Hypoxia-Associated GPNMB+ Macrophages Promote Malignant Progression of Colorectal Cancer and Its Related Risk Signature Are Powerful Predictive Tool for the Treatment of Colorectal Cancer Patients.

Colorectal cancer (CRC) is a highly malignant tumor with hypoxia being a crucial feature during its progression. This study utilized multiple independent CRC cohorts for bioinformatics analysis and in vitro experiments to investigate the role of hypoxia-related subgroups in CRC. Machine learning was employed to construct risk features associated with this subgroup and further explore its therapeutic value in CRC. The study identified the GPNMB+ Macrophage (GPNMB+ Macr) subgroup as most relevant to hypoxia. GPNMB+ Macr showed significantly higher infiltration in tumor tissues compared to non-tumor tissues, increasing with CRC stage. High infiltration of GPNMB+ Macr was associated with poor prognosis in terms of overall and recurrence-free survival in CRC patients. GPNMB+ Macrophages exhibit M2-like characteristics and have the ability to promote 5-FU resistance, proliferation, and metastasis of CRC cells. The study developed the Hypoxia-Related Macrophage Risk Score (HMRS), which not only served as an independent prognostic factor for CRC patients but also demonstrated robust prognostic performance compared to 84 previously published prognostic features. Patients with low HMRS were sensitive to fluorouracil, oxaliplatin (FOLFOX), and anti-PD-1 immunotherapy, while those with high HMRS showed resistance. Additionally, HMRS was identified as an independent prognostic factor in other digestive tract tumors (hepatocellular carcinoma, pancreatic cancer, esophageal cancer, and gastric cancer), indicating potential extrapolation to other tumor types. In conclusion, GPNMB+ Macr promotes the malignant progression of CRC, and HMRS serves as a powerful predictive tool for prognosis, chemotherapy, and immunotherapy in CRC patients, aiding in improving the quality of survival.

Alteration of the gut microbiota changes during the one-year Antarctic deployment in a group of Chinese Han population.

BACKGROUND: It is common knowledge that people's intestinal microbiota is significantly influenced by the external environment. Although the Antarctic continent has been discovered for nearly 200 years, it is still unclear how this environment affects the human intestinal microbiota, especially that of the Chinese Han population. METHODS: Twelve explorers underwent a one-year Antarctic deployment from December 2017 to December 2018. The gut microbiota and clinical indexes at five time points, including two months (T1), five months (T2), eight months (T3), 11 months (T4) of residence in Antarctica and 7 months after returning to China (T5), were investigated. RESULTS: The intestinal microbiota of the participants was changed after one-year Antarctic deployment even after they left Antarctica. For the microbiota tested after returning to China (T5), the amount of Citrobacter, Akkermansia and conditional pathogens such as Escherichia-Shigella increased significantly (P < 0.05). The concentration of the major biochemical indicators in the serum exhibited an increasing trend before T3, and decreased significantly at T4. When tested again at T5, most of the serum concentrations increased, only 5-hydroxytryptamine was significantly decreased. Spearman correlation analysis showed the change in the relative abundance of Anaerotruncus was negatively associated with the changes in the concentration of total thyroxine, alanine transaminase, γ-glutamyl transpeptidase, serum cystatin C and apolipoprotein A1. The relative abundance change in Citrobacter was positively associated with the change in the concentration of uric acid. CONCLUSION: By objectively analyzing the influence of the Antarctic environment on the change of intestinal microbiota, we were able to provide theoretical support for subsequent Antarctic related research.

Exploring the relationship between lignin structure and antioxidant property using lignin model compounds.

