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Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and cause chronic infections, commonly in patients with structural respiratory diseases. However, the molecular and pathophysiological mechanisms of P. aeruginosa respiratory infection are largely unknown. Here, we performed assays for transposase-accessible chromatin using sequencing (ATAC-seq), transcriptomics, and quantitative mass spectrometry-based proteomics and ubiquitin-proteomics in P. aeruginosa-infected lung tissues for multi-omics analysis, while ATAC-seq and transcriptomics were also examined in P. aeruginosa-infected mouse macrophages. To identify the pivotal factors that are involved in host immune defense, we integrated chromatin accessibility and gene expression to investigate molecular changes in P. aeruginosa-infected lung tissues combined with proteomics and ubiquitin-proteomics. Our multi-omics investigation discovered a significant concordance for innate immunological and inflammatory responses following P. aeruginosa infection between hosts and alveolar macrophages. Furthermore, we discovered that multi-omics changes in pioneer factors Stat1 and Stat3 play a crucial role in the immunological regulation of P. aeruginosa infection and that their downstream molecules (e.g., Fas) may be implicated in both immunosuppressive and inflammation-promoting processes. Taken together, these findings indicate that transcription factors and their downstream signaling molecules play a critical role in the mobilization and rebalancing of the host immune response against P. aeruginosa infection and may serve as potential targets for bacterial infections and inflammatory diseases, providing insights and resources for omics analyses.
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Neumonía , Pseudomonas aeruginosa , Animales , Ratones , Multiómica , Cromatina , UbiquitinasRESUMEN
BACKGROUND: Astrocyte elevated gene-1 (AEG-1), also known as metadherin, 3D3, and lysine-rich carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) coisolated, has emerged as an important oncogene that is overexpressed in a variety of cancers. Previous studies revealed that AEG-1 is also involved in multiple physiological and pathological processes, such as development, inflammation, neurodegeneration, migraine, and Huntington's disease. However, the function of AEG-1 in diabetic cardiomyopathy (DCM) has not been reported yet. Therefore, we conducted this study to characterize the potential role and mechanism of AEG-1 in DCM rats. METHODS: DCM was induced by injections of streptozocin (STZ) in Wistar rats. Rats were randomized to be injected with lentivirus carrying AEG-1 small interfering RNA. Haemodynamic changes of Wistar rats, assessment of cardiac weight index, and the expression of AEG-1 and KLF4 were detected and compared among these three groups. RESULTS: The expressions of AEG-1 and KLF4 in the STZ group were significantly elevated in cardiac tissues compared with the control group. Knockdown of AEG-1 significantly increased the values of left ventricular ejection fraction, ±dp/dt max , repressed autophagy, as well as upregulated the expression of KLF4. CONCLUSIONS: Knockdown of AEG-1 suppresses autophagy in DCM by downregulating the expression of KLF4. This study provide first-notion evidence for the potential value of AEG-1 as a therapeutic target for the treatment of the patients with DCM.
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Muerte Celular Autofágica , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Factores de Transcripción de Tipo Kruppel/biosíntesis , Glicoproteínas de Membrana/biosíntesis , Regulación hacia Arriba , Animales , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Glicoproteínas de Membrana/genética , Ratas , Ratas WistarRESUMEN
INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.
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Carvedilol , Hipertensión Portal , Cirrosis Hepática , Carvedilol/uso terapéutico , Carvedilol/farmacología , Humanos , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/etiología , Cirrosis Hepática/complicaciones , Método Doble Ciego , China/epidemiología , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Antagonistas Adrenérgicos beta/uso terapéutico , Femenino , Hígado/efectos de los fármacos , Hígado/fisiopatología , Presión Portal/efectos de los fármacos , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/prevención & control , Diagnóstico por Imagen de Elasticidad , Adulto , MasculinoRESUMEN
Volatile organic compounds (VOCs) are important precursors of ozone (O3) and fine particulate matter (PM2.5). An accurate depiction of the emission characteristics of VOCs is the key to formulating VOC control strategies. In this study, the VOC emission factors and source profiles in five industrial sectors were developed using large-scale field measurements conducted in Guangzhou, China (100 samples for the emission factors and 434 samples for the source profile measurements). The emission factors based on the actual measurement method and the material balance method were 1.6-152.4 kg of VOCs per ton of raw materials (kg/t) and 3.1-242.2 kg/t, respectively. The similarities between the emission factors obtained using these two methods were examined, which showed a coefficient of divergence (CD) of 0.34-0.72. Among the 33 subdivided VOC source profiles developed in this study, sources including light guide plate (LGP), photoresist mask, and plastic products were the first time developed in China. Due to regional diversities in terms of production technologies, materials, and products, the emission characteristics of the VOCs varied, even in the same sector, thereby demonstrating the importance of developing localized source profiles of VOCs. The ozone formation potential (OFP) of the shipbuilding and repair sector from fugitive emissions was the highest value among all the industrial sectors. Controlling the emissions of aromatics and OVOCs was critical to reducing the O3 growth momentum in industrial sectors. In addition, 1,2-dibromoethane showed high carcinogenic risk potentials (CRPs) during most of the industrial sectors and should be prioritized for controlling.
