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INTRODUCTION: Patients with allergic bronchopulmonary aspergillosis (ABPA) suffer from repeated exacerbations. The involvement of T-cell subsets remains unclear. METHODS: We enrolled ABPA patients, asthma patients and healthy controls. T-helper type 1 (Th1), 2 (Th2) and 17 (Th17) cells, regulatory T-cells (Treg) and interleukin (IL)-21+CD4+T-cells in total or sorted subsets of peripheral blood mononuclear cells and ABPA bronchoalveolar lavage fluid (BALF) were analysed using flow cytometry. RNA sequencing of subsets of CD4+T-cells was done in exacerbated ABPA patients and healthy controls. Antibodies of T-/B-cell co-cultures in vitro were measured. RESULTS: ABPA patients had increased Th2 cells, similar numbers of Treg cells and decreased circulating Th1 and Th17 cells. IL-5+IL-13+IL-21+CD4+T-cells were rarely detected in healthy controls, but significantly elevated in the blood of ABPA patients, especially the exacerbated ones. We found that IL-5+IL-13+IL-21+CD4+T-cells were mainly peripheral T-helper (Tph) cells (PD-1+CXCR5-), which also presented in the BALF of ABPA patients. The proportions of circulating Tph cells were similar among ABPA patients, asthma patients and healthy controls, while IL-5+IL-13+IL-21+ Tph cells significantly increased in ABPA patients. Transcriptome data showed that Tph cells of ABPA patients were Th2-skewed and exhibited signatures of follicular T-helper cells. When co-cultured in vitro, Tph cells of ABPA patients induced the differentiation of autologous B-cells into plasmablasts and significantly enhanced the production of IgE. CONCLUSION: We identified a distinctly elevated population of circulating Th2-skewed Tph cells that induced the production of IgE in ABPA patients. It may be a biomarker and therapeutic target for ABPA.
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Aspergilose Broncopulmonar Alérgica , Linfócitos B , Líquido da Lavagem Broncoalveolar , Células Th2 , Humanos , Masculino , Feminino , Aspergilose Broncopulmonar Alérgica/imunologia , Adulto , Células Th2/imunologia , Pessoa de Meia-Idade , Estudos de Casos e Controles , Linfócitos B/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Linfócitos T Reguladores/imunologia , Asma/imunologia , Células Th17/imunologia , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
To develop versatile photocatalysts for efficient degradation of distinct organic pollutants in water is a continuous pursuit in environment remediation. Herein, we directly oxidize Ti3C2 MXene with hydrogen peroxide to produce C-doped anatase TiO2 nanowires with aggregates maintaining a layered architecture of the MXene. The Ti3C2 MXene provides a titanium source for TiO2, a carbon source for in situ C-doping, and templates for nanowire aggregates. Under UV light illumination, the optimized Ti3C2/TiO2 exhibits a reaction rate constant 1.5 times that of the benchmark P25 TiO2 nanoparticles, toward photocatalytic degradations of trace phenol in water. The mechanism study suggests that photogenerated holes play key roles on the phenol degradation, either directly oxidizing phenol molecules or in an indirect way through oxidizing first the surface hydroxyl groups. The unreacted Ti3C2 MXene, although with trace amounts, is supposed to facilitate electron transfer, which inhibits charge recombination. The unique nanostructure of layered aggregates of nanowires, abundant surface oxygen vacancies arising from the carbon doping, and probably the Ti3C2/TiO2 heterojunction guarantee the high photocatalytic efficiency toward removals of organic pollutants in water. The photocatalyst also exhibits an activity superior to, or at least comparable to, the benchmark P25 TiO2 toward photodegradations for typical persistent organic pollutants of phenol, dye molecule of rhodamine B, antibiotic of tetracycline, pharmaceutical wastewater of ofloxacin, and pesticide of N,N-dimethylformamide, when evaluated in total organic carbon removal.