Lignin has a natural polyphenol structure that is expected to replace chemically synthesized antioxidants as a native antioxidant with biodegradable and convenient source characteristics. However, the improvement of the antioxidant property of lignin and its application as an antioxidant are still somewhat limited due to the lack of understanding of the relationship between specific lignin structures and antioxidant property. Therefore, the study of the relationship between lignin structure and antioxidant property is crucial to realize the high-quality application of lignin. In this experiment, the scavenging ability of free 1,1-diphenyl-2-picrylhydrazyl (DPPH·) radicals was determined for different grades of acetylated tannins, typical lignin model compounds and different structural units of milled wood lignin to investigate the relationship between lignin structure and antioxidant property. Based on the experimental results, some structure-activity relationships were proposed and the mechanism of the antioxidant property of lignin was discussed. The number of phenolic hydroxyl groups was linearly and positively correlated with antioxidant property, and the scavenging of DPPH radicals increased significantly with the increase in the number of methoxy groups in the model compounds. Moreover, aldehyde and carboxyl groups had a negative effect on the antioxidant property of lignin, while methoxy, alkyl and alcohol hydroxyl groups played a positive role. The guaiacyl (G) and syringyl (S) units favored the antioxidant property, so the difference in the content of structural units in lignin under certain conditions of phenolic hydroxyl content also affected the antioxidant property. Therefore, the antioxidant property of aspen milled lignin was higher than that of other milled lignin from different wood species. Finally, the mechanism of DPPH free radical scavenging by lignin was revealed to better understand the relationship between lignin structure and antioxidant property.

In vitro simulated digestion and fermentation behaviors of polysaccharides from Pleurotus cornucopiae and their impact on the gut microbiota.

This study investigated the physicochemical characteristics and fermentative behavior between original polysaccharides (PCPs) and polysaccharides extracted after microwave cooking (MPCPs) from Pleurotus cornucopiae during simulated digestion and fecal fermentation. The results revealed notable physicochemical differences between of PCPs and MPCPs. MPCPs exhibited a higher total carbohydrate content, with an increased proportion of glucose. Additionally, MPCPs showed a lower molecular weight (MW) and, a blue shift in Fourier transform infrared spectroscopy (FT-IR). Digestion has a minimal effect on the physicochemical and structural characteristics of PCPs and MPCPs. Within the first 6 h of fermentation, the gut microbiota showed significantly higher utilization of MPCPs. However, PCPs were consumed faster and surpassed MPCPs later. After 24 h, both PCPs and MPCPs were degraded and utilized by the gut microbiota, showing an increased abundance of Firmicutes and Bacteroidota. PCPs excelled in promoting beneficial gut microbiota, such as Phascolarctobacterium, Megamonas, and Bacteroides. Conversely, MPCPs demonstrated a stronger ability to inhibit the growth of harmful opportunistic pathogenic gut microbiota, such as Fusobacterium and Parasutterella. In addition, the content of acetic, propionic, and butyric acids increased significantly in both PCPs and MPCPs. These findings highlight the potential of Pleurotus cornucopiae polysaccharides as prebiotics for intestinal homeostasis.

Synthesis and antibacterial activities of heterocyclic ring-fused 20(S)-protopanaxadiol derivatives.

Multidrug-resistant (MDR) bacterial infections are becoming a life-threatening issue in public health; therefore, it is urgent to develop novel antibacterial agents for treating infections caused by MDR bacteria. The 20(S)-protopanaxadiol (PPD) derivative 9 was identified as a novel antibacterial hit compound in screening of our small synthetic natural product-like (NPL) library. A series of novel PPD derivatives with heterocyclic rings fused at the C-2 and C-3 positions of the A-ring were synthesized and their antibacterial activities against Staphylococcus aureus (S. aureus) Newman strain and MDR S. aureus strains (USA300, NRS-1, NRS-70, NRS-100, NRS-108, NRS-271, XJ017, and XJ036) were evaluated. Among these compounds, quinoxaline derivative 56 (SH617) exhibited the highest activity with MICs of 0.5-4 µg/mL against the S. aureus Newman strain and the eight MDR S. aureus strains. Its antibacterial activity was comparable to that of the positive control, vancomycin. In the zebrafish, 56 revealed no obvious toxicity even at a high administered dose. In vivo, following a lethal infection induced by USA300 strains in zebrafish, 56 exhibited significantly increased survival rates in a dose-dependent manner.

Clinical Efficacy and Prognostic Effects of High-quality Nursing Combined With Albumin in Treating Brainstem Hemorrhage.

