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Sepsis is one of the leading causes of death in critical patients worldwide and its occurrence is related to the excessive activation of macrophages. Chloride loss worsens the prognosis of patients with sepsis but the underlying mechanism is currently unclear. In this study, we founded that macrophages deficient in intracellular Cl- secrete more inflammatory cytokines such as IL-1ß, IL-6 and TNF-α compared with control group. The intracellular chloride level decreased in WNK1 deficiency or activity inhibited macrophages with more severe inflammatory response after LPS treatment. Remimazolam, as classic GABAa receptor agonist, alleviates excessive inflammation cascade by promoting macrophage chloride influx during sepsis progression. Collectively, this study proves that macrophage WNK1 acts as a negative regulator of inflammatory response by sensing chloride to maintain intracellular chloride balance during sepsis coupled with hypochloremia.
Subject(s)
Chlorides , Macrophages , Mice, Inbred C57BL , Sepsis , WNK Lysine-Deficient Protein Kinase 1 , Animals , Sepsis/immunology , Chlorides/metabolism , Mice , Macrophages/immunology , Macrophages/drug effects , Macrophages/metabolism , WNK Lysine-Deficient Protein Kinase 1/metabolism , WNK Lysine-Deficient Protein Kinase 1/genetics , Lipopolysaccharides , Cytokines/metabolism , Mice, Knockout , Male , Benzodiazepines/pharmacology , Benzodiazepines/therapeutic use , HumansABSTRACT
Impact tests on post-fire concrete confined by Carbon Fiber-Reinforced Polymer/Plastic (CFRP) sheets were carried out by using Split Hopkinson Pressure Bar (SHPB) experimental setup in this paper, with emphasis on the effect of exposed temperatures, CFRP layers and impact velocities. Firstly, according to the measured stress-strain curves, the effects of experiment parameters on concrete dynamic mechanical performance such as compressive strength, ultimate strain and energy absorption are discussed in details. Additionally, temperature caused a softening effect on the compressive strength of concrete specimens, while CFRP confinement and strain rate play a hardening effect, which can lead to the increase in dynamic compressive strength by 1.8 to 3.6 times compared to static conditions. However, their hardening mechanisms and action stages are extremely different. Finally, nine widely accepted Dynamic Increase Factor (DIF) models considering strain rate effect were summarized, and a simplified model evaluating dynamic compressive strength of post-fire concrete confined by CFRP sheets was proposed, which can provide evidence for engineering emergency repair after fire accidents.
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BACKGROUND: Corticospinal tract (CST) is the principal motor pathway; we aim to explore the structural plasticity mechanism in CST during stroke rehabilitation. METHODS: A total of 25 patients underwent diffusion tensor imaging before rehabilitation (T1), 1-month post-rehabilitation (T2), 2 months post-rehabilitation (T3), and 1-year post-discharge (T4). The CST was segmented, and fractional anisotropy (FA), axial diffusion (AD), mean diffusivity (MD), and radial diffusivity (RD) were determined using automated fiber quantification tractography. Baseline level of laterality index (LI) and motor function for correlation analysis. RESULTS: The FA values of all segments in the ipsilesional CST (IL-CST) were lower compared with normal CST. Repeated measures analysis of variance showed time-related effects on FA, AD, and MD of the IL-CST, and there were similar dynamic trends in these 3 parameters. At T1, FA, AD, and MD values of the mid-upper segments of IL-CST (around the core lesions) were the lowest; at T2 and T3, values for the mid-lower segments were lower than those at T1, while the values for the mid-upper segments gradually increased; at T4, the values for almost entire IL-CST were higher than before. The highest LI was observed at T2, with a predominance in contralesional CST. The LIs for the FA and AD at T1 were positively correlated with the change rate of motor function. CONCLUSIONS: IL-CST showed aggravation followed by improvement from around the lesion to the distal end. Balance of interhemispheric CST may be closely related to motor function, and LIs for FA and AD may have predictive value for mild-to-moderate stroke rehabilitation. Clinical Trial Registration. URL: http://www.chictr.org.cn; Unique Identifier: ChiCTR1800019474.