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BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by enhanced TH2 inflammatory response. Fractional exhaled nitric oxide (FeNO) measurement has been used as a valuable tool in predicting the development and management of asthma, another typical TH2 inflammation. However, the clinical significance of FeNO in ABPA remains unclear. OBJECTIVE: To investigate the association between FeNO and the prognosis of patients with ABPA to provide a basis for the use of FeNO in evaluating the efficacy of glucocorticoids in ABPA treatment. METHODS: This study comprised 2 parts; 58 patients were enrolled in the retrospective study. Clinical indexes in patients with different prognoses were compared, and receiver operating characteristic curve analysis was used to determine the threshold value. The prospective observational study involved 61 patients who were regularly followed up at 4 to 6 weeks and 6 months since the initial treatment. Patients were grouped on the basis of baseline FeNO values; correlation analysis was performed in the clinical data. RESULTS: Different prognoses were observed between patients with high and low baseline FeNO values, with a threshold value of 57 parts per billion. The percentage of Aspergillus fumigatus-specific IgE, percentage of positive A fumigatus-specific IgG, and relapse/exacerbation rate differed significantly between the high and low FeNO groups. Patients with higher FeNO needed longer treatment duration and showed shorter interval between glucocorticoid withdrawal and the next relapse/exacerbation. CONCLUSION: Our findings indicate that the level of FeNO is associated with the prognosis of ABPA. It can serve as an independent and valuable biomarker for evaluating the effectiveness of glucocorticoid treatment.
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Aspergilose Broncopulmonar Alérgica , Aspergillus fumigatus , Biomarcadores , Glucocorticoides , Óxido Nítrico , Humanos , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Aspergilose Broncopulmonar Alérgica/diagnóstico , Feminino , Masculino , Glucocorticoides/uso terapêutico , Adulto , Prognóstico , Biomarcadores/análise , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Aspergillus fumigatus/imunologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Imunoglobulina E/sangue , Estudos Prospectivos , Teste da Fração de Óxido Nítrico Exalado , Imunoglobulina GRESUMO
BACKGROUND: Hyperuricemia and low level of high-density lipoprotein cholesterol (HDL-C) are both risk factors for coronary artery disease (CAD). The uric acid to HDL-C ratio (UHR) has recently been identified as a new inflammatory and metabolic biomarker. However, the relationship between the UHR and coronary culprit plaques has not been fully investigated in patients with acute coronary syndrome (ACS). METHODS: A total of 346 patients with ACS were enrolled in this study. Culprit lesion characteristics were assessed by optical coherence tomography (OCT). Logistic regression and linear correlation analyses were performed to assess the association between the UHR and culprit plaques. The predictive value of the UHR was investigated by receiver operating characteristic (ROC) curve analysis. RESULTS: The percentages of typical culprit plaques, including ruptures, erosions and thrombi, were greater in the high-UHR subgroup than those in the low-UHR subgroup. A positive relationship was also found between the UHR and diameter stenosis (r = 0.160, P = 0.003) and between the UHR and area stenosis (r = 0.145, P = 0.007). The UHR was found to be independently associated with plaque rupture, erosion and thrombus. Furthermore, ROC analysis suggested that the UHR had a better predictive value than low-density lipoprotein cholesterol. CONCLUSIONS: An elevated UHR level was independently related to the occurrence rate of culprit plaques. The UHR is a simple and easily acquired parameter for detecting culprit plaques in patients with ACS.
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Síndrome Coronariana Aguda , Placa Aterosclerótica , Humanos , Síndrome Coronariana Aguda/diagnóstico por imagem , Ácido Úrico , HDL-Colesterol , Constrição Patológica , Angiografia Coronária/métodos , Placa Aterosclerótica/patologia , Tomografia de Coerência Óptica/métodos , Vasos Coronários/patologiaRESUMO
