Drug-induced liver injury (DILI) is one of the major concerns during drug development. Wide acceptance of the 3 R principles and the innovation of in-vitro techniques have introduced various novel model options, among which the three-dimensional (3D) cell spheroid cultures have shown a promising prospect in DILI prediction. The present study developed a 3D quadruple cell co-culture liver spheroid model for DILI prediction via self-assembly. Induction by phorbol 12-myristate 13-acetate at the concentration of 15.42 ng/mL for 48 hours with a following 24-hour rest period was used for THP-1 cell differentiation, resulting in credible macrophagic phenotypes. HepG2 cells, PUMC-HUVEC-T1 cells, THP-1-originated macrophages, and human hepatic stellate cells were selected as the components, which exhibited adaptability in the designated spheroid culture conditions. Following establishment, the characterization demonstrated the competence of the model in long-term stability reflected by the maintenance of morphology, viability, cellular integration, and cell-cell junctions for at least six days, as well as the reliable liver-specific functions including superior albumin and urea secretion, improved drug metabolic enzyme expression and CYP3A4 activity, and the expression of MRP2, BSEP, and P-GP accompanied by the bile acid efflux transport function. In the comparative testing using 22 DILI-positive and 5 DILI-negative compounds among the novel 3D co-culture model, 3D HepG2 spheroids, and 2D HepG2 monolayers, the 3D culture method significantly enhanced the model sensitivity to compound cytotoxicity compared to the 2D form. The novel co-culture liver spheroid model exhibited higher overall predictive power with margin of safety as the classifying tool. In addition, the non-parenchymal cell components could amplify the toxicity of isoniazid in the 3D model, suggesting their potential mediating role in immune-mediated toxicity. The proof-of-concept experiments demonstrated the capability of the model in replicating drug-induced lipid dysregulation, bile acid efflux inhibition, and α-SMA upregulation, which are the key features of liver steatosis and phospholipidosis, cholestasis, and fibrosis, respectively. Overall, the novel 3D quadruple cell co-culture spheroid model is a reliable and readily available option for DILI prediction.
This study aims to develop professional competence indicators for underwater welding technicians for offshore wind power generation in Taiwan. A literature analysis methodology was employed to gather and investigate research studies related to competence indicators in the underwater welding domain of offshore wind power generation. Subsequently, the Delphi method was utilized to conduct a three-round questionnaire survey, aiming to seek expert opinions regarding the appropriateness and differentiation of these competency indicators. To examine the consistency and significance of expert opinions, the data were subjected to K–S single-sample analysis and K–W one-way analysis of variance. The study identified three main dimensions of professional competency indicators for underwater welding technicians in offshore wind power generation: professional skills, professional knowledge, and workplace attitudes. These dimensions further led to the identification of 10 sub-dimensions, including equipment operation, welding practice, welding inspection, metal materials, welding graphics, occupational safety, quality standards, process improvement, self-management, and teamwork. These sub-dimensions further informed the identification of 75 specific behavioral components as criteria. This study provides findings to enhance future staff training and talent recruitment, benefiting relevant units and managers. These results contribute to enhancing the competence and performance of personnel in underwater welding for offshore wind power generation.
Ethnopharmacological relevance: Peach kernel (taoren: TR) is the dried mature seedof peach, Prunus persica (L.) Batsch, which belongs to the Rosaceae family. Rhubarb(dahuang: DH) is the dried root and rhizome of rhubarb (Rheum tanguticum Maxim. ex Balf.). (DH-TR or DT) is a traditional Chinese medicine herb pair that promotes blood circulation and mitigates blood stasis. DT has been used frequently in recent years, yet the differences in the efficacies of DT drugs of different proportions are still unclear. Aim of study: The purpose of this study was to investigate the composition and pharmacodynamic difference of rhubarb-peach kernel drug pairs with different proportions. Methods: Samples of different ratios of DH to TR (Group A 1:1, B 2:3, C 3:2) were analyzed based on gas chromatography–time-of-flight mass spectrometry non-targeted metabolomics technique.Results: A total of 240 primary metabolites were detected. Forty-one differential metabolites involved nine differential metabolic pathways, of which four were closely related to the efficacy of DT in the treatment of heat and blood stasis syndrome. These pathways included the biosynthesis of amino acid (phenylalanine tyrosine and tryptophan), flavonoids, unsaturated fatty acids, and the glycolysis/glycogenesis pathway.Conclusion: There were significant differences in the efficacy of DT drugs of different proportions. The optimal ratio of DT in treating heat and blood stasis syndrome was 1:1.