Subject(s)
Diffusion Tensor Imaging , Neuronal Plasticity , Pyramidal Tracts , Stroke Rehabilitation , Stroke , Humans , Pyramidal Tracts/diagnostic imaging , Pyramidal Tracts/physiopathology , Pyramidal Tracts/pathology , Male , Female , Middle Aged , Neuronal Plasticity/physiology , Stroke Rehabilitation/methods , Aged , Stroke/physiopathology , Stroke/diagnostic imaging , AdultABSTRACT
To investigate the effects of functional occupational therapy (FOT) combined with different types of exercise on upper limb motor function recovery and brain function remodeling in patients with right hemisphere damage (RHD) by analyzing functional near-infrared spectroscopy (fNIRS). Patients (n = 32) with RHD at Beijing Bo'ai Hospital were recruited and randomly allocated to receive either FOT combined with passive motion (N=16) or FOT combined with assisted active movement (N=16). The passive motion group (FOT-PM) received functional occupational therapy for 20 min and passive exercise for 10 min in each session, while the assisted active movement group (FOT-AAM) received functional occupational therapy for 20 min and assisted active exercise for 10 min. Both groups received conventional drug therapy and other rehabilitation therapy. Treatment was performed once a day, 5 times a week for 4 weeks. The recovery of motor function and activities of daily living (ADL) was assessed using Fugl-Meyer Assessment upper extremity (FMA-UE) and modified Barthel index (MBI) before and after treatment, and brain activation of the bilateral motor area was analyzed with fNIRS. The findings suggested that FOT combined with AAM was more effective than FOT combined with PM in improving the motor function of RHD patients' upper limbs and fingers, improving their ability to perform activities of daily living, and facilitating brain function remodeling of the motor area.
Subject(s)
Activities of Daily Living , Upper Extremity , Humans , Exercise , Fingers , Recovery of FunctionABSTRACT
OBJECTIVE: The objective of this study is to evaluate the correlation between tumor proportionality scores (TPS) and the effectiveness of immune checkpoint inhibitors (ICIs) as the second or subsequent line therapies for individuals who received diagnoses of advanced non-small cell lung cancer (NSCLC). METHODS: The retrospective analysis was conducted on the medical records of a total of 143 patients who received diagnoses of stage IIIB/IV NSCLC and were admitted to our hospital from the beginning of 2019 to the end of September 2022. The follow-up period ended on 01 January 2023. The study used Kaplan-Meier survival curves to assess the progression-free survival (PFS) and overall survival (OS) of patients. Univariate and multivariate Cox proportional risk models were used to analyze the factors associated with the PFS and OS of advanced-stage NSCLC patients who received ICIs as the second or subsequent lines. RESULTS: Patients diagnosed with NSCLC who had a TPS ≥1% and got treatment with ICIs exhibit notably elevated rates of partial response, objective response rate, disease control rate and extended PFS in comparison to NSCLC patients with a TPS of <1% ( P < 0.05). NSCLC patients with TPS within 1-49% [hazard ratio (HR) = 0.372; 95% confidence interval (CI), 0.140-0.993; P = 0.048] or ≥50% (HR = 0.276; 95% CI, 0.095-0.796; P = 0.017) were significantly associated with prolonged PFS, which were conducted by multivariate Cox regression analysis. CONCLUSION: Programmed death protein-1 expression status may be predictive markers of the effectiveness of ICIs as the second or subsequent lines of therapies in advanced NSCLC are influenced by TPS.
Subject(s)
B7-H1 Antigen , Carcinoma, Non-Small-Cell Lung , Immune Checkpoint Inhibitors , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/mortality , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/therapy , Lung Neoplasms/mortality , Male , Female , Retrospective Studies , B7-H1 Antigen/metabolism , B7-H1 Antigen/antagonists & inhibitors , Middle Aged , Immune Checkpoint Inhibitors/therapeutic use , Aged , Immunotherapy/methods , Adult , Follow-Up Studies , Survival Rate , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/analysis , Neoplasm Staging , Prognosis , Progression-Free Survival , Aged, 80 and overABSTRACT
Household storage of pharmaceuticals to extract raw materials synthesized from carbon points facilitates the utilization of solid waste resources. A novel ratiometric fluorescence sensing technique was developed to ascertain the presence of horseradish peroxidase (HRP) in fruits and vegetables. The method employed a fluorescent probe, synthesized from expired amoxicillin (referred to as carbon dots, or A-CDs), serving as a reference fluorophore. Additionally, 2,3-diaminophenazine (DAP) was utilized as a specific response signal. DAP resulted from a catalytic reaction system involving phenylenediamine and hydrogen peroxide under the catalysis of HRP. The fluorescence intensity corresponding to DAP at 562 nm exhibited a substantial increase, simultaneous with the fluorescence quenching of A-CDs at 450 nm. The ratiometric fluorescence nanosensors displayed a broad linear range and high sensitivity for the detection of HRP. Across the concentration range 0.01 to 6 U L-1, the fluorescence intensity ratio between DAP and A-CDs demonstrated a proportional increase with rising HRP concentration, achieving an impressive detection limit of 0.002 U L-1. The recovery of HRP in fruit and vegetable samples ranged from 96.1 to 103%, with an RSD value of less than 3.8%. The proposed method facilitated the screening of inhibitors of HRP enzyme activity, contributing to the preservation of freshness in fruits and vegetables.