The prognosis of advanced lung adenocarcinoma (LUAD) remains unfavorable, with chemotherapy constituting a primary treatment modality. Discerning the efficacy of chemotherapy for advanced LUAD is imperative. Prior investigations have demonstrated the prognostic value of albumin and D-dimer individually for malignancies; however, the predictive capacity of albumin-to-D-dimer ratios (ADR) for advanced LUAD subjected to first-line platinum-based chemotherapy remains unexplored. A cohort of 313 patients with advanced LUAD was retrospectively examined in this study, spanning from January 2017 to January 2021. ADR threshold values were ascertained via receiver operating characteristic analysis, followed by the evaluation of the association between pretreatment ADR and clinicopathological characteristics, disease control rate (DCR), and overall response rate (ORR) pertinent to first-line chemotherapy. Prognostic factors for progression-free survival (PFS) were determined employing Cox univariate and multivariate analyses. Subsequently, survival data were illustrated utilizing the Kaplan-Meier method and scrutinized through the log-rank test across the entire and subgroup populations. ADR demonstrated a superior area under the curve (AUC) value relative to albumin and D-dimer individually and exhibited enhanced prognostic predictive capability compared to albumin-to-fibrinogen ratios (AFR) for advanced LUAD (AUC: 0.805 vs. 0.640, DeLong test: p<0.001). ADR yielded a cut-off value of 16.608. A greater proportion of non-smokers was observed within the high-ADR group (ADR>16.608) compared to the low-ADR group (ADR≤16.608). Patients in the high-ADR group displayed elevated BMI and Na+ levels and reduced neutrophil count, monocyte count, globulin, and alkaline phosphatase (all p<0.05). Notably, the high-ADR group exhibited heightened DCR (96.7% vs. 89.2%, p=0.008) and ORR rates (70.1% vs. 51.0%, p=0.001) relative to the low-ADR group. Multivariate analysis outcomes indicated that high ADR constituted an independent risk factor for PFS (hazard ratio: 0.24, p<0.001). Furthermore, patients in the high-ADR cohort displayed a significantly prolonged median PFS (254 vs. 142 days, p<0.0001) compared to their low-ADR counterparts. In subpopulations exhibiting favorable implications for PFS, as determined by multivariate analysis, high-ADR patients consistently demonstrated extended PFS durations relative to the low-ADR group (all p<0.0001). Collectively, our findings suggest that ADR constitutes a novel and promising prognostic indicator for advanced LUAD patients, surpassing the accuracy of albumin and D-dimer individually and AFR. ADR thus serves as a potent instrument for assessing treatment effects and PFS in advanced LUAD patients undergoing first-line chemotherapy.
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Adenocarcinoma de Pulmão , Produtos de Degradação da Fibrina e do Fibrinogênio , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Prognóstico , Estudos Retrospectivos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Albuminas/uso terapêuticoRESUMO
The development of pure organic room-temperature phosphorescent (RTP) materials greatly facilitates the integrated application of luminescent materials. Herein, a type of photoactivated red RTP material was constructed by simply doping 4-(benzo[c][1,2,5]thiadiazol-5-ylthio)benzonitrile (p-NNS) into a poly(methyl methacrylate) (PMMA) matrix. The obtained film realized a controllable photoactivation process by regulation of diverse solvent levels, demonstrating potential advantages in optical anti-counterfeiting applications. Furthermore, luminescent properties of the doped film were utilized to detect oxygen content from 2.00% to 4.90%, which revealed the exact consumption of ambient oxygen under UV light. Every CIE point of the luminescence corresponds to a certain oxygen content, illustrating the visualization of oxygen content. The remarkable regulation of solvent effect and oxygen content in this work will provide competitive material for further optical applications.
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Cement-stabilization of weak and soft soils is an efficient way for ground improvement. Traditional Portland cement remains the most popular cementitious material in practice, and thus, a proper dosage design of cement-stabilized soil is of practical interest to meet the sustainable engineering requirements and to remedy environmental concerns. Based on the unconfined compression test of cement-stabilized Qiantang River silty clay, the effects of cement content, mixing moisture content, mixing-water-to-cement ratio, and curing time on the unconfined compressive strength were investigated. The results show that the mixing-water-to-cement ratio can comprehensively characterize the effects of cement content and water content on the unconfined compressive strength of the cement-stabilized clay. A prediction method for the unconfined compressive strength of cement-stabilized Qiantang River silty clay has been proposed with considerations for mixing-water-to-cement ratio and curing time. By comparing the experimental data of the present study with the existing literature data, it is found that there is a unified relationship between the unconfined compressive strength and the mixing-water-to-cement ratio of cement-stabilized Qiantang River silty clay, kaolin, Singapore marine clay, and Bangkok clay under the same curing time. The prediction method recommended by the standard may overestimate the unconfined compressive strength of cement-stabilized Qiantang River silty clay cured for 90 days.
