Profibrotic role of the SOX9-MMP10-ECM biosynthesis axis in the tracheal fibrosis after injury and repair.

Fibroblast activation and extracellular matrix (ECM) deposition play an important role in the tracheal abnormal repair process and fibrosis. As a transcription factor, SOX9 is involved in fibroblast activation and ECM deposition. However, the mechanism of how SOX9 regulates fibrosis after tracheal injury remains unclear. We investigated the role of SOX9 in TGF-ß1-induced fibroblast activation and ECM deposition in rat tracheal fibroblast (RTF) cells. SOX9 overexpression adenovirus (Ad-SOX9) and siRNA were transfected into RTF cells. We found that SOX9 expression was up-regulated in RTF cells treated with TGF-ß1. SOX9 overexpression activated fibroblasts and promoted ECM deposition. Silencing SOX9 inhibited cell proliferation, migration, and ECM deposition, induced G2 arrest, and increased apoptosis in RTF cells. RNA-seq and chromatin immunoprecipitation sequencing (ChIP-seq) assays identified MMP10, a matrix metalloproteinase involved in ECM deposition, as a direct target of SOX9, which promotes ECM degradation by increasing MMP10 expression through the Wnt/ß-catenin signaling pathway. Furthermore, in vivo, SOX9 knockdown ameliorated granulation proliferation and tracheal fibrosis, as manifested by reduced tracheal stenosis. In conclusion, our findings indicate that SOX9 can drive fibroblast activation, cell proliferation, and apoptosis resistance in tracheal fibrosis via the Wnt/ß-catenin signaling pathway. The SOX9-MMP10-ECM biosynthesis axis plays an important role in tracheal injury and repair. Targeting SOX9 and its downstream target MMP10 may represent a promising therapeutic approach for tracheal fibrosis.

Interaction between intestinal flora and gastric cancer in tumor microenvironment.

Gastric Cancer (GC) is a prevalent malignancy globally and is the third leading cause of cancer-related deaths. Recent researches focused on the correlation between intestinal flora and GC. Studies indicate that bacteria can influence the development of gastrointestinal tumors by releasing bacterial extracellular vesicles (BEVs). The Tumor microenvironment (TME) plays an important role in tumor survival, with the interaction between intestinal flora, BEVs, and TME directly impacting tumor progression. Moreover, recent studies have demonstrated that intestinal microflora and BEVs can modify TME to enhance the effectiveness of antitumor drugs. This review article provides an overview and comparison of the biological targets through which the intestinal microbiome regulates TME, laying the groundwork for potential applications in tumor diagnosis, treatment, and prognosis.

Increased serum interleukin-41 correlates with disease severity in myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease mediated by pathogenic antibodies produced by abnormally activated B cells, resulting in neuromuscular junction transmission dysfunction. Interleukin-41 (IL-41) is a novel immunomodulatory cytokine that has been implicated in various metabolic, inflammatory, and autoimmune diseases. The role of IL-41 in MG is still unclear up to now, our study aimed to investigate the level of IL-41 in MG patients and its correlation with clinical features and inflammatory indicators. METHODS: Totally, 60 MG patients and 30 healthy controls (HC) were recruited. Baseline data and laboratory parameters were routinely recorded through electronic medical systems. IL-41 levels were measured by enzyme-linked immunosorbent assay. Proportions of T-cell and B-cell subsets and natural killer cells were analyzed by flow cytometry. The correlation between serum IL-41 and MG related parameters was investigated, and the clinical value of IL-41 in the diagnosis of MG was evaluated by receiver operator characteristic curve (ROC) analysis. RESULTS: Serum IL-41 levels in MG patients were higher than in HC, and were higher in Myasthenia Gravis Foundation of America (MGFA) III + IV group than that in MGFA I + II group. Serum IL-41 was positively correlated with MG-specific activities of daily living scale (MG-ADL), MGFA classification, platelet to lymphocyte ratio (PLR), and proportion of CD19+ B cells, while it was negatively correlated with high-sensitive C-reactive protein (hs-CRP) and circulatory plasma cells in MG patients. Serum IL-41 levels increased in patients who were treated with efgartigimod during the first cycle of therapy. However, compared to disease initiation, serum IL-41 levels decreased when clinical features steadily improved. ROC analysis showed that IL-41 had a diagnostic value for MG. CONCLUSION: The present findings suggested that serum IL-41 was increased in MG patients and was positively associated with the severity of the disease. IL-41 may be essential to the immunopathological mechanism of MG and a potential biomarker for MG.