Context: Brainstem hemorrhage is a disease with a high mortality rate and a poor prognosis. Its onset is urgent and critical, and patients need personalized, high-quality nursing. Also, albumin can have significant benefits in treating brainstem hemorrhage. Objective: The study intended to explore the clinical efficacy of and improved prognoses from high-quality nursing combined with albumin in treating patients with brainstem hemorrhage. Design: The research team conducted a prospective randomized controlled trial. Setting: The study took place at Heibei Fengfeng General Hospital of the North China Medical and Health Group in Hebei, China. Participants: Participants were 102 patients with brainstem hemorrhages who received treatment at the hospital between November 2020 and October 2022. Interventions: The research team randomly divided participants into two groups, each with 51 participants: (1) the intervention group, who received high-quality nursing combined with 20% human albumin, and (2) the control group, who received conventional nursing combined with 20% human albumin. Outcome Measures: The research team examined participants': (1) mortality rate; (2) scores on the Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS); (3) quality of life (QoL) scores, using the 36-Item Short Form Survey (SF-36); (4) scores on the Self-Rating Anxiety Scale (SAS); (5) health-behavior scores, using the Health-Behavior Scale, and (6) nursing satisfaction. Results: Postintervention compared with the control group, the intervention group's: (1) total mortality rate was significantly lower (P = .017), (2) GCS and GOS scores were significantly higher (both P < .001), (3) QoL scores for all subdimensions were significantly higher (all P < .001), (4) SAS scores for all subdimensions were significantly lower (all P < .001), (5) health-behavior scores for all subdimensions were significantly higher (P < .001), and (6) nursing satisfaction was significantly higher (P = .015). Conclusions: High-quality nursing interventions combined with albumin for brainstem-hemorrhage patients can effectively increase treatment efficacy, ensure patients' QoL, and facilitate recovery. Thus, high-quality nursing combined with albumin for brainstem-hemorrhage patients is of great significance in clinical practice.

Pan-omics-based characterization and prediction of highly multidrug-adapted strains from an outbreak fungal species complex.

Strains from the Cryptococcus gattii species complex (CGSC) have caused the Pacific Northwest cryptococcosis outbreak, the largest cluster of life-threatening fungal infections in otherwise healthy human hosts known to date. In this study, we utilized a pan-phenome-based method to assess the fitness outcomes of CGSC strains under 31 stress conditions, providing a comprehensive overview of 2,821 phenotype-strain associations within this pathogenic clade. Phenotypic clustering analysis revealed a strong correlation between distinct types of stress phenotypes in a subset of CGSC strains, suggesting that shared determinants coordinate their adaptations to various stresses. Notably, a specific group of strains, including the outbreak isolates, exhibited a remarkable ability to adapt to all three of the most commonly used antifungal drugs for treating cryptococcosis (amphotericin B, 5-fluorocytosine, and fluconazole). By integrating pan-genomic and pan-transcriptomic analyses, we identified previously unrecognized genes that play crucial roles in conferring multidrug resistance in an outbreak strain with high multidrug adaptation. From these genes, we identified biomarkers that enable the accurate prediction of highly multidrug-adapted CGSC strains, achieving maximum accuracy and area under the curve (AUC) of 0.79 and 0.86, respectively, using machine learning algorithms. Overall, we developed a pan-omic approach to identify cryptococcal multidrug resistance determinants and predict highly multidrug-adapted CGSC strains that may pose significant clinical concern.

Developmental epileptic encephalopathy caused by homozygosity of a c.172+1G>C variant in the WWOX gene.

BACKGROUND: Variations in the WWOX gene have been identified as the leading cause of several central nervous system disorders. However, most previous reports have focused on the description of clinical phenotype, neglecting functional verification. Herein, we presented a case of a patient with developmental epileptic encephalopathy (DEE) caused by WWOX gene variation. CASE PRESENTATION: Our patient was a 13-month-old girl with abnormal facial features, including facial hypotonia, arched eyebrows, a broad nose, and a depressed nasal bridge. She also had sparse and yellow hair, a low anterior hairline, and a short neck. Before the age of 8 months, she was suffering from mild seizures. Her developmental delay gradually worsened, and she suffered infantile spasms. After treatment with vigabatrin, seizures subsided. WWOX gene homozygous variation c.172+1G>C was identified using whole exome sequencing. Further minigene assay confirmed that the variation site affected splicing, causing protein truncation and affecting its function. CONCLUSION: Clinical phenotype and minigene results suggest that WWOX gene homozygous variation c.172+1G>C can cause severe DEE. We also concluded that vigabatrin can effectively treat seizures.

Prognostic impact of metformin in solid cancer patients receiving immune checkpoint inhibitors: novel evidences from a multicenter retrospective study.

