-Atom Nanozyme for Synergistic Nanocatalytic Therapy, Photothermal Therapy, Cuproptosis and Immunotherapy.

Single-atom nanozymes (SAzymes) with atomically dispersed active sites are potential substitutes for natural enzymes. A systematic study of its multiple functions can in-depth understand SAzymes's nature, which remains elusive. Here, we develop a novel ultrafast synthesis of sputtered SAzymes by in situ bombarding-embedding technique. Using this method, sputtered copper (Cu) SAzymes (CuSA) is developed with unreported unique planar Cu-C3 coordinated configuration. To enhance the tumor-specific targeting, we employ a bioorthogonal approach to engineer CuSA, denoted as CuSACO. CuSACO not only exhibits minimal off-target toxicity but also possesses exceptional ultrahigh catalase-, oxidase-, peroxidase-like multienzyme activities, resulting in reactive oxygen species (ROS) storm generation for effective tumor destruction. Surprisingly, CuSACO can release Cu ions in the presence of glutathione (GSH) to induce cuproptosis, enhancing the tumor treatment efficacy. Notably, CuSACO's remarkable photothermal properties enables precise photothermal therapy (PTT) on tumors. This, combined with nanozyme catalytic activities, cuproptosis and immunotherapy, efficiently inhibiting the growth of orthotopic breast tumors and gliomas, and lung metastasis. Our research highlights the potential of CuSACO as an innovative strategy to utilize multiple mechanism to enhance tumor therapeutic efficacy, broadening the exploration and development of enzyme-like behavior and physiological mechanism of action of SAzymes.

TET2 Is Downregulated in Early Esophageal Squamous Cell Carcinoma and Promotes Esophageal Squamous Cell Malignant Behaviors.

OBJECTIVE: To explore the expression of the ten eleven translocation (TET) 2 protein in early esophageal squamous cell carcinoma (EESCC), precancerous lesions, and cell lines and to evaluate the effect of TET2 on the functional behavior of EC109 esophageal cancer cells. METHODS: Thirty-one samples of EESCC and precancerous lesions collected via endoscopic submucosal dissection at Taihe Hospital, Shiyan, from February 1, 2017, to February 1, 2019, were analyzed. The study involved evaluating TET2 expression levels in lesion tissue and adjacent normal epithelium, correlating these with clinical pathological features. Techniques including 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide, cell scratch assays, flow cytometry for propidium iodide (PI) staining, Hoechst 333258/PI double staining, and nude mouse tumorigenesis experiments were employed to assess the effect of TET2 on the proliferation, migration, cell cycle, apoptosis, and tumorigenic ability of esophageal cancer cells. RESULTS: TET2 expression was notably reduced in early esophageal cancer tissue and correlated with tumor invasion depth (P < 0.05). Overexpression of TET2 enhanced the proliferation and migration of esophageal cancer cells, increased the cell population in the G0 phase, decreased it in the S phase, and intensified cell necrosis (P < 0.05). There was a partial increase in tumorigenic ability (P = 0.087). CONCLUSION: TET2 downregulation in ESCC potentially influences the necrosis, cell cycle, and tumorigenic ability of esophageal cancer cells, suggesting a role in the onset and progression of esophageal cancer.

Frequency compensated diffusion model for real-scene dehazing.

Due to distribution shift, deep learning based methods for image dehazing suffer from performance degradation when applied to real-world hazy images. In this paper, this study considers a dehazing framework based on conditional diffusion models for improved generalization to real haze. First, our work finds that optimizing the training objective of diffusion models, i.e., Gaussian noise vectors, is non-trivial. The spectral bias of deep networks hinders the higher frequency modes in Gaussian vectors from being learned and hence impairs the reconstruction of image details. To tackle this issue, this study designs a network unit, named Frequency Compensation block (FCB), with a bank of filters that jointly emphasize the mid-to-high frequencies of an input signal. Our work demonstrates that diffusion models with FCB achieve significant gains in both perceptual and distortion metrics. Second, to further boost the generalization performance, this study proposed a novel data synthesis pipeline, HazeAug, to augment haze in terms of degree and diversity. Within the framework, a solid baseline for blind dehazing is set up where models are trained on synthetic hazy-clean pairs, and directly generalize to real data. Extensive evaluations on real dehazing datasets demonstrate the superior performance of the proposed dehazing diffusion model in distortion metrics. Compared to recent methods pre-trained on large-scale, high-quality image datasets, our model achieves a significant PSNR improvement of over 1 dB on challenging databases such as Dense-Haze and Nh-Haze.