Subject(s)
Fruit , Vegetables , Fluorescent Dyes , Carbon , Horseradish PeroxidaseABSTRACT
Citrinin derivatives have been found to have various pharmacological activities, such as anti-inflammatory, anti-tumor, and antioxidant effects. Dicitrinone G (DG) was a new citrinin dimer isolated from marine-derived fungus Penicillium sp. GGF 16-1-2 which has potential activity. Here, we aim to investigate whether DG has anti-pancreatic cancer activity. In xenograft tumor model, 2 × 106 BXPC-3 cells were injected into the hind flank of NU/NU nude mice by subcutaneously for 2 weeks followed by treating with DG (0.25, 0.5, 1 mg/kg) and 5-FU (30 mg/kg) for 4 weeks. Tumor volume and weight were measured, and the expression of CD31, IL-18, NLRP3, and Caspase-1 in tumor tissue were detected. In vitro, HUVECs were treated with conditioned medium (CM) derived from BXPC-3 cells, the effects of DG on angiogenesis were detected by tube formation and western blot analysis. In vivo studies showed that the tumor growth and angiogenesis were greatly suppressed. The tumor weight inhibition rates of DG and 5-FU groups were about 42.36%, 38.94%, 43.80%, and 31.88%. Furthermore, the expression of CD31 and Caspase-1 were decreased. In vitro, CM derived from BXPC-3 cells which treated with DG could inhibit the tube formation and expression of pro-angiogenic NICD in HUVECs. Our study suggests that DG could suppress angiogenesis via the NLRP3/IL-18 pathway and may have the potential to inhibit tumor development.
Subject(s)
Citrinin , Penicillium , Animals , Mice , Humans , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Interleukin-18 , Mice, Nude , Angiogenesis , Caspase 1/metabolism , Fluorouracil/pharmacologyABSTRACT
BACKGROUND: The exceptional protein secretion capacity, intricate post-translational modification processes, and inherent safety features of A. oryzae make it a promising expression system. However, heterologous protein expression levels of existing A. oryzae species cannot meet the requirement for industrial-scale production. Therefore, establishing an efficient screening technology is significant for the development of the A. oryzae expression system. RESULTS: In this work, a high-throughput screening method suitable for A. oryzae has been established by combining the microfluidic system and flow cytometry. Its screening efficiency can reach 350 droplets per minute. The diameter of the microdroplet was enlarged to 290 µm to adapt to the polar growth of A. oryzae hyphae. Through enrichment and screening from approximately 450,000 droplets within 2 weeks, a high-producing strain with α-amylase increased by 6.6 times was successfully obtained. Furthermore, 29 mutated genes were identified by genome resequencing of high-yield strains, with 15 genes subjected to editing and validation. Two genes may individually influence α-amylase expression in A. oryzae by affecting membrane-associated multicellular processes and regulating the transcription of related genes. CONCLUSIONS: The developed high-throughput screening strategy provides a reference for other filamentous fungi and Streptomyces. Besides, the strains with different excellent characteristics obtained by efficient screening can also provide materials for the analysis of genetic and regulatory mechanisms in the A. oryzae expression system.