Objective: Metformin as a common antidiabetic drug, has recently found to exert its anti-cancer and immunomodulatory effect in numerous preclinical studies. This study aims to clarify the prognostic impact of metformin use in solid cancer patients receiving immune checkpoint inhibitors (ICIs). Methods: A retrospective cohort enrolling 516 solid cancer patients who received ICI-based therapy between 2018 and 2023 at three hospitals was analyzed. The primary endpoints included overall survival (OS) and progression-free survival (PFS). In addition, a bioinformatics analysis based on TCGA and GSE cohort was performed to investigate the prognostic significance of metformin target genes (MTGs) and their correlation with immune infiltration in non-small cell lung cancer (NSCLC) patients. Results: In the entire cohort, a total of 76 patients received metformin before and/or during ICI therapy. The global analysis demonstrated that metformin use was unrelated with the OS (p = 0.064) and PFS (p = 0.059) of ICI-treated cancer patients, which was confirmed in the subgroups of esophagus, hepatobiliary or pancreatic cancer (all p > 0.05). However, metformin use was significantly correlated with better OS (p = 0.012) and PFS (p = 0.005) in ICI-treated lung cancer patients. Metformin use was also identified as an independent favorable prognostic factor for these patients. The bioinformatics analysis identified five favorable prognostic MTGs (RPS6KA5, RORA, SH3BP5, NUPR1, and CD40LG) for NSCLC patients, all of which was downregulated in lung cancer tissues as compared with normal tissues. The expressions of five MTGs not only could effectively stratify the OS of NSCLC patients, but also was correlated with infiltration of immune cells such as CD4+ and CD8+ T cells. Conclusion: Metformin use was significantly correlated with better OS and PFS in ICI-treated lung cancer patients. MTGs has the potential to serve as novel clinical biomarkers or druggable targets for cancer immunotherapy. Considering study limitations, the actual impact of metformin use on ICI therapy needs to be clarified by more clinical trials.

Transposition with Tn3-family elements occurs through interaction with the host ß-sliding clamp processivity factor.

Tn3 family transposons are a widespread group of replicative transposons, notorious for contributing to the dissemination of antibiotic resistance, particularly the global prevalence of carbapenem resistance. The transposase (TnpA) of these elements catalyzes DNA breakage and rejoining reactions required for transposition. However, the molecular mechanism for target site selection with these elements remains unclear. Here, we identify a QLxxLR motif in N-terminal of Tn3 TnpAs and demonstrate that this motif allows interaction between TnpA of Tn3 family transposon Tn1721 and the host ß-sliding clamp (DnaN), the major processivity factor of the DNA replication machinery. The TnpA-DnaN interaction is essential for Tn1721 transposition. Our work unveils a mechanism whereby Tn3 family transposons can bias transposition into certain replisomes through an interaction with the host replication machinery. This study further expands the diversity of mobile elements that use interaction with the host replication machinery to bias integration.

Non-linear association between air pollutants and secondary sensitive skin in acne patients.

BACKGROUND: There is a growing number of patients suffering from sensitive skin secondary to acne, but its prevalence and influencing factors are not yet well-understood. OBJECTIVE: The aim of this study is to investigate the nonlinear relationship between air pollutants and secondary sensitive skin in acne patients. METHODS: A cross-sectional study comprising 4325 acne outpatients in China was carried out between September 2021 and December 2022, employing a simple random sampling approach. Air pollutants data was derived from the nearest air quality monitoring station corresponding to the subjects' residential locations. Furthermore, socio-economic characteristics, biological attributes, and lifestyle data of patients were acquired via questionnaire surveys. The data were subsequently analyzed utilizing the XGBoost machine learning model. RESULTS: A nonlinear relationship has been observed between secondary sensitive skin in acne patients and various factors, including particulate matter (PM2.5), inhalable particulate matter (PM10), ozone (O3), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), the severity of depression, different levels of exercise intensity, acne grading, frequency of sunscreen application, gender, and age. CONCLUSION: The occurrence of secondary sensitive skin in acne patients be mitigated through the implementation of measures such as the control of air pollutant emissions, regulation of negative emotions, and improvement of personal lifestyle.

Identification of Novel Protein Biomarkers and Drug Targets for Acne Vulgaris by Integrating Human Plasma Proteome with Genome-Wide Association Data.