Rescue treatment with add-on efgartigimod in a patient with impending myasthenic crisis: a case report.

Myasthenia gravis (MG) is an autoimmune disorder characterized by fluctuating muscle weakness. Severe patients may develop life-threatening respiratory failure and experience crisis. Plasma exchange or intravenous immunoglobulin (IVIg) is the first-line treatment option for myasthenia crisis, but some patients still poorly respond to them. Here, we first reported a generalized MG patient from China who was in a state of impending myasthenic crisis and did not respond effectively to IVIg but was successfully rescued by add-on efgartigimod. Especially, we also detected meaningful changes in T-cell and B-cell subsets after efgartigimod, promoting a potential role of efgartigimod in re-establishing immune homeostasis.

Engineering an Almost All-Waterborne System for Transparent yet Superhydrophobic Surfaces with High Liquid Impalement Resistance.

Realistically, green manufacturing of transparent superhydrophobic surfaces (SHSs) and high liquid impalement resistance for outdoor engineering are very necessary but pretty challenging. To address this, an almost all-waterborne system composed of synthesized partially open-cage fluorinated polyhedral oligomeric silsesquioxane bearing a pair of -OH (poc-FPOSS-2OH), silica sol, and resin precursor is engineered. The transparent SHSs facilely formed by this system are featured with the exclusive presence of wrapped silica nanoparticle (SiNP) dendritic networks at solid-gas interfaces. The wrapped SiNP dendritic networks have a small aggregation size and low distribution depth, making SHSs highly transparent. The Si-O polymeric wrappers render mechanical flexibility to SiNP dendritic networks and thus enable transparent SHSs to resist high-speed water jet impinging with a Weber number of ≥19 800 in conjunction with the extremely low-surface-energy poc-FPOSS-2OH, which is the highest liquid impalement resistance so far among waterborne SHSs, and can rival the state-of-the-art solventborne SHSs.

Kinematic analysis and process optimization of root-cutting systems in field harvesting of garlic based on computer simulation technology.

Introduction: Root cutting is an important process in garlic field harvesting but is the weakest link in the full mechanization of garlic production. To improve the current situation of technological backwardness and poor operational quality of mechanized garlic root-cutting in the main garlic-producing regions of China, this study combined the physical characteristics and agronomic requirements of garlic plants, and proposed an innovative floating root-cutting technology for garlic combine harvesters that enables the top alignment of bulb, adaptive profiling floating of cutter, and embedded cutting of roots. Methods: Through the kinematic analysis of the floating cutting process, the coordinate equations of the initial contact point of the bulb, the mathematical model of the floating displacement of the cutting component. Using computer simulation techniques, the dynamic simulation study of the floating cutting process was carried out in the rigid-flexible coupling numerical simulation model of root-cutting mechanism and garlic plant. The influence law of garlic conveying speed, extension spring preload force and stiffness on the floating displacement of the cutting component and the angular velocity of swing arm reset and its formation causes were analyzed by a single-factor simulation test. The key operating parameters of the root-cutting mechanism were optimized through the computerized virtual orthogonal test and fuzzy comprehensive evaluation. Results and discussion: The significance of the factors affecting the floating cutting performance decreased in the following order: extension spring preload force, garlic conveying speed and extension spring stiffness. The optimal parameter combination of the root cutting mechanism obtained from the optimization were as follow: extension spring preload force was 16 N, garlic conveying speed was 0.8 m/s, and extension spring stiffness was 215 N/m. Tests conducted with the optimal parameter combination yielded a root excision rate of 92.72%, which meets the requirements of Chinese garlic field harvesting quality. This study provides computer simulation optimization methods for the optimal design of the root-cutting mechanism, and also provides technical and equipment support for the full mechanization of garlic production in China.