Development and validation of a model integrating clinical and coronary lesion-based functional assessment for long-term risk prediction in PCI patients.

OBJECTIVES: To establish a scoring system combining the ACEF score and the quantitative blood flow ratio (QFR) to improve the long-term risk prediction of patients undergoing percutaneous coronary intervention (PCI). METHODS: In this population-based cohort study, a total of 46 features, including patient clinical and coronary lesion characteristics, were assessed for analysis through machine learning models. The ACEF-QFR scoring system was developed using 1263 consecutive cases of CAD patients after PCI in PANDA III trial database. The newly developed score was then validated on the other remaining 542 patients in the cohort. RESULTS: In both the Random Forest Model and the DeepSurv Model, age, renal function (creatinine), cardiac function (LVEF) and post-PCI coronary physiological index (QFR) were identified and confirmed to be significant predictive factors for 2-year adverse cardiac events. The ACEF-QFR score was constructed based on the developmental dataset and computed as age (years)/EF (%) + 1 (if creatinine ≥ 2.0 mg/dL) + 1 (if post-PCI QFR ≤ 0.92). The performance of the ACEF-QFR scoring system was preliminarily evaluated in the developmental dataset, and then further explored in the validation dataset. The ACEF-QFR score showed superior discrimination (C-statistic = 0.651; 95% CI: 0.611-0.691, P < 0.05 versus post-PCI physiological index and other commonly used risk scores) and excellent calibration (Hosmer-Lemeshow χ2 = 7.070; P = 0.529) for predicting 2-year patient-oriented composite endpoint (POCE). The good prognostic value of the ACEF-QFR score was further validated by multivariable Cox regression and Kaplan-Meier analysis (adjusted HR = 1.89; 95% CI: 1.18-3.04; log-rank P < 0.01) after stratified the patients into high-risk group and low-risk group. CONCLUSIONS: An improved scoring system combining clinical and coronary lesion-based functional variables (ACEF-QFR) was developed, and its ability for prognostic prediction in patients with PCI was further validated to be significantly better than the post-PCI physiological index and other commonly used risk scores.

Efficacy and Safety of Nirmatrelvir/Ritonavir in Severe Hospitalized Patients with COVID-19 and in Patients at High Risk for Progression to Critical Illness: A Real-World Study.

Background: Nirmatrelvir/Ritonavir is an orally administered anti-SARS-Cov-2 drug used in mild-to-moderate COVID-19 patients. Our retrospective cohort study aims to evaluate the efficacy and safety of Nirmatrelvir/Ritonavir in severe hospitalized patients with Omicron infection, as well as in patients at high risk for progression to critical illness in real-world settings. Methods: A total of 350 patients received Nirmatrelvir/Ritonavir while 350 matched controls did not. Patients with confirmed COVID-19 were administered Nirmatrelvir 300 mg and Ritonavir 100 mg orally twice a day for 5 days, with the medication initiated on the first day after admission. The primary endpoint of the study was a composite outcome of hospitalization or death from any cause within 28 days. Secondary endpoints included the occurrence of adverse events and the evaluation of serum levels of IL-6 and viral load. Results: We documented the mortality risk from any cause within 28 days, viral load, serum IL-6 levels, and adverse events. Nirmatrelvir/Ritonavir reduced the 28-day risk of all-cause mortality by 86% (P = .011, hazard ratio (HR) = 0.14, 95% confidence interval (CI) = 0.03, 0.64). At baseline, the serum level of IL-6 was significantly higher in the antiviral treatment group compared to the control group (P < .001), but no significant difference (P = .990) was found between the two groups at discharge. In CKD patients undergoing hemodialysis, no significant worsening of renal function was observed in the Nirmatrelvir/Ritonavir treatment group compared to the control group. Conclusion: Nirmatrelvir/Ritonavir may reduce the 28-day risk of all-cause mortality in critically ill patients with COVID-19 and in patients at high risk for critical disease progression.

Identification of peanut skin components for treating hepatocellular carcinoma via network pharmacology and in vitro experiments.