Background: Despite the availability of numerous therapies, the treatment of acne vulgaris remains challenging. Novel drug targets for acne vulgaris are still needed. Methods: We conducted a Mendelian randomization analysis to explore possible drug targets for acne vulgaris. We utilized summary statistics obtained from the dataset of acne vulgaris, including 399,413 individuals of European ancestry. We gathered genetic instruments for 566 plasma proteins from genome-wide association studies. In order to strengthen the findings from Mendelian randomization, various methods were employed, including bidirectional Mendelian randomization analysis, Bayesian co-localization, phenotype scanning, and single-cell analysis. These methods facilitated the identification of reverse causality, the search for reported variant-trait associations, and the determination of the cell types that is the primary source of protein. Furthermore, using the plasma proteins in the deCODE cohort, we conducted a replication of the Mendelian randomization analysis as an external validation. Results: At the significance level of Bonferroni (P < 8.83×10-5), a protein-acne pair was discovered through Mendelian randomization analysis. In plasma, increasing TIMP4 (OR = 1.15; 95% CI, 1.09-1.21; P = 1.01×10-7) increased the risk of acne vulgaris. The absence of reverse causality was observed in the TIMP4 protein. According to Bayesian co-localization analysis, TIMP4 shared the same variant with acne vulgaris (PPH4 = 0.93). TIMP4 was replicated in deCODE cohort (OR = 1.17; 95% CI, 1.10-1.24; P = 1.48×10-7). Single-cell analysis revealed that TIMP4 was predominantly detected in myeloid cells in blood, and was detected in almost all cell types in skin tissue. Conclusion: The integrative analysis revealed that the level of plasma TIMP4 has a direct influence on the risk of developing acne vulgaris. This implies that TIMP4 protein could serve as a potential target for the development of drugs aimed at treating acne vulgaris.

High-performance electrode materials of heteroatom-doped lignin-based carbon materials for supercapacitor applications.

Supercapacitors are the preferred option for supporting renewable energy sources owing to many benefits, including fast charging, long life, high energy and power density, and saving energy. While electrode materials with environmentally friendly preparation, high performance, and low cost are important research directions of supercapacitors. At present, the growing global population and the increasingly pressing issue of environmental pollution have drawn the focus of numerous researchers worldwide to the development and utilization of renewable biomass resources. Lignin, a renewable aromatic polymer, has reserves second only to cellulose in nature. Ten million tonnes of industrial lignin are produced in pulp and paper mills annually, most of which are disposed of as waste or burned for fuel, seriously depleting natural resources and polluting the environment. One practical strategy to accomplish sustainable development is to employ lignin resources to create high-value materials. Based on the high carbon content and rich functional groups of lignin, the lignin-based carbon materials generated after carbonization treatment display specific electrochemical properties as electrode materials. Nevertheless, low electrochemical activity of untreated lignin precludes it from achieving its full potential for application in energy storage. Heteroatom doping is a common modification method that aims to improve the electrochemical performance of the electrode materials by optimizing the structure of the lignin, improving its pore structure and increasing the number of active sites on its surface. This paper aims to establish theoretical foundations for design, preparation, and optimizing the performance of heteroatom-doped lignin-based carbon materials, as well as for developing high-value-added lignin materials. The most reported the mechanism of supercapacitors, the doping process involving various types of heteroatoms, and the analysis of how heteroatoms affect the performance of lignin-based carbon materials are also detailed in this review.

A dynamic nomogram for predicting in-hospital major adverse cardiovascular and cerebrovascular events in patients with both coronary artery disease and atrial fibrillation: a multicenter retrospective study.

BACKGROUND AND OBJECTIVE: Patients with both coronary artery disease (CAD) and atrial fibrillation (AF) are at a high risk of major adverse cardiovascular and cerebrovascular events (MACCE) during hospitalization. Accurate prediction of MACCE can help identify high-risk patients and guide treatment decisions. This study was to elaborate and validate a dynamic nomogram for predicting the occurrence of MACCE during hospitalization in Patients with CAD combined with AF. METHODS: A total of 3550 patients with AF and CAD were collected. They were randomly assigned to a training group and a validation group in a ratio of 7 : 3. Univariate and multivariate analyses were utilized to identify risk factors (P < 0.05). To avoid multicollinearity and overfit of the model, the least absolute shrinkage and selection operator was conducted to further screen the risk factors. Calibration curves, receiver operating characteristic curves, and decision curve analyses are employed to assess the nomogram. For external validation, a cohort consisting of 249 patients was utilized from the Medical Information Mart for Intensive Care IV Clinical Database, version 2.2. RESULTS: Eight indicators with statistical differences were screened by univariate analysis, multivariate analysis, and the least absolute shrinkage and selection operator method (P < 0.05). The prediction model based on eight risk factors demonstrated good prediction performance in the training group, with an area under the curve (AUC) of 0.838. This performance was also maintained in the internal validation group (AUC = 0.835) and the external validation group (AUC = 0.806). Meanwhile, the calibration curve indicates that the nomogram was well-calibrated, and decision curve analysis revealed that the nomogram exhibited good clinical utility. CONCLUSION: The nomogram we constructed may aid in stratifying the risk and predicting the prognosis for patients with CAD and AF.