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Breast cancer can metastasize to various organs, including the lungs. The immune microenvironment of the organs to be metastasized plays a crucial role in the metastasis of breast cancer. Infection with pathogens such as viruses and bacteria can alter the immune status of the lung. However, the effect of chronic inflammation caused by bacteria on the formation of a premetastatic niche within the lung is unclear, and the contribution of specific immune mediators to tumor metastasis also remains largely undetermined. Here, we used a mouse model revealing that chronic pulmonary bacterial infection augmented breast cancer lung metastasis by recruiting a distinct subtype of tumor-infiltrating MHCIIhi neutrophils into the lung, which exhibit cancer-promoting properties. Functionally, MHCIIhi neutrophils enhanced the lung metastasis of breast cancer in a cell-intrinsic manner. Furthermore, we identified CCL2 from lung tissues as an important environmental signal to recruit and maintain MHCIIhi neutrophils. Our findings clearly link bacterial-immune crosstalk to breast cancer lung metastasis and define MHCIIhi neutrophils as the principal mediator between chronic infection and tumor metastasis.
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Infecciones Bacterianas , Neoplasias Pulmonares , Neumonía , Ratones , Animales , Neutrófilos , Infección Persistente , Pulmón/patología , Neoplasias Pulmonares/patología , Neumonía/patología , Bacterias , Infecciones Bacterianas/patología , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND: Somatic cells could be reprogrammed to induced pluripotent stem cells (iPS) by ectopic expression of OCT4, SOX2, KLF4 and MYC (OSKM). We aimed to gain insights into the early mechanisms underlying the induction of pluripotency. METHODS: GSE28688 containing 14 gene expression profiles were downloaded from GEO, including untreated human neonatal foreskin fibroblasts (HFF1) as control, OSKM-induced HFF1 (at 24, 48, 72 h post-transduction of OSKM encoding viruses), two iPS cell lines, and two embryonic stem (ES) cell lines. Differentially expressed genes (DEGs) were screened between different cell lines and the control by Limma package in Bioconductor. KEGG pathway enrichment analysis was performed by DAVID. The STRING database was used to construct protein-protein interaction (PPI) network. Activities and regulatory networks of transcription factors (TFs) were calculated and constructed by Fast Network Component Analysis (FastNCA). RESULTS: Compared with untreated HFF1, 117, 347, 557, 2263 and 2307 DEGs were obtained from three point post-transduction HFF1, iPS and ES cells. Meanwhile, up-regulated DEGs in first two days of HFF1 were mainly enriched in RIG-I-like receptor (RLR) and Toll-like receptor (TLR) signaling pathways. Down-regulated DEGs at 72 h were significantly enriched in focal adhesion pathway which was similar to iPS cells. Moreover, ISG15, IRF7, STAT1 and DDX58 were with higher degree in PPI networks during time series. Furthermore, the targets of six selected TFs were mainly enriched in screened DEGs. CONCLUSION: In this study, screened DEGs including ISG15, IRF7 and CCL5 participated in OSKM-induced pluripotency might attenuate immune response post-transduction through RLR and TLR signaling pathways. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2503890341543007 .
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Regulación de la Expresión Génica/genética , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factor 3 de Transcripción de Unión a Octámeros/genética , Proteínas Proto-Oncogénicas c-myc/genética , Factores de Transcripción SOXB1/genética , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Linaje de la Célula , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/genética , Humanos , Factor 4 Similar a Kruppel , Transducción de Señal/genéticaRESUMEN
Plants in the desert may locally change the aeolian process, and hence the pattern of sand ripples traveling nearby. The effect of plants on ripples is investigated using a coupled map lattice model with nonuniform coupling coefficients.