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The increasing concern over climate change has spurred significant interest in exploring the potential of microalgae for wastewater treatment. Among the various types of industrial wastewaters, high-salinity NH4+-N wastewater stands out as a common challenge. Investigating microalgae's resilience to NH4+-N under high-salinity conditions and their efficacy in NH4+-N utilization is crucial for advancing industrial wastewater microalgae treatment technologies. This study evaluated the effectiveness of employing nitrogen-efficient microalgae, specifically Oocystis lacustris, for NH4+-N removal from saline wastewater. The results revealed Oocystis lacustris's tolerance to a Na2SO4 concentration of 5 g/L. When the Na2SO4 concentration reached 10 g/L, the growth inhibition experienced by Oocystis lacustris began to decrease on the 6th day of cultivation, with significant alleviation observed by the 7th day. Additionally, the toxic mechanism of saline NH4+-N wastewater on Oocystis lacustris was analyzed through various parameters, including chlorophyll-a, soluble protein, oxidative stress indicators, key nitrogen metabolism enzymes, and microscopic observations of algal cells. The results demonstrated that when the Oocystis lacustris was in the stationary growth phase with an initial density of 2 × 107 cells/L, NH4+-N concentrations of 1, 5, and 10 mg/L achieved almost 100% removal of the microalgae on the 1st, 2nd, and 4th days of treatment, respectively. On the other hand, saline NH4+-N wastewater minimally impacted photosynthesis, protein synthesis, and antioxidant systems within algal cells. Additionally, NH4+-N within the cells was assimilated into glutamic acid through glutamate dehydrogenase-mediated pathways besides the conventional pathway involving NH4+-N conversion into glutamine and assimilation amino acids.
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The selective hydrodeoxygenation (HDO) of sustainable lignocellulosic biomass plays a pivotal role in the conversion of biomass into high-value fuels and chemicals. Nevertheless, HDO for biomass upgrading always demands high temperatures and high hydrogen (H2) pressure. Photothermal catalysis has been recognized as an effective approach for boosting chemical reactions under mild conditions while maintaining superior selectivity. Herein, we report the design of palladium-decorated defective tungsten oxide (Pd/WO3-x) catalysts with enhanced photothermal catalytic performances for the efficient HDO of vanillin. Pd/WO3-x nanoflowers have been synthesized through a solvothermal/in-situ reduction two-step strategy, and they exhibit notable photoabsorption in a wide range (200-1100 nm), high photothermal conversion and efficient charge separation efficiency. Under simulated sunlight irradiation (0.3 W cm-2), Pd/WO3-x exhibits a maximum vanillin conversion up to 86.8 % with a 2-methoxy-4-methylphenol (MMP) selectivity of 100 %, which is obviously higher than that (vanillin conversion = 33.1 %, MMP selectivity = 100 %) in the oil bath at the same temperature. Such higher conversion efficiency and selectivity under sunlight should result from the synergistic integration of hot electrons and photothermal heating, both of which are derived from localized surface plasmon resonance (LSPR) in WO3-x. Importantly, Pd/WO3-x catalyst demonstrates good stability and high selectivity to MMP even after 5 cycles. This work may offer a novel viewpoint on the advancement of photothermal catalysts and the realization of photothermal catalytic biomass conversion under mild conditions.
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BACKGROUND: Previous studies have shown an association between increased arterial stiffness and reduced bone mineral density. However, the relationship between arterial stiffness and fragility fracture remains unclear. In this study, we explored the impact of arterial stiffness on the risk of new-onset fragility fracture. METHODS: The study included 53,107 participants in the Kailuan Study in whom brachial-ankle pulse wave velocity (baPWV) measurements were obtained between 2010 and 2021. All participants were free of fragility fractures at baseline. A Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95 % confidence interval (CI) for incident fragility fracture on the baseline baPWV groups: <1400 cm/s (reference), 1400 ≤ baPWV < 1800 cm/s, and ≥1800 cm/s. RESULTS: In total, 327 incident fragility fractures were recorded during an average follow-up of 4.99 ± 3.02 years. After adjustment for potential confounders, the HR for the risk of new-onset fragility fracture was 1.66 (95 % CI 1.14-2.42) for the arterial stiffness group in comparison with the normal baPWV group. The risk of fragility fracture was higher in men (HR 1.64, 95 % CI 1.05-2.57). There was a linear association between higher baPWV and fragility fracture. CONCLUSIONS: Arterial stiffness as measured by baPWV was associated with the risk of fragility fracture.