Abstract Current low‐temperature plasma (LTP) devices essentially use a rare gas source with a short working distance (8 to 20 mm), low gas flow rate (0.12 to 0.3 m 3 /h), and small effective treatment area (1‐5 cm 2 ), limiting the applications for which LTP can be utilised in clinical therapy. In the present study, a novel type of LTP equipment was developed, having the advantages of a free gas source (surrounding air), long working distance (8 cm), high gas flow rate (10 m 3 /h), large effective treatment area (20 cm 2 ), and producing an abundance of active substances (NOγ, OH, N 2 , and O), effectively addressing the shortcomings of current LTP devices. Furthermore, it has been verified that the novel LTP device displays therapeutic efficacy in terms of acceleration of wound healing in normal and Type I diabetic rats, with enhanced wound kinetics, rate of condensation of wound area, and recovery ratio. Cellular and molecular analysis indicated that LTP treatment significantly reduced inflammation and enhanced re‐epithelialization, fibroblast proliferation, deposition of collagen, neovascularization, and expression of TGF‐β, superoxide dismutase, glutathione peroxidase, and catalase in Type I diabetic rats. In conclusion, the novel LTP device provides a convenient and efficient tool for the treatment of clinical wounds.
Aquaporin-4 immunoglobulin G (AQP4-IgG)-induced astrocytes injury is a key mechanism in the pathogenesis of neuromyelitis spectrum disorder (NMOSD), and although CCL2 is involved, its specific role has not been reported. We aimed to further investigate the role and potential mechanisms of CCL2 in AQP4-IgG-induced astrocyte injury.First, we evaluated CCL2 levels in paired samples of subject patients by automated microfluidic platform, Ella®. Second, we knock down astrocyte's CCL2 gene in vitro and in vivo to define the function of CCL2 in AQP4-IgG-induced astrocyte injury. Third, astrocyte injury and brain injury in live mice were assessed by immunofluorescence staining and 7.0T MRI, respectively. Western blotting and high-content screening were conducted to clarify the activation of inflammatory signaling pathways, and changes in CCL2 mRNA and cytokine/chemokines were measured by qPCR technique and flow cytometry, respectively.There were greatly higher CSF-CCL2 levels in NMOSD patients than that in other non-inflammatory neurological diseases (OND) groups. Blocking astrocyte CCL2 gene expression can efficiently mitigate AQP4-IgG-induced damage in vitro and in vivo. Interestingly, prevention of CCL2 expression could decrease other inflammatory cytokines released, including IL-6 and IL-1β. Our data suggest that CCL2 involves in the initiation and plays a pivotal role in AQP4-IgG-damaged astrocytes.Our results indicate that CCL2 may serve as a promising candidate target for inflammatory disorder therapy, including NMOSD.