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This paper takes the panel data of 283 prefecture-level cities in China from 2011 to 2020 as the research sample, measures the comprehensive index of industrial structure optimization and air quality by using GRA-TOPSIS comprehensive evaluation method, explores the spatial and temporal divergence characteristics of industrial structure optimization and air quality and the spatial and temporal evolution pattern of coupled and coordinated development by using ArcGIS spatial analysis and coupled coordination degree model, and analyzes the driving factors of coupled coordination degree of industrial structure optimization and air quality by combining multi-scale geographically weighted regression model. The study found the following: (1) The overall level of China's urban industrial structure is low, and shows an obvious eastern > central > western decreasing trend; urban air quality has a strong spatial clustering and spatial locking effect. (2) During the study period, the coupling coordination degree of industrial structure optimization and air quality showed an inverted "W" shape fluctuation from 2011 to 2020. The coupling degree and coupling coordination degree in 2020 were both higher than that in 2011, and most cities were in the run-in stage and moderate coordination stage. (3) There is a consistency in the temporal evolution trend and spatial evolution pattern of industrial structure optimization and air quality coupling degree and coupling coordination degree. (4) The driving factors are ranked according to the scale of action: public transportation intensity > population density > government intervention > GDP per capita > industrialization level. At present, China is in a critical period of promoting high-quality development by ecological civilization, and it is recommended to optimize regional industrial structure, improve urban air quality, and promote coordinated urban development.
Subject(s)
Industrial Development , Industry , China , Cities , Economic DevelopmentABSTRACT
BACKGROUND: Nursing talent training should be adjusted in accordance with policies and regulations, the priority areas of health care, the development of nursing disciplines, and changes in nurses' roles. Experience from nursing education stakeholders indicates that postgraduate education faces numerous challenges. Thus, it is necessary to discuss postgraduates' experience in cultivating innovative practical ability. OBJECTIVES: To analyze the experiences of nursing specialist postgraduates in cultivating innovative practical ability to provide a reference for further improvement of the Master of Nursing Specialist program. DESIGN: A qualitative study. SETTING: A university and its three affiliated tertiary hospitals in H city, China. PARTICIPANTS AND METHODS: Individual, semi-structured interviews were conducted face-to-face with 12 postgraduates currently in clinical practice and six postgraduate nurses within two years of graduation between April and June 2022. All interviews were audio-recorded and transcribed verbatim, and the data were analyzed using the Colaizzi method. RESULTS: Three key themes emerged: (1) the cognition of innovative practical ability; (2) the experience of cultivating innovative practical ability at school; and (3) the experience of cultivating innovative practical ability in the hospital. CONCLUSIONS: With a full understanding of the training experience of postgraduates' innovative practical ability, policymakers and training units can clarify the shortcomings of the training model, make targeted improvements, and work together to build a more scientific and complete MNS training model. Our findings have the potential to inform faculty structure, catalyze curriculum reform, optimize clinical practice to facilitate the development of Master of Nursing Specialist programs, improve the quality of care, and promote patient recovery.
Subject(s)
Education, Nursing , Humans , Nurse's Role , Qualitative Research , Cognition , ChinaABSTRACT
OBJECTIVE: In this retrospective study, we aimed to assess the relationship between mutations in the Kirsten rats sarcoma viral oncogene (KRAS )/ tumor protein p53 (TP53 ) genes and the efficacy of immune checkpoint inhibitors (ICIs) therapy as a second-line or later-line treatment for patients with stage IIIB/IV non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed the clinical data of 143 patients with stage IIIB/IV NSCLC who were admitted to the Cancer Hospital of Harbin Medical University between January 2019 and September 2022. Kaplan-Meier survival curve analysis was performed to analyze the survival outcomes. Univariate and multivariate Cox proportional risk models were used to analyze the factors associated with the progression-free survival (PFS) and overall survival (OS) of advanced-stage NSCLC patients who received ICIs as second-line or later-line therapy. RESULTS: NSCLC patients with KRAS or TP53 mutations treated with ICIs showed significantly higher objective response rate, disease control rate, PFS, and OS compared to NSCLC patients with wild-type KRAS / TP53 (P â <â 0.05). Multivariate Cox regression analysis showed that a combined treatment regimen of ICIs plus chemotherapy was significantly associated with prolonged PFS [hazard ratioâ =â 0.192; 95% confidence interval (CI), 0.094-0.392; P â <â 0.001] and OS (hazard ratioâ =â 0.414; 95% CI, 0.281-0.612; P â <â 0.001). CONCLUSION: KRAS or TP53 mutations were associated with improved PFS of advanced NSCLC patients treated with ICIs as second-line or later-line therapy. KRAS or TP53 mutations show great potential as clinical biomarkers to predict the efficacy of ICIs therapy.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Immunotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Prognosis , Proto-Oncogene Proteins p21(ras)/genetics , Retrospective Studies , Tumor Suppressor Protein p53/geneticsABSTRACT