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Índice Tornozelo-Braço , Rigidez Vascular , Masculino , Humanos , Feminino , Estudos de Coortes , Fatores de Risco , Análise de Onda de Pulso , China/epidemiologiaRESUMO
Metal pollutants in fine particulate matter (PM2.5) are physiologically toxic, threatening ecosystems through atmospheric deposition. Biotoxicity and bioavailability are mainly determined by the active speciation of metal pollutants in PM2.5. As a megacity in China, Beijing has suffered severe particulate pollution over the past two decades, and the health effects of metal pollutants in PM2.5 have received significant attention. However, there is a limited understanding of the active forms of metals in PM2.5 and their ecological risks to plants, soil or water in Beijing. It is essential that the ecological risks of metal pollutants in PM2.5 are accurately evaluated based on their bioavailability, identifying the key pollutants and revealing historic trends to future risks control. A two-year project measured the chemical speciation of pollution elements (As, Cd, Cu, Cr, Ni, Mn, Pb, Sb, Sr, Ti, and Zn) in PM2.5 in Beijing, in particular their bioavailability, assessing ecological risks and identifying key pollutants. The mass concentrations of total and active species of pollution elements were 199.12 ng/m3 and 114.97 ng/m3, respectively. Active fractions accounted for 57.7 % of the total. Cd had the highest active proportion. Based on the risk assessment code (RAC), most pollution elements except Ti had moderate or high ecological risk, with RAC exceeding 30 %. Cd, with an RAC of 70 %, presented the strongest ecological risk. Comparing our data with previous research shows that concentrations of pollution elements in PM2.5 in Beijing have decreased over the past decade. However, although the total concentrations of Cd in PM2.5 have decreased by >50 % over the past decade, based on machine model simulation, its ecological risk has reduced by only 10 %. Our research shows that the ecological risks of pollution elements remain high despite their decreasing concentrations. Controlling the active species of metal pollutants in PM2.5 in Beijing in the future is vital.
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Poluentes Atmosféricos , Monitoramento Ambiental , Metais , Material Particulado , Material Particulado/análise , Medição de Risco , Pequim , Poluentes Atmosféricos/análise , Metais/análise , Disponibilidade BiológicaRESUMO
Bacterial biofilm formation protects bacteria from antibiotics and the immune system, excessive inflammation further complicates treatment. Here, iron-based metal-organic framework (MIL-101)-loaded riboflavin nanoparticles are designed for the therapeutic challenge of biofilm infection and hyperinflammation in bacterial keratitis. Specifically, MIL-101 produces a thermal effect under exogenous near-infrared light irradiation, which synergizes with ferroptosis-like bacterial death induced by iron ions to exert an effective biofilm infection eradication effect. On the other hand, the disintegration of MIL-101 sustains the release of riboflavin, which inhibits the pro-inflammatory response of macrophage over-activation by modulating their phenotypic switch. In addition, to solve the problems of short residence time, poor permeability, and low bioavailability of corneal medication, the MR@MN microneedle patch is further prepared by loading nanoparticles into SilMA hydrogel, which ultimately achieves painless, transepithelial, and highly efficient drug delivery. In vivo and ex vivo experiments demonstrate the effectiveness of this approach in eliminating bacterial infection and promoting corneal healing. Therefore, the MRMN patch, acting as an ocular drug delivery system with the ability of rapid corneal healing, promises a cost-effective solution for the treatment of bacterial keratitis, which may also lead to a new approach for treating bacterial keratitis in clinics.