Azvudine and mortality in patients with coronavirus disease 2019: A retrospective cohort study.

OBJECTIVES: Several studies have found that azvudine (FNC) can inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication both in vivo and in vitro. However, the effect of FNC on the risk of death in patients with coronavirus disease 2019 (COVID-19) is unclear. This study aims to investigate the effect of FNC on the risk of death in patients with coronavirus disease 2019 (COVID-19). METHODS: Charts of consecutive patients hospitalized at five hospitals in Chongqing with confirmed COVID-19. The primary outcome of the study was 28-day mortality. Secondary outcomes were: ICU admission rates, length of hospital and ICU stay, and also the range of mechanical ventilation days when admission. We compared primary outcome in patients who received FNC with those in patients who did not, using a multivariable model with inverse probability weighting according to the propensity score. RESULTS: We included 1,110 patients in our study cohort. Of the 236 patients treated with FNC, 30 died within 28 days (12.7%), and of the 874 patients not treated with FNC, 206 died within 28 days (23.6%). In the crude, unadjusted analysis, a significant beneficial effect of FNC in terms of the 28-day mortality (OR 0.472, 95% CI 0.312-0.714; p < 0.001) in the overall population was detected. The adjusted odds ratio by multivariate analysis was (OR 0.498, 95% CI 0.287-0.864; p = 0.013). In the multivariate analysis with inverse probability weighting according to the propensity score, a significantly beneficial effect of FNC in terms of the 28-day mortality was further confirmed (OR 0.754, 95% CI 0.614-0.925; p = 0.007). Moreover, multivariable propensity-score analyses with matching also yielded similar results (OR 0.438, 95% CI 0.246-0.778; p = 0.005). CONCLUSION: Our results reveal that in patients with COVID-19, FNC administration was associated with a significantly reduced 28-day mortality.

E3 ligase HECTD3 promotes RNA virus replication and virus-induced inflammation via K33-linked polyubiquitination of PKR.

Uncontrolled viral replication and excessive inflammation are the main causes of death in the host infected with virus. Hence inhibition of intracellular viral replication and production of innate cytokines, which are the key strategies of hosts to fight virus infections, need to be finely tuned to eliminate viruses while avoid harmful inflammation. The E3 ligases in regulating virus replication and subsequent innate cytokines production remain to be fully characterized. Here we report that the deficiency of the E3 ubiquitin-protein ligase HECTD3 results in accelerated RNA virus clearance and reduced inflammatory response both in vitro and in vivo. Mechanistically, HECTD3 interacts with dsRNA-dependent protein kinase R (PKR) and mediates Lys33-linkage of PKR, which is the first non-proteolytic ubiquitin modification for PKR. This process disrupts the dimerization and phosphorylation of PKR and subsequent EIF2α activation, which results in the acceleration of virus replication, but promotes the formation of PKR-IKK complex and subsequent inflammatory response. The finding suggests HECTD3 is the potential therapeutic target for simultaneously restraining RNA virus replication and virus-induced inflammation once pharmacologically inhibited.

Characteristics analysis of 157 cases of central airway stenosis due to tracheobronchial tuberculosis: A descriptive study.

Background: Tracheobronchial stenosis, particularly central airway stenosis, which frequently results in severe complications such as lung damage, occurs in patients with tracheobronchial tuberculosis (TBTB). Objectives: To analyze the clinical characteristics of patients with central airway stenosis due to tuberculosis (CASTB). Methods: Retrospective analysis was performed on the clinical features, radiological features, bronchoscopic features and treatment of 157 patients who were diagnosed with CASTB in two tertiary hospitals in Chongqing, China, from May 2020 to May 2022. Results: CASTB mostly occurs in young patients and females. Patients with CASTB exhibited different symptoms repeatedly during the disease, especially varying degrees of dyspnea, prompting many patients to undergo bronchoscopic intervention and even surgery. Patients with cicatricial strictures constituted the highest proportion of the TBTB subtype with CASTB and 35.7% of the patients with CASTB were found to have tracheobronchomalacia (TBM) under bronchoscopy. CASTB and TBM mainly involved the left main bronchus. Patients with lower levels of education had higher rates of TBM. Patients with TBM manifested shortness of breath more frequently than patients without TBM. Patients with TBTB who had undergone bronchoscopic interventions have a higher rate of TBM. Conclusions: Despite mostly adequate anti-tuberculosis chemotherapy, patients with TBTB can present with CASTB involving severe scarring stenosis, bronchial occlusion, tracheobronchomalacia and even destroyed lung.