Early intervention in kidney cancer helps to improve survival rates. Abdominal computed tomography (CT) is often used to diagnose renal masses. In clinical practice, the manual segmentation and quantification of organs and tumors are expensive and time-consuming. Artificial intelligence (AI) has shown a significant advantage in assisting cancer diagnosis. To reduce the workload of manual segmentation and avoid unnecessary biopsies or surgeries, in this paper, we propose a novel end-to-end AI-driven automatic kidney and renal mass diagnosis framework to identify the abnormal areas of the kidney and diagnose the histological subtypes of renal cell carcinoma (RCC). The proposed framework first segments the kidney and renal mass regions by a 3D deep learning architecture (Res-UNet), followed by a dual-path classification network utilizing local and global features for the subtype prediction of the most common RCCs: clear cell, chromophobe, oncocytoma, papillary, and other RCC subtypes. To improve the robustness of the proposed framework on the dataset collected from various institutions, a weakly supervised learning schema is proposed to leverage the domain gap between various vendors via very few CT slice annotations. Our proposed diagnosis system can accurately segment the kidney and renal mass regions and predict tumor subtypes, outperforming existing methods on the KiTs19 dataset. Furthermore, cross-dataset validation results demonstrate the robustness of datasets collected from different institutions trained via the weakly supervised learning schema.
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Based on Panel data collected from 2011 to 2020 targeted to 50 prefecture-level cities in the Yellow River Basin, this paper adopted standard deviation ellipse and spatial Dubin model to explore the nonlinear effects and spatial spillover effects of urbanization on air pollution and ecological resilience in the Yellow River Basin. The results show that the degree of air pollution in the southeast of the Yellow River Basin is higher than that in the northwest of the Yellow River Basin, the distribution range of air pollution is shrinking, the concentration of ecological resilience is enhanced, and the ecological environment is developing for the better. There is a significant U-shaped relationship between urbanization and air pollution in the Yellow River Basin, and an inverted U-shaped relationship between urbanization and ecological resilience. For every 1% increase in urbanization, air pollution decreases by 0.0873%, ecological resilience increases by 0.4046%. For every 1% increase in the square term of urbanization, air pollution increases by 0.2271%, ecological resilience decreases by 0.1789%. The urbanization of the Yellow River Basin has a spatial spillover effect on air pollution and ecological resilience, and urbanization has a significant negative impact on the ecological environment of neighboring cities. The robustness of the above conclusions is verified by introduce an inverse distance weight matrix replacing the spatial weight matrix.
Subject(s)
Air Pollution , Urbanization , Rivers , Air Pollution/analysis , Cities , China , Economic DevelopmentABSTRACT
Objective: The study objective was to investigate the prognostic risk factors related to overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and metastasis-free survival (MFS) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Patients were then divided into different risk groups (based on their number of prognostic risk factors), and specific postoperative treatment plans were formulated for patients in different risk groups. Methods: We retrospectively analyzed the data of 401 patients with UTUC who underwent RNU between 2010 and 2020. Univariate and multivariate Cox regression analyses were used to evaluate the associations of clinicopathological variables with prognosis among UTUC patients. Kaplan-Meier survival analysis of patients in different risk groups (based on their number of prognostic risk factors) was conducted. Results: Multivariate Cox regression analysis showed that sex (being male), LVI, pT stage (>pT2), and lack of postoperative intravesical instillation were independent risk predictors of shorter OS, CSS, RFS, and MFS (all P<0.05). Laparoscopic RNU was also associated with shorter OS, CSS, and MFS, but not with shorter RFS (P=0.068). After risk stratification, the 5-year OS, CSS, RFS, and MFS in the high-risk group were 42.3%, 46.4%, 41%, and 46%, respectively. Conclusions: Sex (being male), LVI, pT stage (>pT2), and intravesical instillation were independent predictors of OS, CSS, RFS, and MFS for UTUC. All were risk factors, except for intravesical instillation, which was a protective factor. Additionally, laparoscopic RNU was an independent risk factor for OS, CSS, and MFS. Patients in the high-risk group may benefit greatly from adjuvant or neoadjuvant chemotherapy.