Abstract Background: Keratoconus (KCN) is a bilateral and usually asymmetrical disease in which the ectatic cornea becomes conical. Diagnosis of unimproved visual acuity (VA) as KCN might sometimes be missed out due to lack of consideration. However, combination of the electrophysiology test and other common ophthalmological examinations could help to locate the lesion for the unimproved VA and realize the possibility of the existence of KCN, which could be diagnosed via corneal topography. The purpose of this report is to describe the diagnosis process of a case of KCN after the hint of lesion location by electrophysiological tests. Case presentation: A 23-year-old young male presented to our ophthalmology clinic complaining of decreased visual acuity in the left eye for 5 months. Clinical evaluation showed best corrected visual acuity of 1.0 OD, and 0.06 OS. The dilated fundus examination revealed no specific abnormality. Spectral-domain optical coherence tomography (SD-OCT) of macular revealed no obvious change on macular and the thickness of peripapillary nerve fiber layer on both eyes. No leakage of fluorecein was found under Fluorescein angiogram (FFA) of both eyes. Indocyanine green angiography (ICGA) did not showed abnormality. The full-field electroretinogram (ffERG) revealed no obvious changes of amplitudes in all responses. Pattern visual evoked potentials (PVEP) detected a reduced amplitude and delayed phase in P100-wave in both eyes. The amplitude and latency of P2-wave in Flash VEP (FVEP) were comparable in both eyes and were within normative ranges. Corneal topography was finally performed and KCN was diagnosed with the presence of asymmetrical bowtie pattern in both eyes, which was worse in the OS. Conclusions: The hint of lesion location by electrophysiological studies (ffERG, PVEP and FVEP) could be of favor to diagnose the conditions with unimproved VA, such as KCN. Consideration of KCN should be suspected in patients with unimproved VA and significant irregular stigmatism, while no obvious lesion exists in other parts of the eye.
Space cooling is currently the fastest-growing end-user in buildings. The global warming trend combined with increased population and economic development will lead to accelerated growth in space cooling in the future, especially in China. The hot summer and cold winter (HSCW) zone is the most densely populated and economically developed region in China, but with the worst indoor thermal environment. Relatively few studies have been conducted on the actual measurements in the optimization of insulation design under typical intermittent cooling modes in this region. This case study was conducted in Chengdu—the two residences selected were identical in design, but the south bedroom of the case study residence had interior insulation (inside insulation on all opaque interior surfaces of a space) retrofitted in the bedroom area in 2017. In August 2019, a comparative on-site measurement was done to investigate the effect of the retrofit work under three typical intermittent cooling patterns in the real-life scenario. The experimental result shows that interior insulation provides a significant improvement in energy-saving and the indoor thermal environment. The average energy savings in daily cooling energy consumption of the south bedroom is 42.09%, with the maximum reaching 48.91%. In the bedroom with interior insulation retrofit, the indoor temperature is closer to the set temperature and the vertical temperature difference is smaller during the cooling period; when the air conditioner is off, the room remains a comfortable temperature for a slightly longer time.
Mobile machinery is in desperate need of weight reduction. To achieve this goal, their hydraulic reservoirs are developing in the direction of miniaturization and lightweight. However, this development of the hydraulic reservoir can lead to excessive air content in the hydraulic system and hard pump suction. At present, how to solve this conflict has not been studied and how the hydraulic reservoir structure influences the deaeration and inside pressure drop is not clear. In this paper, a U-shaped flow channel in a minimized hydraulic reservoir was numerically optimized and analysed for efficient deaeration of hydraulic systems and minimal inside pressure drop. Based on the multiphase flow simulation database, radial basis function neural networks and an NSGA-II were combined for the flow channel optimization. Results showed that two optimized structures raised the degassing rate by 8.8% and 18.1% and reduced the pressure drop rate by 23.7% and 13.5%, respectively. The flow field analysis and bubble motions were investigated among the initial and optimized flow channel structures. On the baffle's left side, bubbles were degassed by the buoyance force. On the baffle's right side, the wall confinement bubbly jet transformed bubbles to the free surface and degassed, but this jet formed by the deep baffle would increase the pressure drop, which agrees with the parameter sensitivity result. Additionally, vortex structures caused by the jet flow entrained bubbles and impeded deaeration. Consequently, the strong vortex was suppressed in optimum models to increase degassing capacity.
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