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Bile acids play important roles in lipid metabolism and glucose homeostasis. Limited research exist on the association between serum total bile acid (TBA) levels and major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS), particularly those with comorbid type 2 diabetes mellitus (T2DM). This study was conducted to examine the relationship between baseline serum TBA level and T2DM status in patients with ACS after percutaneous coronary intervention (PCI) and to identify the predictive value of TBA levels for a 2-year risk of MACEs. 425 ACS patients underwent PCI were recruited and divided into three groups based on baseline serum TBA concentration. An analysis of the association between the T2DM status and baseline serum TBA levels was conducted using univariate linear regression and multivariate linear regression. The predictive relevance of serum TBA levels was evaluated using the receiver operating characteristic (ROC) curve and Cox regression. Kaplan-Meier curves were employed to analyze the differences among groups in predicting MACEs over a 2-year follow-up period. Baseline serum TBA levels were higher in ACS patients who were diagnosed with T2DM (the median 3.6 µmol/L) than those without T2DM (the median 3.0 µmol/L). T2DM status in ACS patients was positively correlated with baseline serum TBA concentrations (ß: 1.7, 95% confidence interval [CI] 0.3-3.0), particularly in the male (ß: 2.0, 95% CI 0.3-3.6) and 50-69-year-old (ß: 2.5, 95% CI 0.6-4.4) populations. The areas under the ROC curve of baseline serum TBA levels predicted MACEs in ACS and ACS-T2DM patients following PCI were 0.649 (95% CI 0.595-0.703) and 0.783 (95% CI 0.685-0.881), respectively. Furthermore, Cox regression analysis showed that baseline serum TBA level was associated with the occurrence of MACEs in patients with ACS after PCI over a 2-year follow-up period, especially in those diagnosed with T2DM, whose baseline TBA concentration was lower than 10.0 µmol/L. ACS Patients with T2DM had higher serum TBA levels. TBA level at baseline was an independent predictor of MACEs in ACS patients who underwent PCI, especially with comorbid T2DM.
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Síndrome Coronariana Aguda , Diabetes Mellitus Tipo 2 , Intervenção Coronária Percutânea , Humanos , Masculino , Intervenção Coronária Percutânea/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Estudos Prospectivos , Coração , Fatores de RiscoRESUMO
Neurological pain (NP) is always accompanied by symptoms of depression, which seriously affects physical and mental health. In this study, we identified the common hub genes (Co-hub genes) and related immune cells of NP and major depressive disorder (MDD) to determine whether they have common pathological and molecular mechanisms. NP and MDD expression data was downloaded from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (Co-DEGs) for NP and MDD were extracted and the hub genes and hub nodes were mined. Co-DEGs, hub genes, and hub nodes were analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, the hub nodes, and genes were analyzed to obtain Co-hub genes. We plotted Receiver operating characteristic (ROC) curves to evaluate the diagnostic impact of the Co-hub genes on MDD and NP. We also identified the immune-infiltrating cell component by ssGSEA and analyzed the relationship. For the GO and KEGG enrichment analyses, 93 Co-DEGs were associated with biological processes (BP), such as fibrinolysis, cell composition (CC), such as tertiary granules, and pathways, such as complement, and coagulation cascades. A differential gene expression analysis revealed significant differences between the Co-hub genes ANGPT2, MMP9, PLAU, and TIMP2. There was some accuracy in the diagnosis of NP based on the expression of ANGPT2 and MMP9. Analysis of differences in the immune cell components indicated an abundance of activated dendritic cells, effector memory CD8+ T cells, memory B cells, and regulatory T cells in both groups, which were statistically significant. In summary, we identified 6 Co-hub genes and 4 immune cell types related to NP and MDD. Further studies are needed to determine the role of these genes and immune cells as potential diagnostic markers or therapeutic targets in NP and MDD.
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Biologia Computacional , Transtorno Depressivo Maior , Biologia de Sistemas , Humanos , Transtorno Depressivo Maior/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Neuralgia/genética , Neuralgia/metabolismo , Redes Reguladoras de Genes , Ontologia Genética , Mapas de Interação de Proteínas/genética , Bases de Dados GenéticasRESUMO
Ursolic acid (UA), a pentacyclic triterpenoid that has been found in a broad variety of fruits, spices and medicinal plants, has various biological effects such as reducing inflammation, protecting cells from damage, and preserving brain function. However, its impact on ferroptosis in cancer stemlike cells remains unexplored. The present study investigated the effect of UA on MDAMB231 and BT549 cellderived triplenegative breast CSCs (BCSCs) and its potential ferroptosis pathway. The effects of ferroptosis on BCSCs were demonstrated by the detection of ferroptosisrelated indexes including the intracellular level of glutathione, malondialdehyde, reactive oxygen species and iron. The effects of UA on the biological behaviors of BCSCs were analyzed by Cell Counting Kit8, stemness indexes detection and mammosphere formation assay. The mechanism of UA induction on BCSCs was explored by reverse transcriptionquantitative PCR and western blotting. BALB/cnude mice were subcutaneously injected with MDAMB231derived BCSCs to establish xenograft models to detect the effects of UA in vivo. The results revealed that BCSCs have abnormal iron metabolism and are less susceptible to ferroptosis. UA effectively reduces the stemness traits and proliferation of BCSCs in spheroids and mice models by promoting ferroptosis. It was observed that UA stabilizes Kelchlike ECHassociated protein 1 and suppresses nuclear factor erythroidrelated factor 2 (NRF2) activation. These findings suggested that the ability of UA to trigger ferroptosis through the inhibition of the NRF2 pathway could be a promising approach for treating BCSCs, potentially addressing metastasis and drug resistance in triplenegative breast cancer (TNBC). This expands the clinical applications of UA and provides a theoretical basis for its use in TNBC treatment.