Peanut skin (PS) contains various flavonoids and phenols that have antitumor and antioxidant effects. However, no research has been conducted on PS and hepatocellular carcinoma (HCC). Therefore, this study sought to explore the potential mechanism of PS in treating HCC. PS was searched for in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and SYMMAP databases. HCC targets were searched for in five major databases. Protein-protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses were performed. Molecular docking and molecular dynamics simulation were used for verification. Furthermore, in vitro experiments were used to verify the regulation of PS on human HCC (HepG2) cells. Ten ingredients and 95 common targets were identified for PS and HCC, respectively. The key targets of ingredients mainly relate to pathways such as hepatitis B, lipid and atherosclerosis, advanced glycation end products (AGEs)-AGE receptors (RAGEs) signaling pathway in diabetic complications, interleukin-17 (IL-17) signaling pathway, mitogen activated kinase-like protein (MAPK) signaling pathway, the PI3K-Akt signaling pathway. In addition, the molecular docking and molecular dynamics simulation analysis indicated the ingredients had strong binding ability with the targets. Moreover, in vitro experiments confirmed that luteolin can promote the apoptosis of HepG2 cells by controlling the expression of phosphorylated protein-tyrosine kinase (p-AKT). This study provides preliminary evidence that PS produces a marked effect in regulating multiple signaling pathways in HCC through multiple ingredients acting on multiple core genes, including AKT serine/threonine kinase 1 (AKT1), MYC, caspase 3 (CASP3), estrogen receptor 1 (ESR1), epidermal growth factor receptor (EGFR), jun proto-oncogene(JUN), and provides the basis for follow-up research to verify the mechanism of action of PS in treating HCC.

Plasma TNF-α and phosphorylated α-syn are associated with fatigue in patients with Parkinson's disease.

BACKGROUD: Fatigue is one of the most common non-motor symptoms among patients with Parkinson's disease (PD).However, the pathogenesis keeps largely unknown. Moreover, it is lack of objective biomarker. OBJECTIVE: To investigate the relationship between plasma inflammatory cytokines and α-syn levels and fatigue in patients with PD. METHODS: A total of 63 PD patients were enrolled, including 35 patients with fatigue and 28 patients without fatigue. We compared the difference between plasma cytokines and alpha-synuclein (α-syn) in the two groups. Meanwhile, we analyzed the relationship between plasma cytokines and p-α-syn levels and fatigue. RESULTS: PD patients with fatigue had older age, longer disease duration, more severe motor scores. There were significant differences in the plasma levels of IL-1ß, IL-18, TNF-α, and phosphorylated α-syn (p-α-syn) between the two groups. The plasm inflammatory cytokine levels (IL-1ß, IL-18 and TNF-α) were positively associated with FSS scores. Moreover, the plasma p-α-syn level was significantly positively correlated with FSS scores. Furthermore, the higher PDQ-39 scores and higher plasma levels of TNF-α and p-α-syn were strongly associated with fatigue in PD. The ROC curve analysis showed the AUC of TNF-α for fatigue in PD was 0.663 with a sensitivity of 65.71% and specificity of 67.86%, while the AUC of p-α-syn was 0.786 with a sensitivity of 74.29% and specificity of 64.29%. The combination of TNF-α and p-α-syn improves the AUC to 0.803 with a sensitivity of 88.57% and specificity of 64.29%. CONCLUSION: The high plasma levels of TNF-α and p-α-syn were strongly associated with fatigue in PD.

Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease with substantial mitochondrial and metabolic dysfunctions. SBMA is caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Activating or increasing the NAD+-dependent deacetylase, SIRT3, reduced oxidative stress and death of cells modeling SBMA. However, increasing diminished SIRT3 in AR100Q mice failed to reduce acetylation of the SIRT3 target/antioxidant, SOD2, and had no effect on increased total acetylated peptides in quadriceps. Yet, overexpressing SIRT3 resulted in a trend of motor recovery, and corrected TCA cycle activity by decreasing acetylation of SIRT3 target proteins. We sought to boost blunted SIRT3 activity by replenishing diminished NAD+ with PARP inhibition. Although NAD+ was not affected, overexpressing SIRT3 with PARP inhibition fully restored hexokinase activity, correcting the glycolytic pathway in AR100Q quadriceps, and rescued motor endurance of SBMA mice. These data demonstrate that targeting metabolic anomalies can restore motor function downstream of polyQ-expanded AR.

The Effect of Nozzle Temperature on the Low-Temperature Printing Performance of Low-Viscosity Food Ink.