GATA6 triggers fibroblast activation and tracheal fibrosis through the Wnt/ß-catenin pathway.

Tracheal fibrosis is a key abnormal repair process leading to fatal stenosis, characterized by excessive fibroblast activation and extracellular matrix (ECM) deposition. GATA6, a zinc finger-containing transcription factor, is involved in fibroblast activation, while its role in tracheal fibrosis remains obscure. The present study investigated the potential role of GATA6 as a novel regulator of tracheal fibrosis. It was found that GATA6 and α-smooth muscle actin (α-SMA) were obviously increased in tracheal fibrotic granulations and in TGFß1-treated primary tracheal fibroblasts. GATA6 silencing inhibited TGFß1-stimulated fibroblast proliferation and ECM synthesis, promoted cell apoptosis, and inactivated Wnt/ß-catenin pathway, whereas GATA6 overexpression showed the reverse effects. SKL2001, an agonist of Wnt/ß-catenin signaling, restored collagen1a1 and α-SMA expression which was suppressed by GATA6 silencing. Furthermore, in vivo, knockdown of GATA6 ameliorated tracheal fibrosis, as manifested by reduced tracheal stenosis and ECM deposition. GATA6 inhibition in rat tracheas also impaired granulation proliferation, increased apoptosis, and inactivated Wnt/ß-catenin pathway. In conclusion, our findings indicate that GATA6 triggers fibroblast activation, cell proliferation, and apoptosis resistance in tracheal fibrosis via the Wnt/ß-catenin signaling pathway. Targeting GATA6 may represent a promising therapeutic approach for tracheal fibrosis.

Combination therapy with long-acting bronchodilators and the risk of major adverse cardiovascular events in patients with COPD: a systematic review and meta-analysis.

INTRODUCTION: Accumulated high-quality data from randomised controlled trials (RCTs) indicate that long-acting muscarinic antagonist (LAMA)/long-acting ß2 agonist (LABA) combination therapy significantly improves clinical symptoms and health status in patients with chronic obstructive pulmonary disease (COPD) and reduces exacerbation risk. However, there is a growing concern that LAMA/LABA therapy may increase the risk of cardiovascular disease in patients with COPD. The aim of this paper is to determine whether the use of LAMA/LABA combination therapy modifies the risk of cardiovascular disease in patients with COPD. METHODS: Two reviewers independently searched Embase, PubMed and Cochrane Library to identify relevant RCTs of LAMA/LABA or LABA/LAMA/inhaled corticosteroids (ICS) for the management of patients with COPD that reported on cardiovascular end-points. The primary outcome was major adverse cardiovascular events (MACE), which was a composite of cardiovascular death, myocardial infarction or stroke. RESULTS: A total of 51 RCTs enrolling 91 021 subjects were analysed. Both dual LAMA/LABA (1.6% versus 1.3%; relative risk 1.42, 95% CI 1.11-1.81) and triple therapy (1.6% versus 1.4%; relative risk 1.29, 95% CI 1.03-1.61) significantly increased the risk of MACE compared with ICS/LABA. The excess risk was most evident in RCTs in which the average underlying baseline risk for MACE was >1% per year. Compared with LAMA only, LABA only or placebo, dual LAMA/LABA therapy did not significantly increase the risk of MACE, though these comparisons may have lacked sufficient statistical power. CONCLUSION: Compared with ICS/LABA, dual LAMA/LABA or triple therapy increases cardiovascular risk in patients with COPD. This should be considered in the context of the incremental benefits of these therapies for symptoms and exacerbation rates in patients with COPD, especially in those with a MACE risk of >1% per year.