In Vitro Activitiy of Rezafungin in Comparison with Anidulafungin and Caspofungin against Invasive Fungal Isolates (2017 to 2022) in China.

The efficacy of different echinocandins is assessed by evaluating the in vitro activity of a novel antifungal, rezafungin, against invasive fungal isolates in comparison with anidulafungin and caspofungin. Using the broth microdilution (BMD) method, the susceptibility of 1000 clinical Candida isolates (including 400 C. albicans, 200 C. glabrata, 200 C. parapsilosis, 150 C. tropicalis and 50 C. krusei) and 150 Aspergillus isolates (100 A. fumigatus and 50 A. flavus) from the Eastern China Invasive Fungi Infection Group (ECIFIG) was tested for the antifungals including anidulafungin, rezafungin, caspofungin and fluconazole. The echinocandins showed strong activity against C. albicans that was maintained against fluconazole-resistant isolates. The GM MIC (geometric mean minimum inhibitory concentration) value of rezafungin was found to be comparable to that of anidulafungin or caspofungin against the five tested common Candida species. C. tropicalis exhibited higher resistance rates (about 8.67-40.67% in different antifungals) than the other four Candida species. Through the sequencing of FKS genes, we searched for mutations in echinocandin-resistant C. tropicalis isolates and found that all displayed alterations in FKS1 S654P. The determined MEC (minimal effective concentration) values against A. fumigatus and A. flavus for rezafungin (0.116 µg/mL, 0.110 µg/mL) are comparable to those of caspofungin (0.122 µg/mL, 0.142 µg/mL) but higher than for anidulafungin (0.064 µg/mL, 0.059 µg/mL). Thus, the in vitro activity of rezafungin appears comparable to anidulafungin and caspofungin against most common Candida and Aspergillus species. Rezafungin showed higher susceptibility rates against C. glabrata. Rezafungin indicates its potent activity for potential clinical application.

Characterization and properties of phenolic resin doped modified lignin.

Phenolic resins occupy an important position in industrial applications, but phenol, one of the raw materials for synthesis, is a non-renewable resource. Lignin, as a natural polymer containing phenolic hydroxyl groups, alcohol hydroxyl groups and other reactive groups, can replace some of the phenol in the synthesis of phenolic resins, which can reduce the amount of phenol, thus reducing the cost of phenolic resins, while effectively promoting the high value-added use of renewable biomass resources. Due to its low reactivity, alkaline lignin is usually discharged as production waste, unaware that lignin macromolecules can be modified. In this paper, the phenolic monomers were obtained by acid-catalyzed depolymerization of DES (choline chloride/p-toluenesulfonic acid or choline chloride/lactic acid) from waste alkaline lignin, and the recovery rate of the DES solution during the catalytic treatment was more than 85 %, in which the main monomer was 2-methoxy-4-(1-propyl) phenol. The degradation of alkaline lignin is still favorable after five times of DES solvent recovery. The depolymerized lignin monomer replaced phenol by 50 wt% and then ternary co-polymerized with phenol and formaldehyde to form a biomass phenol-based phenolic resin, providing a green route for phenolic resin production. The cost of resin preparation was economically calculated, and it was found that the cost of resin after accumulating 4 cycles of DES treatment was only 51.1 % of that of pure phenolic resin. The density functional theory (DFT) was used to simulate the possible radical reactions in the intermediate process of phenolic resin reaction, to explore the microscopic mechanism and competition, to provide theoretical reference for further experimental realization of resin structure control and optimization, and to improve the theoretical system of resin synthesis.