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Volatile fatty acid recovery from waste activated sludge (WAS) was highly suggested to supplement carbon source for nitrogen removal. However, it was not easy to separate them from the metabolites under the ex-situ fermentation. In this study, in-situ WAS fermentation combined in the denitrification system was established to treat low carbon wastewater (COD/TN = 4), and riboflavin was employed as a redox mediator. This coupled process could simultaneously enhance the WAS fermentation and nitrogen removal, and riboflavin could significantly enrich the fermentative bacteria (Firmicutes phylum), denitrifying bacteria (Denitratisoma genus) and related functional genes (narGHJI, napABC, nirKS, nosZ, norBC), generating more available carbon sources for efficient nitrogen removal. This resulted in the effluent TN (<15 mg/L) satisfying the required discharge standard in China. This study provided new insights into the efficient nitrogen removal from low carbon wastewater, realizing the carbon-neutral operation of new concept wastewater treatment plant in China.
Subject(s)
Sewage , Water Purification , Bioreactors , Carbon , Denitrification , Fatty Acids, Volatile/metabolism , Fermentation , Nitrogen/metabolism , Riboflavin , Sewage/microbiology , Waste Disposal, Fluid/methods , WastewaterABSTRACT
Triboelectric sensors provide an effective approach to solving the power supply problem for distributed sensing nodes. However, the poor stability and repeatability of the output signal limit its further development due to structural deficiencies and intrinsic working mechanisms. This work proposes a contact-separation mode laminated triboelectric nanogenerator (L-TENG) by introducing multifunctional layers to regulate triboelectric charges. A liquid metal Galinstan and PDMS mixture with a dense microstructure array is fabricated as the dielectric layer. Liquid squalene is filled in the space between two triboelectric layers to eliminate the influence of moisture in the air. A Cu shield film is sputtered on the surface to screen the electrostatic interference and enhance the repeatability. Owing to the effective design, the sensitivity of the L-TENG could reach 6.66 kPa-1 in the low-pressure region and 0.79 kPa-1 in the high-pressure region with a wide detection range from 8 Pa to 71.85 kPa. In addition, it also illustrates fast response and recovery times of 30 and 10 ms, respectively, and great stability in a humid environment. Finally, the L-TENG has been successfully demonstrated to monitor various physical activities in humans such as swallowing, finger bending, and so forth. This work has important scientific significance in opening up a new strategy for the structure optimization and performance improvement of triboelectric sensors.
ABSTRACT
Contrast agents are commonly used to highlight blood vessels, organs, and other structures in magnetic resonance imaging (MRI) and computed tomography (CT) scans. However, these agents may cause allergic reactions or nephrotoxicity, limiting their use in patients with kidney dysfunctions. In this paper, we propose a generative adversarial network (GAN) based framework to automatically synthesize contrast-enhanced CTs directly from the non-contrast CTs in the abdomen and pelvis region. The respiratory and peristaltic motion can affect the pixel-level mapping of contrast-enhanced learning, which makes this task more challenging than other body parts. A perceptual loss is introduced to compare high-level semantic differences of the enhancement areas between the virtual contrast-enhanced and actual contrast-enhanced CT images. Furthermore, to accurately synthesize the intensity details as well as remain texture structures of CT images, a dual-path training schema is proposed to learn the texture and structure features simultaneously. Experiment results on three contrast phases (i.e. arterial, portal, and delayed phase) show the potential to synthesize virtual contrast-enhanced CTs directly from non-contrast CTs of the abdomen and pelvis for clinical evaluation.
Subject(s)
Abdomen , Tomography, X-Ray Computed , Abdomen/diagnostic imaging , Humans , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging , Pelvis/diagnostic imaging , Pelvis/pathology , Tomography, X-Ray Computed/methodsABSTRACT
Abnormal increases in glucagon (GCG) are the primary cause of type II diabetes mellitus. When GCG interacts with a glucagon receptor (GCGR), GCG can increase the blood glucose level. In this paper, a compound that could interfere with the binding of GCG and GCGR to inhibit the increase of blood glucose was investigated. First, molecular docking was used to conduct preliminary screening of compounds whose active components could combine with GCGR by AutoDock Vina. The binding of the receptor-ligand complex was analyzed by PyMOL. Results showed that dauricine could tightly bind to the receptor pocket. Second, the plasmid pcDNA3.1(+)-GCGR containing the target gene was transfected into HEK293 cells for expression, which was the cell model established to screen GCGR antagonist. Dauricine, the lead compound of glucagon receptor antagonist (GRA), was screened using the GRA screening model in vitro. Finally, using [Des-His1, Glu9]-Glucagon amide as the positive control, flow cytometry was used to express the antagonistic effect of the compound. Consequently, dauricine can antagonize the GCGR.