Low STING expression in lung adenocarcinoma promotes tumor progression via inhibiting endoplasmic reticulum stress / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：分析干扰素基因刺激因子（STING）在肺腺癌中的表达及其与肺腺癌患者临床特征间的关系，探讨STING与内质网应激的相关性及其在调控肺腺癌进展中的作用机制。方法：利用TIMER数据库分析STING基因在泛癌水平的表达情况，利用UALCAN和HPA数据库分析STING在肺腺癌组织中的表达及其与肺腺癌患者临床特征间的关系，利用Kaplan-Meier生存函数分析STING表达与肺腺癌患者OS率间的关系。利用LinkedOmics数据库对肺腺癌表达谱数据进行STING基因共表达分析，对STING相关差异表达基因（DEG）进行GO功能与KEGG通路富集分析，通过GSEA筛选STING调控肺腺癌的潜在通路。使用STING激动剂diABZI及内质网应激抑制剂TUDCA对肺腺癌A549与H460细胞进行处理，通过qPCR、WB法检测STING及内质网应激相关分子的表达，通过CCK-8法检测细胞增殖活力。结果：肺腺癌组织和细胞中STING的表达水平均显著低于正常肺组织（均P<0.01），STING高表达肺腺癌患者5年OS率显著高于低表达患者（P<0.01），STING的表达与肺腺癌患者的年龄、性别等临床特征密切相关（均P<0.01）。STING高表达在肺腺癌外源性抗原处理及提呈等通路上存在富集（均P<0.01）。使用STING激动剂可显著诱导肺腺癌细胞发生内质网应激（P<0.05），STING诱导活化后肺腺癌细胞增殖活力显著下降（均P<0.01），内质网应激抑制剂能部分恢复STING活化诱导后下降的细胞活力（P<0.05）。结论：STING基因在肺腺癌中低表达，其表达下调与肺腺癌患者预后不良相关，其机制可能是STING通过诱导内质网应激而抑制肺腺癌细胞活力。

Strategy toward fluorinated polyhedral oligomeric silsesquioxane wrapping nanoparticles for superomniphobic surfaces.

For engineering implementation of an ultralow-surface-energy hierarchically micro/nanostructured topography for superomniphobic surfaces, a strategy involving the design of a partially open-cage fluorinated polyhedral oligomeric silsesquioxane bearing an -OH pair (poc-F13POSS-2OH) and the subsequent wrapping of nanoparticles with poc-F13POSS-2OH as a result of weak-acid-triggered -OH protonation is developed. The poc-F13POSS-wrapped nanoparticle-based surfaces showed broad-spectrum superomniphobicity. This work has advanced the engineering of state-of-the-art superomniphobic solid surfaces/interfaces.

The transmembrane endoplasmic reticulum-associated E3 ubiquitin ligase TRIM13 restrains the pathogenic-DNA-triggered inflammatory response.

The endoplasmic reticulum (ER)-localized stimulator of interferon genes (STING) is the core adaptor for the pathogenic-DNA-triggered innate response. Aberrant activation of STING causes autoinflammatory and autoimmune diseases, raising the concern about how STING is finely tuned during innate response to pathogenic DNAs. Here, we report that the transmembrane domain (TM)-containing ER-localized E3 ubiquitin ligase TRIM13 (tripartite motif containing 13) is required for restraining inflammatory response to pathogenic DNAs. TRIM13 deficiency enhances pathogenic-DNA-triggered inflammatory cytokine production, inhibits DNA virus replication, and causes age-related autoinflammation. Mechanistically, TRIM13 interacts with STING via the TM and catalyzes Lys6-linked polyubiquitination of STING, leading to decelerated ER exit and accelerated ER-initiated degradation of STING. STING deficiency reverses the enhanced innate anti-DNA virus response in TRIM13 knockout mice. Our study delineates a potential strategy for controlling the homeostasis of STING by transmembrane ER-associated TRIM13 during the pathogenic-DNA-triggered inflammatory response.