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Proliferação de Células , Ferroptose , Fator 2 Relacionado a NF-E2 , Células-Tronco Neoplásicas , Neoplasias de Mama Triplo Negativas , Triterpenos , Ácido Ursólico , Ensaios Antitumorais Modelo de Xenoenxerto , Ferroptose/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Triterpenos/farmacologia , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Camundongos , Feminino , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Purpose: The purpose of this study was to establish and validate a deep learning model to screen vascular aging using retinal fundus images. Although vascular aging is considered a novel cardiovascular risk factor, the assessment methods are currently limited and often only available in developed regions. Methods: We used 8865 retinal fundus images and clinical parameters of 4376 patients from two independent datasets for training a deep learning algorithm. The gold standard for vascular aging was defined as a pulse wave velocity ≥1400 cm/s. The probability of the presence of vascular aging was defined as deep learning retinal vascular aging score, the Reti-aging score. We compared the performance of the deep learning model and clinical parameters by calculating the area under the receiver operating characteristics curve (AUC). We recruited clinical specialists, including ophthalmologists and geriatricians, to assess vascular aging in patients using retinal fundus images, aiming to compare the diagnostic performance between deep learning models and clinical specialists. Finally, the potential of Reti-aging score for identifying new-onset hypertension (NH) and new-onset carotid artery plaque (NCP) in the subsequent three years was examined. Results: The Reti-aging score model achieved an AUC of 0.826 (95% confidence interval [CI] = 0.793-0.855) and 0.779 (95% CI = 0.765-0.794) in the internal and external dataset. It showed better performance in predicting vascular aging compared with the prediction with clinical parameters. The average accuracy of ophthalmologists (66.3%) was lower than that of the Reti-aging score model, whereas geriatricians were unable to make predictions based on retinal fundus images. The Reti-aging score was associated with the risk of NH and NCP (P < 0.05). Conclusions: The Reti-aging score model might serve as a novel method to predict vascular aging through analysis of retinal fundus images. Reti-aging score provides a novel indicator to predict new-onset cardiovascular diseases. Translational Relevance: Given the robust performance of our model, it provides a new and reliable method for screening vascular aging, especially in undeveloped areas.
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Envelhecimento , Aprendizado Profundo , Fundo de Olho , Vasos Retinianos , Humanos , Feminino , Idoso , Masculino , Pessoa de Meia-Idade , Envelhecimento/fisiologia , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/patologia , Curva ROC , Análise de Onda de Pulso/métodos , Fatores de Risco , Área Sob a Curva , Idoso de 80 Anos ou mais , Hipertensão/fisiopatologiaRESUMO
Cell-surface receptors form the front line of plant immunity. The leucine-rich repeat (LRR)-receptor-like kinases SOBIR1 and BAK1 are required for the functionality of the tomato LRR-receptor-like protein Cf-4, which detects the secreted effector Avr4 of the pathogenic fungus Fulvia fulva. Here, we show that the kinase domains of SOBIR1 and BAK1 directly phosphorylate each other and that residues Thr522 and Tyr469 of the kinase domain of Nicotiana benthamiana SOBIR1 are required for its kinase activity and for interacting with signalling partners, respectively. By knocking out multiple genes belonging to different receptor-like cytoplasmic kinase (RLCK)-VII subfamilies in N. benthamiana:Cf-4, we show that members of RLCK-VII-6, -7, and -8 differentially regulate the Avr4/Cf-4-triggered biphasic burst of reactive oxygen species. In addition, members of RLCK-VII-7 play an essential role in resistance against the oomycete pathogen Phytophthora palmivora. Our study provides molecular evidence for the specific roles of RLCKs downstream of SOBIR1/BAK1-containing immune complexes.