Subject(s)
Diabetes Mellitus, Type 2 , Receptors, Glucagon , Benzylisoquinolines , Blood Glucose/metabolism , Glucagon/metabolism , Glucagon/pharmacology , HEK293 Cells , Humans , Molecular Docking Simulation , Receptors, Glucagon/genetics , Receptors, Glucagon/metabolism , TetrahydroisoquinolinesABSTRACT
BACKGROUND: Berberine has received rising attention for its application in cardiovascular disease because of its relationship with inflammation. The endothelial NLRP3 inflammasome triggers inflammatory vascular injury which would lead to cardiovascular disease. Endothelial calcium signalling plays a crucial role in both the activation of NLRP3 inflammasome and endothelial cells dysfunction. However, the efficacy of BBR on the endothelial NLRP3 inflammasome in inflammatory vascular injury remains unknown. PURPOSE: In this study, we focused on the NLRP3 pathway to determine whether BBR regulates endothelial junction function in inflammatory vascular injury. METHODS: The integrity of the junction proteins VE-cadherin (VEC) and zonula occludens-1 (ZO-1) detected by immunofluorescence and immunoblotting was used to determine the therapeutic effect of BBR (50, 100, or 200 mg/kg/day) in LPS (100 µg/kg/day)-induced inflammatory vascular injury in mice and mouse microvascular endothelial cells (MECs) treated with LPS (1 µLPS ) and ATP (5 mM). Endothelial permeability was assessed by FITC-labelled dextran and trans-endothelial electrical resistance (TEER) in vitro. The assembly and activation of NLRP3 inflammasomes were detected by western blotting and immunofluorescence. Pharmacophore-based virtual molecular docking studies and calcium imaging analyses were used to determine the interaction of BBR with the ATP-gated Ca2+ channel P2X7R (purinergic P2X receptor 7) in the context of inflammatory vascular injury. RESULTS: BBR recovered the expression of ZO-1 and VEC and inhibited endothelial NLRP3 inflammasome activation in coronary microvascular endothelium and in MECs. These results suggested a crucial role of the NLRP3 inflammasome in BBR-regulated endothelial integrity. Further analysis demonstrated that BBR treatment suppressed the binding of TXNIP (thioredoxin interacting protein) with NLRP3. Intriguingly, eliminating extracellular Ca2+ showed a similar effect as BBR. Virtual docking analysis indicated that R574 of P2X7R is a potential target for BBR binding. Ca2+ imaging showed that BBR inhibited the Ca2+ influx in response to ATP, supporting the potential interaction of BBR with P2X7R. CONCLUSIONS: These findings suggest that BBR exhibits potential and specific therapeutic value by targeting calcium signals and the endothelial NLRP3 inflammasome in inflammatory vascular injury.
Subject(s)
Berberine , Cardiovascular Diseases , Vascular System Injuries , Adenosine Triphosphate/metabolism , Animals , Berberine/pharmacology , Calcium/metabolism , Cardiovascular Diseases/metabolism , Endothelial Cells , Inflammasomes , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , NLR Family, Pyrin Domain-Containing 3 Protein/metabolismABSTRACT
Colorectal cancer (CRC) is one of the most common tumors and ranks second in tumor mortality. N6-methyladenosine (m6A) modification is the most prevalent RNA modification in eukaryotes. As the critical m6A methyltransferase, the role of METTL3 in the metastasis regulation of CRC might be controversial and need to be further explored. In this study, we confirmed that METTL3 could promoted CRC metastasis in vitro and in vivo. METTL3 was upregulated in CRC tissues and led to poor survival in CRC metastasis. We found METTL3 upregulated PLAU mRNA in an m6A-dependent manner, and then participated in MAPK/ERK pathway to promote angiogenesis and metastasis in CRC. Our study provided new therapeutic targets in CRC metastasis treatment.