Inhibition of OGG1 ameliorates pulmonary fibrosis via preventing M2 macrophage polarization and activating PINK1-mediated mitophagy.

BACKGROUND: 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. METHODS: A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. RESULTS: In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. CONCLUSION: OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.

A Machine learning model for predicting sepsis based on an optimized assay for microbial cell-free DNA sequencing.

OBJECTIVE: To integrate an enhanced molecular diagnostic technique to develop and validate a machine-learning model for diagnosing sepsis. METHODS: We prospectively enrolled patients suspected of sepsis from August 2021 to August 2023. Various feature selection algorithms and machine learning models were used to develop the model. The best classifier was selected using 5-fold cross validation set and then was applied to assess the performance of the model in the testing set. Additionally, we employed the Shapley Additive exPlanations (SHAP) method to illustrate the effects of the features. RESULTS: We established an optimized mNGS assay and proposed using the copies of microbe-specific cell-free DNA per milliliter of plasma (CPM) as the detection signal to evaluate the real burden, with strong precision and high accuracy. In total, 237 patients were eligible for participation, which were randomly assigned to either the training set (70 %, n = 165) or the testing set (30 %, n = 72). The random forest classifier achieved accuracy, AUC and F1 scores of 0.830, 0.918 and 0.856, respectively, outperforming other machine learning models in the training set. Our model demonstrated clinical interpretability and achieved good prediction performance in differentiating between bacterial sepsis and non-sepsis, with an AUC value of 0.85 and an average precision of 0.91 in the testing set. Based on the SHAP value, the top nine features of the model were PCT, CPM, CRP, ALB, SBPmin, RRmax, CREA, PLT and HRmax. CONCLUSION: We demonstrated the potential of machine-learning approaches for predicting bacterial sepsis based on optimized mcfDNA sequencing assay accurately.

MiRNA-224-5p regulates the defective permeability barrier in sensitive skin by targeting claudin-5.

BACKGROUND: Sensitive skin is hypersensitive to various external stimuli and a defective epidermal permeability barrier is an important clinical feature of sensitive skin. Claudin-5 (CLDN5) expression levels decrease in sensitive skin. This study aimed to explore the impact of CLDN5 deficiency on the permeability barrier in sensitive skin and the regulatory role of miRNAs in CLDN5 expression. MATERIALS AND METHODS: A total of 26 patients were retrospectively enrolled, and the CLDN5 expression and permeability barrier dysfunction in vitro were assessed. Then miRNA-224-5p expression was also assessed in sensitive skin. RESULTS: Immunofluorescence and electron microscopy revealed reduced CLDN5 expression, increased miR-224-5p expression, and disrupted intercellular junctions in sensitive skin. CLDN5 knockdown was associated with lower transepithelial electrical resistance (TEER) and Lucifer yellow penetration in keratinocytes and organotypic skin models. The RNA-seq and qRT-PCR results indicated elevated miR-224-5p expression in sensitive skin; MiR-224-5p directly interacted with the 3`UTR of CLDN5, resulting in CLDN5 deficiency in the luciferase reporter assay. Finally, miR-224-5p reduced TEER in keratinocyte cultures. CONCLUSION: These results suggest that the miR-224-5p-induced reduction in CLDN5 expression leads to impaired permeability barrier function, and that miR-224-5p could be a potential therapeutic target for sensitive skin.

Application of sourdough in gluten-free bakery products.

ABSTRACTSIn recent years, the demand for gluten-free (GF) bakery products has grown rapidly due to the remarkable rising number of celiac patients and the increasing health awareness of GF products. However, GF products generally suffer from defects such as poor sensorial level, low nutritional value, high prices and short shelf life. Sourdough is the important starter culture applied in bakery field, and it has been proven to be ideal for enhancing the overall quality of bakery products. This review aims to systematically reviewed the application of sourdough in GF bakery products and its improvement to GF bakery products in terms of texture, shelf life, nutrition and flavor. Its positive effects derive from the complex metabolic activities of sourdough microorganisms, such as acidification, proteolysis, production of exopolysaccharides (EPS), activation of endogenous enzymes, and production of antibacterial substances. Finally, researchers are encouraged to expand the use of sourdough in GF bakery products to increase the variety of GF products. And the technical and nutritional potential of sourdough should be developed more widely.