Low-temperature food printing technology is used in many fields, such as personalized nutrition, cooking art, food design and medical nutrition. By precisely controlling the deposition temperature of the ink, a food with a finer and more controllable structure can be produced. This paper investigates the influence of nozzle temperature on printing performance via a numerical simulation and experimental research. The results indicate that the ink gradually changed from a granular state to a fLow-characteristic deposition structure when the nozzle temperature increased from 19 °C to 27 °C. When the nozzle temperature exceeded 21 °C, the ink demonstrated excellent extrusion behavior and tended to flow. The widths of the rectangular frame deposition showed no obvious changes and were 4.07 mm, 4.05 mm and 4.20 mm, respectively. The extrusion behavior of the ink showed a structural mutation in the temperature range of 19-21 °C. Its line width changed from 3.15 mm to 3.73 mm, and its deposition structure changed from a grainy shape to a normal shape. Under the influence of different environmental control capabilities, bulk structure deposition demonstrates an ideal printing performance at 21, 23 and 25 °C, and the latter temperature is more suitable in the case of large external interference. The ink flowed violently when the nozzle temperature reached 27 °C, at which point the deposit structure flowed and deformed seriously. On the other hand, evaporation losses had a strong effect on Low-viscosity ink. To reach the full potential of this promising technology, it is necessary to determine the effect of nozzle temperature on printing performance. This article provides a method for developing and applying Low-viscosity, Low-temperature food printing.

A Study of the Gelatin Low-Temperature Deposition Manufacturing Forming Process Based on Fluid Numerical Simulation.

Low-temperature deposition manufacturing has attracted much attention as a novel printing method, bringing new opportunities and directions for the development of biological 3D printing and complex-shaped food printing. In this article, we investigated the rheological and printing properties of gelatin solution and conducted numerical simulation and experimental research on the low-temperature extrusion process of gelatin solution. The velocity, local shear rate, viscosity, and pressure distribution of the material in the extrusion process were calculated using Comsol software. The effects of the initial temperature, inlet velocity, and print head diameter of the material on the flow field distribution and printing quality were explored. The results show that: (1) the fluidity and mechanical properties of gelatin solution vary with its concentration; (2) the initial temperature of material, inlet velocity, and print head diameter all have varying degrees of influence on the distribution of the flow field; (3) the concentration change of the material mainly affects the pressure distribution in the flow channel; (4) the greater the inlet velocity, the greater the velocity and shear rate in the flow field and the higher the temperature of the material in the outlet section; and (5) the higher the initial temperature of the gel, the lower the viscosity in the flow field. This article is of great reference value for the low-temperature 3D printing of colloidal materials that are difficult to form at room temperature.

Impact of plaque and luminal morphology in balloon angioplasty of the femoropopliteal artery: an intravascular ultrasound analysis.

Objective: To assess the effect of plaque and luminal morphologies in balloon angioplasty of femoropopliteal lesions using intravascular ultrasound (IVUS). Methods: This retrospective, observational study analyzed 836 cross-sectional images using IVUS, from 35 femoropopliteal arteries of patients who underwent endovascular treatment between September 2020 and February 2022. Pre- and post-balloon angioplasty images were matched per 5 mm. Post-balloon angioplasty images were grouped into successful (n = 345) and unsuccessful (n = 491) groups. Plaque and luminal morphologies (such as severity of calcification, vascular remodeling, and plaque eccentricity) were extracted before the balloon angioplasty procedure to identify the predictors of unsuccessful balloon angioplasty. Additionally, 103 images with severe dissection were analyzed using IVUS and angiography. Results: In univariate analyses, the predictive factors for unsuccessful balloon angioplasty were vascular remodeling (p < .001), plaque burden (p < .001), lumen eccentricity (p < .001), and balloon/vessel ratio (p = .01). Predictive factors for severe dissections were the guidewire route (p < .001) and balloon/vessel ratio (p = .04). In multivariate analysis, the predictive factors for unsuccessful balloon angioplasty included lumen eccentricity (odds ratio [OR]: 3.99, 95% confidence interval [CI]: 1.28-12.68, p = .02) and plaque burden (OR: 1.03, 95% CI: 1.02-1.04; p < .001). For severe dissections, the independent risk factor was an eccentric guidewire route (OR: 2.10, 95% CI: 1.22-3.65, p = .01). Conclusion: High plaque burden and luminal eccentricity were risk factors for failed femoropopliteal artery balloon angioplasty. Additionally, eccentric guidewire routes predicted severe dissection.

Comparison of angiography and ultrasound for femoropopliteal angioplasty: decision-making and 12-month outcomes.

BACKGROUND: This study aimed to investigate whether intravascular ultrasound (IVUS) combined with angiography during percutaneous transluminal angioplasty impacts treatment strategies and the 12-month patency of the femoropopliteal artery, compared to angiography alone. METHODS: This retrospective, single-center study enrolled 137 patients who underwent a femoropopliteal endovascular intervention between February 2020 and May 2021. Among these interventions, 43 were guided by IVUS combined with angiography and the remaining 94 were guided by angiography only. Treatment strategies and 12-month patency were analyzed in both groups. Multivariable analysis was performed to clarify the predictors of restenosis within 12 months. RESULTS: Primary patency at 12 months was significantly higher in the IVUS group than in the angiography group (56.4% vs. 76.7%, P=0.047). The reference diameter on IVUS images was greater than that on angiography images. Therefore, the IVUS group presented a higher balloon-to-vessel ratio [1.0 (0.97, 1.01) vs. 1.06 (1.0.1.25)]. More adjunctive stents were required in the angiography group. However, more dissections were performed in the IVUS group, with no difference in flow-limiting dissections between groups. Target disease length (odds ratio 1.02, P=0.021) and balloon-to-vessel ratio (odds ratio 0.01, P=0.021) were independent predictors of restenosis. CONCLUSIONS: Compared with angiography guidance alone, IVUS guidance for femoropopliteal artery-related treatment can significantly increase primary patency. This finding may be explained by the selection of larger balloons in IVUS and the resulting sufficient plaque compression and elastic membrane stretch. Moreover, IVUS was shown to detect more non-flow-limiting dissections than angiography.

Baicalin enhances the efficacy of 5-Fluorouracil in gastric cancer by promoting ROS-mediated ferroptosis.

BACKGROUND: 5-Fluorouracil (5-Fu) is one of the most commonly used chemotherapy drugs for gastric cancer (GC). But the increase of drug resistance makes the prognosis of patients worse. Studies have shown that Baicalin can not only inhibit various cancers but also increase the sensitivity of cancers to chemotherapy. However, how Baicalin works in chemotherapeutic resistance of GC are unclear. METHODS: CCK8 (Cell Counting Kit 8) was used to detect the IC50 (half maximal inhibitory concentration) of Baicalin and 5-Fu. Proliferation, migration, and invasion of GC were tested through colony formation assay and transwell assay. Fluorescent probes detected intracellular reactive oxygen species (ROS). RNA-seq (RNA sequencing) detected differentially expressed genes and pathways, and qPCR (Quantitative Real-time PCR) tested the expression of ferroptosis-related genes. RESULTS: The combination of Baicalin and 5-Fu inhibited GC progression and increased intracellular ROS levels. Both the inhibition of malignant phenotype of gastric cancer cells and the generation of intracellular ROS caused by Baicalin could be saved by the inhibitor of ferroptosis-Ferrostatin-1 (Fer-1). Heat map of enriched differentially expressed genes identified by RNA-seq included four ferroptosis-related genes, and subsequent GO (Gene Ontology) analysis suggested an association between the ferroptosis pathway and Baicalin treatment. The changes in expression of ferroptosis-related genes were validated by qPCR, and the result confirmed that the combination of Baicalin and 5-Fu promoted ferroptosis in GC. CONCLUSIONS: Baicalin inhibits GC and enhances 5-Fu by promoting ROS-related ferroptosis in GC.

Levels of oxidative stress in patients with neoadjuvant chemotherapy for gastric cancer: correlation with treatment response.

Objective: The intent of this study was to investigate the relationship between oxidative stress and treatment response in gastric cancer patients undergoing neoadjuvant chemotherapy. Methods: Blood samples from 108 patients and 108 healthy subjects were collected, and all patients were enrolled in SOX chemotherapy. The patients received four cycles of neoadjuvant chemotherapy. Blood samples were collected to determine oxidative stress levels at baseline prior to beginning chemotherapy, and at the end of cycles 2 and 4. The patients receiving neoadjuvant chemotherapy were followed up for several months to years. A survival curve was created according to the follow-up information from the patients. In addition, the correlation between oxidative stress level and treatment effect was evaluated and ROC curves were plotted according to the final collected data. Results: Compared with the normal group, the levels of the antioxidant index decreased while the peroxide index increased in the patients. Conversely, when patients were compared before and after chemotherapy, the antioxidant index increased but the peroxide index decreased. Furthermore, the antioxidant index increased in the response group while the peroxide index decreased in the non-response group. Conclusion: Patients with an increased antioxidant index after chemotherapy have good treatment responsiveness. These indicators can also be used as predictors to judge the patients' response to chemotherapy.